Publications by authors named "Anthony Stein"

108 Publications

Posttransplant cyclophosphamide as GVHD prophylaxis for peripheral blood stem cell HLA-mismatched unrelated donor transplant.

Blood Adv 2021 06;5(12):2650-2659

Department of Hematology and HCT.

Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients' median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.
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http://dx.doi.org/10.1182/bloodadvances.2021004192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270662PMC
June 2021

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

Use of high-dose mesna and hyperhydration leads to lower incidence of hemorrhagic cystitis after posttransplant cyclophosphamide-based allogeneic transplantation.

Bone Marrow Transplant 2021 Jun 9. Epub 2021 Jun 9.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA, USA.

Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome.
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http://dx.doi.org/10.1038/s41409-021-01364-0DOI Listing
June 2021

Efficacy of blinatumomab for MRD relapse in ALL post allogenic HCT.

Leuk Res 2021 05 30;104:106579. Epub 2021 Mar 30.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, United States. Electronic address:

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http://dx.doi.org/10.1016/j.leukres.2021.106579DOI Listing
May 2021

Allogeneic Hematopoietic Cell Transplantation for Relapsed and Refractory Philadelphia Negative B Cell ALL in the Era of Novel Salvage Therapies.

Transplant Cell Ther 2021 03 22;27(3):255.e1-255.e9. Epub 2020 Dec 22.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California.

Introduction of novel salvage therapies and expansion of the donor pool within the past decade have allowed more patients with relapsed/refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL) to receive allogeneic hematopoietic cell transplantation (alloHCT). The impact of each salvage therapy on transplant outcomes have not been compared. Our primary objective was to determine post-HCT relapse-free survival (RFS) in adult patients with r/r Philadelphia-chromosome negative (Ph) B-ALL. We retrospectively studied alloHCT outcomes in 108 adult patients with r/r Ph B-ALL transplanted in morphological remission achieved by salvage therapy. Salvage therapies were chemotherapy-based combination (n = 45, 42%), blinatumomab (n=43, 40%), inotuzumab (n = 14, 13%), or CAR T cells (n = 6, 6%). The 2-year RFS and overall survival (OS) were 44% and 50%, respectively. In multivariable analysis, conditioning with reduced-intensity or non-myeloablative regimens (hazard ratio [HR] = 2.23, 95% confidence interval [CI], 1.31-3.80; P = .003), having received ≥3 lines of therapies prior to transplant (HR = 2.66, 95% CI, 1.56-4.54; P < .001), and inotuzumab (HR = 2.42, 95% CI, 1.14-5.12; Wald P value = .021) were independently associated with lower RFS. Blinatumomab (HR = 1.10, 95% CI, 0.62-1.96) had comparable RFS to chemotherapy. Incidence of hepatic sinusoidal syndrome was highest with inotuzumab (P < .001); however, 30-day mortality and intensive care unit admissions were not different per salvage therapy. The alloHCT in r/r Ph B-ALL after remission induction with blinatumomab or chemotherapy led to encouraging outcomes if morphologic CR was achieved. In contrast, pretransplantation inotuzumab therapy was associated with inferior RFS. Larger studies are warranted to confirm our observations. Early transplantation after relapse and the utilization of myeloablative conditioning, when feasible, were key factors associated with improved outcomes after alloHCT in these patients.
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http://dx.doi.org/10.1016/j.jtct.2020.12.020DOI Listing
March 2021

Blinatumomab as first salvage versus second or later salvage in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia: Results of a pooled analysis.

Cancer Med 2021 04 18;10(8):2601-2610. Epub 2021 Mar 18.

Global Development, Amgen Research (Munich) GmbH, Munich, Germany.

