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2.
Blood ; 135(9): 595-596, 2020 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-32106307
3.
Pediatr Blood Cancer ; 67(4): e28149, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31981407

RESUMO

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.

5.
Curr Hematol Malig Rep ; 14(5): 451-459, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31332617

RESUMO

PURPOSE OF REVIEW: Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable remission induction rates for relapsed/refractory B cell malignancies. However, loss of the CAR-targeted antigen, known as antigen escape, accounts for a substantial percentage of relapses following CAR therapy and is a major barrier to durable remission. Here, we discuss mechanisms for antigen escape and strategies to prevent this pattern of relapse, including the use of multi-specific CARs, which recognize and target multiple tumor-associated antigens simultaneously. RECENT FINDINGS: Preclinical and early clinical trial data indicates that multi-specific CAR therapy for B cell malignancies is both safe and effective. Optimal combinations of target antigens, as well as different multi-specific CAR formats, are currently being evaluated. Although still in early stages of development, multi-specific CAR therapy represents a promising approach to mitigate antigen loss-related relapses and improve durability of remission in patients with refractory B cell malignancies, and may be applicable to other types of cancer.

7.
Mol Ther ; 27(7): 1275-1285, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31178392

RESUMO

As clinical applications for chimeric antigen receptor T cell (CART) therapy extend beyond early phase trials, commercial manufacture incorporating cryopreservation steps becomes a logistical necessity. The effect of cryopreservation on CART characteristics is unclear. We retrospectively evaluated the effect of cryopreservation on product release criteria and in vivo characteristics in 158 autologous CART products from 6 single-center clinical trials. Further, from 3 healthy donor manufacturing runs, we prospectively identified differentially expressed cell surface markers and gene signatures among fresh versus cryopreserved CARTs. Within 2 days of culture initiation, cell viability of the starting fraction (peripheral blood mononuclear cells [PBMNCs]) decreased significantly in the cryo-thawed arm compared to the fresh arm. Despite this, PBMNC cryopreservation did not affect final CART fold expansion, transduction efficiency, CD3%, or CD4:CD8 ratios. In vivo CART persistence and clinical responses did not differ among fresh and cryopreserved final products. In healthy donors, compared to fresh CARTs, early apoptotic cell-surface markers were significantly elevated in cryo-thawed CARTs. Cryo-thawed CARTs also demonstrated significantly elevated expression of mitochondrial dysfunction, apoptosis signaling, and cell cycle damage pathways. Cryopreservation during CART manufacture is a viable strategy, based on standard product release parameters. The clinical impact of cryopreservation-related subtle micro-cellular damage needs further study.


Assuntos
Autoantígenos/imunologia , Criopreservação/métodos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Adolescente , Adulto , Idoso , Apoptose , Relação CD4-CD8 , Ciclo Celular , Sobrevivência Celular , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/terapia , Fenótipo , Estudos Prospectivos , Estudos Retrospectivos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Adulto Jovem
8.
Clin Cancer Res ; 25(17): 5329-5341, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31110075

RESUMO

PURPOSE: Chimeric antigen receptor T-cell (CART) therapy targeting CD22 induces remission in 70% of patients with relapsed/refractory acute lymphoblastic leukemia (ALL). However, the majority of post-CD22 CART remissions are short and associated with reduction in CD22 expression. We evaluate the implications of low antigen density on the activity of CD22 CART and propose mechanisms to overcome antigen escape. EXPERIMENTAL DESIGN: Using ALL cell lines with variable CD22 expression, we evaluate the cytokine profile, cytotoxicity, and in vivo CART functionality in the setting of low CD22 expression. We develop a high-affinity CD22 chimeric antigen receptor (CAR) as an approach to improve CAR sensitivity. We also assess Bryostatin1, a therapeutically relevant agent, to upregulate CD22 and improve CAR functionality. RESULTS: We demonstrate that low CD22 expression negatively impacts in vitro and in vivo CD22 CART functionality and impairs in vivo CART persistence. Moreover, low antigen expression on leukemic cells increases naïve phenotype of persisting CART. Increasing CAR affinity does not improve response to low-antigen leukemia. Bryostatin1 upregulates CD22 on leukemia and lymphoma cell lines for 1 week following single-dose exposure, and improves CART functionality and in vivo persistence. While Bryostatin1 attenuates IFNγ production by CART, overall in vitro and in vivo CART cytotoxicity is not adversely affected. Finally, administration of Bryostain1 with CD22 CAR results in longer duration of in vivo response. CONCLUSIONS: We demonstrate that target antigen modulation is a promising strategy to improve CD22 CAR efficacy and remission durability in patients with leukemia and lymphoma.See related commentary by Guedan and Delgado, p. 5188.


