Showing papers by "Constance M. Yuan published in 2020"
TL;DR: The remission induction rate supports further development of CD22 CAR T cells as a therapeutic option in patients resistant to CD19-targeted immunotherapy, and novel information on the impact of manufacturing changes on clinical outcomes is provided.
Abstract: PURPOSEPatients with B-cell acute lymphoblastic leukemia who experience relapse after or are resistant to CD19-targeted immunotherapies have limited treatment options. Targeting CD22, an alternativ...
224 citations
TL;DR: This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily or 200 mg once daily in 48 patients with relapsed/refractory or high-risk treatment naïve CLL.
52 citations
TL;DR: Achieving MRD-free CR of HCL after first-line cladribine is greatly enhanced by concurrent rituximab and less so by delayed ritudine, and long-term follow-up will determine if MRd-free survival leads to less need for additional therapy or cure of H CL.
Abstract: PURPOSESingle-agent purine analog, usually cladribine, has been the standard first-line therapy of hairy cell leukemia (HCL) for 30 years. High complete remission (CR) rates often include minimal r...
49 citations
TL;DR: This analysis included 56 subjects, 55 with relapsed/ refractory ALL, and one with DLBCL, the majority of whom were referred for CD22-targeted therapies, and revealed that 16 of patients had a change in CD19 expression.
Abstract: CD19-targeting immunotherapies including blinatumomab, a (CD19/CD3) bispecific T-cell engaging antibody, and CD19-chimeric antigen receptor (CAR) T cells have been highly effective for B-cell acute lymphoblastic leukemia (ALL) [1, 2]. However, up to 50% of B-cell ALL patients relapse after CD19-targeted therapies, the majority with CD19-negative disease [3–5]. Given increasing utilization of these newly FDA-approved therapies in standard treatment paradigms, serial evaluations of CD19 surface expression following these therapies will be necessary to monitor for changes in leukemic phenotype. As a referral center for therapies targeting CD22, an alternate B-cell antigen, we have a unique population of children and young adults with relapse or refractory disease to CD19 targeting [6–8]. Utilizing this cohort, we retrospectively analyzed serial CD19 surface expression to evaluate for dynamic changes in surface expression following immunotherapy. Patients were defined as CD19 negative, partial (bimodal disease population with at least 5% negative blasts), or positive (>95% CD19 expression) based primarily on disease assessments from the peripheral blood and/or bone marrow by flow cytometry (Supplementary Table S1). CD19 expression was quantified on B-lymphoblasts by the amount of anti-CD19 antibody bound per cell (ABC). “Dim” expression was defined as CD19-positive blasts expressing a CD19 site density between 200 and 2000, a delineation based on the lowest 10% of CD19 expression seen in our prior patients. This analysis included 56 subjects, 55 with relapsed/ refractory ALL, and one with DLBCL (Table S2), the majority of whom were referred for CD22-targeted therapies. Most (47/56, 84%) were relapsed/refractory to CD19targeted therapies, amongst whom 33 (70%) had previously achieved a complete response (CR) to CD19 targeting. Patients had serial evaluations over a median of 164 days (IQR 69–376 days) as a part of routine assessment during their care at the NIH. Patients were divided by leukemic CD19 expression at referral (not at diagnosis) into CD19negative, -partial, or -positive subgroups (Table 1). Twentythree (41%) were CD19 negative, all post one or more CD19-targeted therapies. Eight were CD19 partial; six had received CD19-targeted therapy, the remaining two were immunotherapy naive and had inherent 28% and 81% CD19-expressing partial populations, respectively. Twentythree (41%) were CD19-positive, 16 had prior CD19targeted therapy of which 2 were CD19-dim, and both had received blinatumomab. Serial evaluations revealed that 16 (29%) of patients had a change in CD19 expression (Table 1). Most CD19negative patients remained negative (74%) (Fig. 1a). Two became completely CD19 positive at relapse, one post-CR after CD22 CAR (with CD19-positive isolated CNS relapse) and the other after both CD22 CAR and stem cell transplant (SCT). The latter patient had CD19-positive nonneoplastic B cells (hematogones) concurrently with CD19-negative leukemia; no detectable CD19-positive * Nirali N. Shah nirali.shah@nih.gov
27 citations
20 citations
TL;DR: A novel, fully-human, heavy-chain-only anti-BCMA binding domain designated FHVH33 is used to reduce the risk of recipient immune responses against CAR T cells, which resulted in objective responses (OR) in 20 patients and two patients came off study due to progressive MM.
14 citations
TL;DR: The gold standard used to evaluate response in the United States includes morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow by flow cytometry (FC).