Background: Blinatumomab is a BiTE immuno-oncology therapy indicated for the treatment of patients with relapsed or refractory (r/r) B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Aims To assess the efficacy and safety of blinatumomab as first salvage versus second or later salvage in patients with r/r BCP ALL. Materials & Methods Patient-level pooled data were used for this analysis. In total, 532 adults with r/r BCP ALL treated with blinatumomab were included (first salvage, n = 165; second or later salvage, n = 367). Results Compared with patients who received blinatumomab as second or later salvage, those who received blinatumomab as first salvage had a longer median overall survival (OS; 10.4 vs. 5.7 months; HR, 1.58; 95% CI, 1.26-1.97; P < .001) and relapse-free survival (10.1 vs. 7.3 months; HR, 1.38; 95% CI, 0.98-1.93; P = .061), and higher rates of remission (n = 89 [54%] vs. n = 150 [41%]; odds ratio, 0.59; 95% CI, 0.41-0.85; P = .005), minimal residual disease response (n = 68 [41%] vs. n = 118 [32%]), and allogeneic hematopoietic stem cell transplant (alloHSCT) realization (n = 60 [36%] vs. n = 88 [24%]), and alloHSCT in continuous remission (n = 33 [20%] vs. n = 52 (14%]). In a subgroup analysis, there was no apparent effect of prior alloHSCT on median OS in either salvage group. The safety profile of blinatumomab was generally similar between the groups; however, cytokine release syndrome, febrile neutropenia, and infection were more frequent with second or later salvage than with first salvage. Discussion In this pooled analysis, the logistic regression analyses indicated greater benefit with blinatumomab as first salvage than as second or later salvage, as evident by the longer median OS, longer median RFS, and higher rates of remission. Conclusion Overall, blinatumomab was beneficial as first salvage and as second or later salvage, but the effects were favorable as first salvage.
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http://dx.doi.org/10.1002/cam4.3731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026950PMC
April 2021

Cytokine gene polymorphisms are associated with response to blinatumomab in B-cell acute lymphoblastic leukemia.

Eur J Haematol 2021 Jun 24;106(6):851-858. Epub 2021 Mar 24.

Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA, USA.

Blinatumomab is a bispecific T cell-engaging antibody approved for treatment of relapsed/refractory (r/r) ALL, with 40%-50% complete response (CR)/CR with incomplete count recovery (CRi). Cytokine release syndrome (CRS) as a major adverse effect after blinatumomab therapy. Here, we evaluated the possible association between single-nucleotide polymorphisms (SNPs) in cytokine genes, disease response, and CRS in r/r ALL patients who received blinatumomab between 2012 and 2017 at our center (n = 66), using patients' archived DNA samples. With a median duration of 9.5 months (range: 1-37), 37 patients (56.1%) achieved CR/CRi, 54 (81.8%) experienced CRS (G1: n = 35, G2: n = 14, G3: n = 5), and 9 (13.6%) developed neurotoxicity. By multivariable analysis, after adjusting for high disease burden, one SNP on IL2 (rs2069762), odds ratio (OR) = 0.074 (95% CI: NE-0.43, P = .01) and one SNP on IL17A (rs4711998), OR = 0.28 (95% CI: 0.078-0.92, P = .034) were independently associated with CR/CRi. None of the analyzed SNPs were associated with CRS. To our knowledge, this is the first study demonstrating a possible association between treatment response to blinatumomab and SNPs. Our hypothesis-generated data suggest a potential role for IL-17 and IL-2 in blinatumomab response and justify a larger confirmatory study, which may lead to personalized blinatumomab immunotherapy for B-ALL.
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http://dx.doi.org/10.1111/ejh.13622DOI Listing
June 2021

Venetoclax-containing regimens in acute myeloid leukemia.

Ther Adv Hematol 2021 11;12:2040620720986646. Epub 2021 Feb 11.

Gehr Family Center for Leukemia Research, City of Hope, 1500 Duarte Road, Duarte, CA 91010, USA.