Assuntos
Linfoma , Linfócitos T/imunologia , Antígenos CD19 , Humanos , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos
9.
Cancer J ; 25(3): 178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31135524
10.
Mol Ther ; 27(7): 1262-1274, 2019 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-31043341

RESUMO

Chimeric antigen receptor (CAR) T cell therapies have demonstrated impressive initial response rates in hematologic malignancies. However, relapse rates are significant, and robust efficacies in other indications, such as solid tumors, will likely require novel therapeutic strategies and CAR designs. To that end, we sought to develop simple, highly selective targeting domains (D domains) that could be incorporated into complex, multifunctional therapeutics. Herein, we describe the identification and characterization of D domains specific for CD123, a therapeutic target for hematologic malignancies, including acute myelogenous leukemia (AML). CARs comprised of these D domains mediate potent T cell activation and cytolysis of CD123-expressing target cells and induce complete durable remission in two AML xenograft models. We describe a strategy of engineering less immunogenic D domains through the identification and removal of putative T cell epitopes and investigate the binding kinetics and affinity requirements of the resultant D domain CARs. Finally, we extended the utility of D domains by generating functional, bi-specific CARs comprised of a CD123-specific D domain and a CD19-specific scFv. The properties of D domains suggest that this class of targeting domain may facilitate the development of multi-functional CARs where conventional, scFv-based designs may be suboptimal.


Assuntos
Antineoplásicos/uso terapêutico , Imunoterapia Adotiva/métodos , Subunidade alfa de Receptor de Interleucina-3/imunologia , Domínios Proteicos/imunologia , Proteínas/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T/imunologia , Animais , Antígenos CD19/imunologia , Antineoplásicos/imunologia , Epitopos de Linfócito T/imunologia , Células HEK293 , Humanos , Células K562 , Leucemia Mieloide Aguda/terapia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Ligação Proteica/imunologia , Proteínas/imunologia , Receptores de Antígenos Quiméricos/imunologia , Anticorpos de Cadeia Única/imunologia , Transfecção , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Nat Rev Clin Oncol ; 16(6): 372-385, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30837712

RESUMO

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma - the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.


Assuntos
Imunoterapia Adotiva/métodos , Linfoma de Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Antígenos CD19/imunologia , Ensaios Clínicos como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Humanos , Linfoma de Células B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Prevenção Secundária
12.
J Clin Invest ; 129(4): 1551-1565, 2019 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-30694219

RESUMO

Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies.


Assuntos
Transferência Adotiva , Engenharia Genética , Neoplasias Experimentais/terapia , Receptores de Antígenos Quiméricos , Transdução de Sinais/imunologia , Microambiente Tumoral/imunologia , Animais , Proteína Ligante Fas/genética , Proteína Ligante Fas/imunologia , Proteína de Domínio de Morte Associada a Fas/genética , Proteína de Domínio de Morte Associada a Fas/imunologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neoplasias Experimentais/genética , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/uso terapêutico , Transdução de Sinais/genética , Microambiente Tumoral/genética , Receptor fas/genética , Receptor fas/imunologia
13.
Biol Blood Marrow Transplant ; 25(3): 577-586, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30342913

RESUMO

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.


Assuntos
Infecções por Citomegalovirus/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Antivirais/uso terapêutico , Infecções por Citomegalovirus/etiologia , Feminino , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , National Institutes of Health (U.S.) , Estudos Retrospectivos , Fatores de Risco , Esteroides/efeitos adversos , Doadores de Tecidos , Estados Unidos
14.
Mol Ther Oncolytics ; 11: 127-137, 2018 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-30581986

RESUMO

Despite high remission rates following CAR-T cell therapy in B-ALL, relapse due to loss of the targeted antigen is increasingly recognized as a mechanism of immune escape. We hypothesized that simultaneous targeting of CD19 and CD22 may reduce the likelihood of antigen loss, thus improving sustained remission rates. A systematic approach to the generation of CAR constructs incorporating two target-binding domains led to several novel CD19/CD22 bivalent CAR constructs. Importantly, we demonstrate the challenges associated with the construction of a bivalent CAR format that preserves bifunctionality against both CD19 and CD22. Using the most active bivalent CAR constructs, we found similar transduction efficiency compared to that of either CD19 or CD22 single CARs alone. When expressed on human T cells, the optimized CD19/CD22 CAR construct induced comparable interferon γ and interleukin-2 in vitro compared to single CARs against dual-antigen-expressing as well as single-antigen-expressing cell lines. Finally, the T cells expressing CD19/CD22 CAR eradicated ALL cell line xenografts and patient-derived xenografts (PDX), including a PDX generated from a patient with CD19- relapse following CD19-directed CAR therapy. The CD19/CD22 bivalent CAR provides an opportunity to test whether simultaneous targeting may reduce risk of antigen loss.