Abstract: Background Accurate disease detection is integral to risk stratification in B-cell acute lymphoblastic leukemia (ALL). The gold standard used to evaluate response in the United States includes morphologic evaluation and minimal residual disease (MRD) testing of aspirated bone marrow (BM) by flow cytometry (FC). This MRD assessment is usually made on a single aspirate sample that is subject to variability in collection techniques and sampling error. Additionally, central nervous system (CNS) assessments for ALL include evaluations of cytopathology and cell counts, which can miss subclinical involvement. Procedure We retrospectively compared BM biopsy, aspirate, and FC samples obtained from children and young adults with relapsed/refractory ALL to identify the frequency and degree of disease discrepancies in this population. We also compared CNS FC and cytopathology techniques. Results Sixty of 410 (14.6%) BM samples had discrepant results, 41 (10%) of which were clinically relevant as they resulted in a change in the assignment of marrow status. Discrepant BM results were found in 28 of 89 (31.5%) patients evaluated. Additionally, cerebrospinal fluid (CSF) FC identified disease in 9.7% of cases where cytopathology was negative. Conclusions These results support further investigation of the role of concurrent BM biopsy, with aspirate and FC evaluations, and the addition of FC to CSF evaluations, to fully assess disease status and response, particularly in patients with relapsed/refractory ALL. Prospective studies incorporating more comprehensive analysis to evaluate the impact on clinical outcomes are warranted.
11 citations
TL;DR: Dual IHC stain is a sensitive tool in detecting HCL, even in cases with minimal disease involvement, and it is found that all IHC-positive cases concurred with flow cytometric data, even when HCL burden was extremely low in the flow cytometry specimens.
Abstract: Objectives We evaluated efficacy of two dual immunohistochemistry (IHC) staining assays in assessing hairy cell leukemia (HCL) involvement in core biopsies and compared the results with concurrently collected flow cytometric data. Methods Overall, 148 patients with HCL (123 male, 25 female; mean age: 59.8 years; range: 25-81 years) had multiparameter flow cytometry performed using CD19, CD20, CD22, CD11c, CD25, CD103, CD123, surface light chains, CD5, and CD23. In parallel, bone marrow IHC was done using PAX5/CD103 and PAX5/tartrate-resistant alkaline phosphatase (TRAP) dual IHC stains. Results Overall sensitivity of dual IHC stains was 81.4%, positive predictive value was 100%, and negative predictive value was 81.7%. All IHC-positive cases concurred with flow cytometry data, even when HCL burden was extremely low in the flow cytometry specimens (as low as 0.02% of all lymphoid cells). Conclusions Dual IHC stain is a sensitive tool in detecting HCL, even in cases with minimal disease involvement.
10 citations
Cincinnati Children's Hospital Medical Center1, University of Southern California2, Children's Oncology Group3, Children's Hospital of Philadelphia4, Children's Hospital Los Angeles5, Baylor College of Medicine6, University of Utah7, Johns Hopkins University School of Medicine8, University of Florida9, University of Colorado Boulder10, University of California, San Francisco11
TL;DR: Results from the COG AALL1621 phase 2 trial evaluated the efficacy of InO in children and young adults with relapsed/refractory CD22+ B-cell ALL report results of central surface CD22 expre...
Abstract: 10519Background: The COG AALL1621 phase 2 trial evaluated the efficacy of InO in children and young adults with relapsed/refractory CD22+ B-cell ALL. We report results of central surface CD22 expre...
8 citations
TL;DR: In the preliminary experience, CD19/22 CAR was well tolerated and effective in CAR naive patients, with 4/6 patients achieving MRD negative CR and Relapses were antigen positive likely due to limited CAR persistence.