Venetoclax in combination with hypomethylating agents (HMAs) or low-dose cytarabine (LDAC) has demonstrated exceptional activity in elderly and unfit patients with newly diagnosed acute myeloid leukemia (AML). Notably, the safety profile of venetoclax-based induction regimens was favorable, with a low rate of early treatment-related mortality, even in frail study participants. Thus, the introduction of venetoclax has transformed the landscape of AML therapy in elderly patients. Given these promising results, venetoclax in combination with other agents is now being studied as a frontline therapy in younger patients with AML, as well as in relapsed/refractory AML patients. Here, we review clinical data for venetoclax-based therapy in AML, both from prospective as well as retrospective studies, and highlight ongoing novel studies of venetoclax-containing regimens and discuss future research directions.
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http://dx.doi.org/10.1177/2040620720986646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7882757PMC
February 2021

Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study.

Eur J Cancer 2021 Mar 13;146:107-114. Epub 2021 Feb 13.

Gehr Family Center for Leukemia Research, City of Hope, Duarte, CA, United States.

Aim: To evaluate long-term durability of blinatumomab, a BiTE® (bispecific T-cell engager) molecule, in adults with relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) B-cell precursor acute lymphoblastic leukaemia (ALL).

Methods: In this final analysis of an open-label, single-arm, phase 2, multicentre ALCANTARA study (NCT02000427), adults (age ≥18 years) with Ph+ ALL who had relapsed or were refractory to at least one TKI were included. The primary endpoint was the proportion of patients who achieved complete remission (CR)/CR with partial haematologic recovery (CRh) during the first two cycles of blinatumomab treatment.

Results: The final analysis included 45 patients who completed the study between 3rd January 2014 and 6th January 2017, of which 16 (35.6%; 95% CI, 21.9%-51.2%) achieved CR/CRh within the first two blinatumomab cycles. After a median follow-up of 16.1 months, median relapse-free survival (RFS) was 6.8 (95% CI, 4.4-not estimable [NE]) months. Median overall survival (OS) was 9.0 (95% CI, 5.7-13.5) months with a median follow-up of 25.1 months. Median OS in patients with CR (19.8 [95% CI, 12.1-NE] months) was greater than in those without CR (6.0 [95% CI, 2.9-7.1] months). Of 16 patients with CR/CRh, 14 achieved complete minimal residual disease (MRD) response; the median duration of complete MRD response was 9.7 (95% CI, 5.2-NE) months. Treatment-related adverse events were consistent with those previously reported.

Conclusion: Long-term durability of responses to blinatumomab was demonstrated in patients with R/R Ph+ ALL.
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http://dx.doi.org/10.1016/j.ejca.2020.12.022DOI Listing
March 2021

Rebound thrombocytosis is associated with response in AML patients treated with venetoclax and hypomethylating agents.

Am J Hematol 2021 05 18;96(5):E140-E143. Epub 2021 Feb 18.

Department of Hematology and HCT, Gehr Center for Leukemia Research, City of Hope, Duarte, CA, USA.

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http://dx.doi.org/10.1002/ajh.26117DOI Listing
May 2021

Immune Biology of Acute Myeloid Leukemia: Implications for Immunotherapy.

J Clin Oncol 2021 Feb 12;39(5):419-432. Epub 2021 Jan 12.

Department of Medicine III, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany.

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http://dx.doi.org/10.1200/JCO.20.00475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078464PMC
February 2021

CD33 directed bispecific antibodies in acute myeloid leukemia.

Best Pract Res Clin Haematol 2020 12 18;33(4):101224. Epub 2020 Nov 18.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA. Electronic address:

Despite the approval of a number of new targeted therapies for acute myeloid leukemia (AML), median overall survival still remains poor, ranging from 12 to 18 months in most patients. Based on the success of blinatumomab, the CD19-targeted bispecific antibody for the treatment of acute lymphoblastic leukemia, the development of several CD33-targeted bispecific antibodies for AML are being investigated in clinical trials. In this review article of CD33-targeted bispecific antibodies, we describe the rationale for targeting CD3 x CD33, summarize the data from four ongoing phase 1 studies, review the major toxicity associated with CD33-targeted bispecific antibody therapy of cytokine release syndrome (CRS) and steps to mitigate CRS, and describe possible mechanisms of resistance to CD33-targeted bispecific antibody therapy. Future development to try to improve outcomes include combination therapies to reduce the tumor burden prior to starting treatment, combining with immune checkpoint inhibition therapy such as anti-PD-1/PDL1 antibodies, and the use of second generation bispecific antibodies that target two different antigens and recruit other effector cells such as nature killer cells and macrophages.
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http://dx.doi.org/10.1016/j.beha.2020.101224DOI Listing
December 2020

Long-term survival of patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab.

Cancer 2021 Feb 3;127(4):554-559. Epub 2020 Nov 3.

The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Blinatumomab is a CD19 BiTE (bispecific T-cell engager) immuno-oncology therapy that mediates the lysis of cells expressing CD19.

Methods: A pooled analysis of long-term follow-up data from 2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome-negative, relapsed/refractory B-cell precursor acute lymphoblastic leukemia was conducted.

Results: A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval [CI], 5.5-8.5 months); the median follow-up time for OS was 36.0 months (range, 0.3-60.8 months). The median relapse-free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2-10.0 months); the median follow-up time for RFS was 35.0 months (range, 9.5-59.5 months). OS and RFS plateaued with 3-year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3-year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3-30.0 months) with a 3-year survival rate of 37.2%.

Conclusions: These data suggest that long-term survival is possible after blinatumomab therapy.

Lay Summary: Immuno-oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells. This study combined follow-up data from 2 blinatumomab-related clinical trials to evaluate long-term survival in patients with relapsed and/or refractory B-cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes. Among patients who achieved a deep response with blinatumomab, one-third lived 3 years or longer. These findings suggest that long-term survival is possible after treatment with blinatumomab.
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http://dx.doi.org/10.1002/cncr.33298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894150PMC
February 2021

Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.

J Clin Oncol 2021 01 29;39(1):57-65. Epub 2020 Oct 29.

University of Oxford, Oxford, United Kingdom.

Purpose: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of -mutant (m) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis.

Patients And Methods: This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m on days 1-7 in 28-day cycles in patients with newly diagnosed m AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922).

Results: Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission.

Conclusion: Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m mutation clearance.
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http://dx.doi.org/10.1200/JCO.20.01632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771719PMC
January 2021

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study.

Blood 2021 Apr;137(13):1792-1803

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.

Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
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http://dx.doi.org/10.1182/blood.2020007233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020270PMC
April 2021

Tumor-intrinsic and -extrinsic determinants of response to blinatumomab in adults with B-ALL.

Blood 2021 01;137(4):471-484

Department of Pathology, St Jude Children's Research Hospital, Memphis, TN.

Blinatumomab, a bispecific antibody that directs CD3+ T cells to CD19+ tumor cells, shows variable efficacy in B-progenitor acute lymphoblastic leukemia (B-ALL). To determine tumor-intrinsic and -extrinsic determinants of response, we studied 44 adults with relapsed or refractory B-ALL (including 2 minimal residual disease positive) treated with blinatumomab using bulk tumor and single-cell sequencing. The overall response rate in patients with hematological disease was 55%, with a high response rate in those with CRLF2-rearranged Philadelphia chromosome-like ALL (12 [75%] of 16). Pretreatment samples of responders exhibited a tumor-intrinsic transcriptomic signature of heightened immune response. Multiple mechanisms resulted in loss of CD19 expression, including CD19 mutations, CD19-mutant allele-specific expression, low CD19 RNA expression, and mutations in CD19 signaling complex member CD81. Patients with low hypodiploid ALL were prone to CD19- relapse resulting from aneuploidy-mediated loss of the nonmutated CD19 allele. Increased expression of a CD19 isoform with intraexonic splicing of exon 2, CD19 ex2part, at baseline or during therapy was associated with treatment failure. These analyses demonstrate both tumor-intrinsic and -extrinsic factors influence blinatumomab response. We show that CD19 mutations are commonly detected in CD19- relapse during blinatumomab treatment. Identification of the CD19 ex2part splice variant represents a new biomarker predictive of blinatumomab therapy failure.
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http://dx.doi.org/10.1182/blood.2020006287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845009PMC
January 2021