Abstract: Background: With the hypothesis that dual antigen targeting strategies may prevent antigen negative escape, we tested a novel humanized bispecific CD19/CD22 CAR T cell construct in patients with relapsed/refractory B ALL. Building upon our experience with effective CD19 (NCT01593696) and CD22 (NCT02315612) CAR T cell constructs, we report our initial findings. Design: This was a phase 1 dose escalation study which started at 3 x 105 transduced CAR T-cell/kg. The CD19/CD22 construct was comprised of FMC63 (CD19 scFv) and m971 (CD22 scFv) with a 4-1BB costimulatory domain (NCT: 03448393). The primary objective was safety and toxicity; secondary objectives included efficacy, CAR persistence and cytokine profiling. CAR T cells were manufactured onsite utilizing a closed system device (CliniMACS Prodigy®). ASTCT consensus guidelines were used for cytokine release syndrome (CRS) grading. Prior CAR T cells were not exclusionary. Results: Eleven subjects (median age 21) were infused at 3 dose levels. Four experienced mild, reversible CRS without neurotoxicity (Table). Eight subjects had an objective response (MRD negative CR, n=4; partial response, n=4), and 2 proceeded to transplant. Complete responders were CAR naive and received > 1 x 106 CAR T-cells/kg. CAR expansion peaked at a median of 13 days (range, 6-20) and were detectable by flow cytometry to a median of 54 days (range: 25-110 days) post infusion. Patients with higher disease burden trended towards having higher CRS, CAR expansion, and cytokine elevation. Two patients have relapsed (1 post BMT) with CD19+/CD22+ disease. Conclusion: In our preliminary experience, CD19/22 CAR was well tolerated and effective in CAR naive patients, with 4/6 patients achieving MRD negative CR. Relapses were antigen positive likely due to limited CAR persistence. Future plans include exploring an additional dose level, intensifying lymphodepletion for prior CAR patients, and evaluating CAR T-cell product characteristics with outcomes. Citation Format: Haneen Shalabi, Bonnie Yates, Shilpa Shahani, Haiying Qin, Steven L. HIghfill, Sandhya Panch, Minh Tran, David Stroncek, Leah Hoffman, Lauren Little, Katherine Graap, Maryalice Stetler-Stevenson, Constance Yuan, Hao-Wei Wang, Terry J. Fry, Nirali N. Shah. Safety and efficacy of CD19/CD22 CAR T cells in children and young adults with relapsed/refractory ALL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT051.
7 citations
TL;DR: Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A, which may be a useful biomarker for these leukemias.
Abstract: Hairy cell leukemia (HCL) is a purine analog-responsive B-cell malignancy containing the BRAF V600E mutation, expressing CD22, CD11c, CD103, tartrate resistant acid phosphatase (TRAP) CD25, CD123, and annexin 1A. BRAF V600E and the latter 4 markers are usually absent in the more aggressive and chemoresistant variant HCLv. To evaluate differences between HCL and HCLv, expression microarrays comparing HCL with HCLv were performed for 24694 genes using 47323 probes. Microarray data from 35 HCL and 27 HCLv purified samples showed the greatest HCL-HCLv difference in the muscle-associated gene MYF6, expressed by its 2 probes 18.5- and 10.8-fold higher in HCL than HCLv (p<0.0001). By real-time quantitative PCR (RQ-PCR), 100% of 152 classic HCL samples were MYF6-positive, vs 5 (6%) of 90 blood donors. MYF6-expression was also detected in 18 (35%) of 51 with HCLv, 11 (92%) of 12 with HCL expressing unmutated IGHV4-34, 35 (73%) of 48 with chronic lymphocytic leukemia (CLL), and 1 (8%) of 12 with mantle cell lymphoma. Hypomethylation status of MYF6 supported expression in HCL more than HCLv. Posttreatment blood samples becoming negative by flow cytometry remained MYF6+ by RQ-PCR in 42 (48%) of 87 HCL patients, and MYF6 RQ-PCR could detect 1 HCL in 105 normal cells. MYF6, universally expressed in HCL and in most CLL samples, may be a useful biomarker for these leukemias. Further studies are underway to determine the role of MYF6 in HCL.
TL;DR: It is shown that rates of MRD negativity are high and they are sustained with the use of KRd-R, and these support the initial pilot study in using effective therapy with KRD-R as early intervention.
TL;DR: The authors suggest that cessation of prophylactic transfusions used to prevent stroke in sickle cell disease in children and young adults in the post-STOP era should be considered.
Abstract: REFERENCES 1. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med. 1998;339(1):5-11. 2. Adams RJ, Brambilla D. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med. 2005;353(26): 2769-2778. 3. DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4(8):1554-1588. 4. Hurlet-Jensen AM, Prohovnik I, Pavlakis SG, Piomelli S. Effects of total hemoglobin and hemoglobin S concentration on cerebral blood flow during transfusion therapy to prevent stroke in sickle cell disease. Stroke. 1994;25(8):1688-1692. 5. Kwiatkowski JL, Yim E, Miller S, Adams RJ, Investigators SS. Effect of transfusion therapy on transcranial Doppler ultrasonography velocities in children with sickle cell disease. Pediatr Blood Cancer. 2011;56(5):777-782. 6. Adams RJ, Lackland DT, Brown L, et al. Transcranial doppler re-screening of subjects who participated in STOP and STOP II. Am J Hematol. 2016;91(12):1191-1194. 7. Kwiatkowski JL, Voeks JH, Kanter J, et al. Ischemic stroke in children and young adults with sickle cell disease in the post-STOP era. Am J Hematol. 2019;94(12):1335-1343.