Outcome of Allogeneic Hematopoietic Cell Transplantation after Venetoclax and Hypomethylating Agent Therapy for Acute Myelogenous Leukemia.

Biol Blood Marrow Transplant 2020 12 29;26(12):e322-e327. Epub 2020 Aug 29.

Department of Hematology and Hematopoietic Cell Transplantation, Gehr Family Center for Leukemia Research, City of Hope Medical Center, Duarte, California. Electronic address:

The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML.
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http://dx.doi.org/10.1016/j.bbmt.2020.08.027DOI Listing
December 2020

Retreatment with venetoclax and hypomethylating agents among AML patients who have relapsed after initial response and subsequent interruption of therapy.

Leuk Lymphoma 2020 12 19;61(14):3532-3533. Epub 2020 Aug 19.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.

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http://dx.doi.org/10.1080/10428194.2020.1808213DOI Listing
December 2020

Venetoclax and hypomethylating agents in FLT3-mutated acute myeloid leukemia.

Am J Hematol 2020 Jul 6. Epub 2020 Jul 6.

Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Gehr Family Center for Leukemia Research, Duarte, California, USA.

FMS-like tyrosine kinase 3 (FLT3) mutations are prevalent in acute myeloid leukemia (AML), and their presence confers adverse risk. FLT3-mutated (FLT3m) AML is a challenging leukemia to manage, particularly in older and unfit patients as well as patients with relapsed/refractory (r/r) disease. We retrospectively analyzed the outcomes of 50 FLT3m AML patients (17 treatment-naïve, 33 r/r) treated with venetoclax (VEN) and hypomethylating agents (HMA). The overall CR/CRi rate with VEN-HMA was 60% (94% in treatment-naïve AML and 42% in r/r AML). Early (60-days) treatment related mortality was 2%. The r/r AML setting was an independent predictor of lower complete response (OR: 0.08; 95%CI: 0.00-0.60, P = .03). Cytogenetics-molecular risk, concurrent mutations, the type of FLT3 mutation (ITD vs TKD), the ITD allelic ratio, the type of HMA, age, prior exposure to HMA and receipt of prior allogeneic transplant did not independently impact response or leukemia-free survival (LFS). Concurrent IDH mutations were associated with lower CR/CRi (P = .01), while ASXL1 or TET2 mutations showed a non-significant association toward higher CR/CRi (P = .07, for both). However, none of the concurrent mutations were an independent predictor for response when adjusted to AML setting. In conclusion, VEN-HMA is associated with encouraging efficacy in FLT3m AML among both newly diagnosed unfit and r/r patients.
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http://dx.doi.org/10.1002/ajh.25929DOI Listing
July 2020

Curative outcomes following blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia.

Leuk Lymphoma 2020 11 3;61(11):2665-2673. Epub 2020 Jul 3.

Comprehensive Cancer Center Mainfranken, Uniklinikum Würzburg, Würzburg, Germany.

Minimal residual disease (MRD) is the strongest predictor of relapse in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In BLAST study (NCT01207388), adults with BCP-ALL in remission with MRD after chemotherapy received blinatumomab, a CD19 BiTE immuno-oncotherapy, 15 µg/m/day for up to four 6-week cycles (4 weeks continuous infusion, 2 weeks off). Survival was evaluated for 110 patients, including 74 who received HSCT in continuous complete remission. With a median follow-up of 59·8 months, median survival (months) was 36·5 (95% CI: 22.0-not reached [NR]). Median survival was NR (29.5-NR) for complete MRD responders ( = 84) and 14.4 (3.8-32.3) for MRD non-responders ( = 23;  = 0.002); after blinatumomab and HSCT, median survival was NR (25.7-NR) ( = 61) and 16.5 (1.1-NR) ( = 10;  = 0.065), respectively. This final analysis suggests complete MRD response during blinatumomab treatment is curative. Post-hoc analysis of study data suggests while post blinatumomab HSCT may be beneficial in appropriate patients, long-term survival without HSCT is also possible.
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http://dx.doi.org/10.1080/10428194.2020.1780583DOI Listing
November 2020

Long-Term Outcomes of Allogeneic Hematopoietic Cell Transplant with Fludarabine and Melphalan Conditioning and Tacrolimus/Sirolimus as Graft-versus-Host Disease Prophylaxis in Patients with Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2020 08 19;26(8):1425-1432. Epub 2020 May 19.

Department of Hematology and HCT, City of Hope, Duarte, California; Department of Computational Quantitative Medicine/BRI, City of Hope, Duarte, California. Electronic address:

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.
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http://dx.doi.org/10.1016/j.bbmt.2020.04.015DOI Listing
August 2020

Targeting MCL-1 in hematologic malignancies: Rationale and progress.

Blood Rev 2020 11 21;44:100672. Epub 2020 Feb 21.

Gehr Family Center for Leukemia, City of Hope Medical Center, Duarte, CA, USA.

Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway.
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http://dx.doi.org/10.1016/j.blre.2020.100672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7442684PMC
November 2020

The efficacy of venetoclax and hypomethylating agents in acute myeloid leukemia with extramedullary involvement.

Leuk Lymphoma 2020 08 19;61(8):2020-2023. Epub 2020 Mar 19.

Gehr Family Center for Leukemia Research, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA, USA.

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http://dx.doi.org/10.1080/10428194.2020.1742908DOI Listing
August 2020

Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Biol Blood Marrow Transplant 2020 06 5;26(6):1084-1090. Epub 2020 Feb 5.

Department of Hematology and HCT, City of Hope, Duarte, California.

Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.
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http://dx.doi.org/10.1016/j.bbmt.2020.01.029DOI Listing
June 2020

A systematic review of outcomes after stem cell transplantation in acute lymphoblastic leukemia with or without measurable residual disease.

Leuk Lymphoma 2020 05 21;61(5):1052-1062. Epub 2020 Jan 21.

City of Hope National Medical Center, Duarte, CA, USA.

This systematic literature review compared clinical outcomes post-stem cell transplantation (SCT) among patients with vs. without the measurable residual disease (MRD) pre-transplant. Relevant literature on adults undergoing transplant with known MRD status pre-transplant was extracted from the MEDLINE, Embase, and CENTRAL databases (through 8 May 2018) and oncology conferences (2014-2018) using keywords for acute lymphoblastic leukemia and MRD. Thirty primary studies reporting SCT outcomes were identified. Hazard ratios (HRs) for overall survival indicated that patients with MRD pre-transplant were more likely to die post-SCT vs. patients with no detectable MRD (HR: 1.51-3.856). In post-SCT relapse studies, 16-100% of patients with MRD vs. 0-50% of patients without MRD relapsed. This review found evidence of markedly worse outcomes post-transplant among patients with vs. without MRD pre-transplant, including shorter median survival (overall, relapse-free, and event-free survival), higher risk of death, more relapse events, and decreased likelihood of remaining in hematologic remission.
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http://dx.doi.org/10.1080/10428194.2019.1709834DOI Listing
May 2020

Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.

Blood 2020 02;135(7):463-471

Agios Pharmaceuticals, Inc, Cambridge, MA; and.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839.
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http://dx.doi.org/10.1182/blood.2019002140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019193PMC
February 2020