15.
Nat Med ; 24(10): 1499-1503, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30275568

RESUMO

We report a patient relapsing 9 months after CD19-targeted CAR T cell (CTL019) infusion with CD19- leukemia that aberrantly expressed the anti-CD19 CAR. The CAR gene was unintentionally introduced into a single leukemic B cell during T cell manufacturing, and its product bound in cis to the CD19 epitope on the surface of leukemic cells, masking it from recognition by and conferring resistance to CTL019.


Assuntos
Antígenos CD19/imunologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Epitopos/imunologia , Leucemia/tratamento farmacológico , Adulto , Antígenos CD19/uso terapêutico , Linfócitos B/imunologia , Terapia Baseada em Transplante de Células e Tecidos , Humanos , Leucemia/imunologia , Leucemia/patologia , Masculino , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos , Linfócitos T/imunologia , Adulto Jovem
16.
Blood ; 132(18): 1899-1910, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30209120

RESUMO

Adoptive transfer of patient-derived T cells modified to express chimeric antigen receptors (CARTs) has demonstrated dramatic success in relapsed/refractory pre-B-cell acute lymphoblastic leukemia (ALL), but response and durability of remission requires exponential CART expansion and persistence. Tumors are known to affect T-cell function, but this has not been well studied in ALL and in the context of chimeric antigen receptor (CAR) expression. Using TCF3/PBX1 and MLL-AF4-driven murine ALL models, we assessed the impact of progressive ALL on T-cell function in vivo. Vaccines protect against TCF3/PBX1.3 but were ineffective when administered after leukemia injection, suggesting immunosuppression induced early during ALL progression. T cells from leukemia-bearing mice exhibited increased expression of inhibitory receptors, including PD1, Tim3, and LAG3, and were dysfunctional following adoptive transfer in a model of T-cell receptor (TCR)-dependent leukemia clearance. Although expression of inhibitory receptors has been linked to TCR signaling, pre-B-cell ALL induced inhibitory receptor expression, at least in part, in a TCR-independent manner. Finally, introduction of a CAR into T cells generated from leukemia-bearing mice failed to fully reverse poor in vivo function.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Células Precursoras de Linfócitos B/patologia , Linfócitos T/patologia , Transferência Adotiva/métodos , Animais , Vacinas Anticâncer/uso terapêutico , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Camundongos Endogâmicos C57BL , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos Quiméricos/análise
17.
J Natl Compr Canc Netw ; 16(9): 1092-1106, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30181421

RESUMO

Patients with relapsed or refractory (R/R) cancers have a poor prognosis and limited treatment options. The recent approval of 2 chimeric antigen receptor (CAR) autologous T-cell products for R/R B-cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma treatment is setting the stage for what is possible in other diseases. However, there are important factors that must be considered, including patient selection, toxicity management, and costs associated with CAR T-cell therapy. To begin to address these issues, NCCN organized a task force consisting of a multidisciplinary panel of experts in oncology, cancer center administration, and health policy, which met for the first time in March 2018. This report describes the current state of CAR T-cell therapy and future strategies that should be considered as the application of this novel immunotherapy expands and evolves.


Assuntos
Imunoterapia Adotiva/métodos , Recidiva Local de Neoplasia/terapia , Neoplasias/terapia , Comitês Consultivos , Institutos de Câncer/organização & administração , Resistencia a Medicamentos Antineoplásicos/imunologia , Política de Saúde , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/tendências , Comunicação Interdisciplinar , Oncologia/organização & administração , Recidiva Local de Neoplasia/imunologia , Neoplasias/imunologia , Receptores de Antígenos Quiméricos/imunologia , Sociedades Médicas/organização & administração , Linfócitos T/imunologia , Linfócitos T/transplante , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Transplante Autólogo/tendências , Estados Unidos
18.
J Immunother ; 41(7): 350-358, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30048343

RESUMO

Neurotoxicity associated with CAR-T cell therapy can be life-threatening. With rapid development of CAR-T therapies, a systematic method is needed to identify and monitor symptoms of neurotoxicity, elucidate potential etiologies, and compare toxicity across trials. This paper presents a systematic evaluation developed and used to prospectively assess neurotoxicity in our phase I anti-CD22 CAR-T-cell trial and describes the symptoms of neurotoxicity identified using this methodology. Central nervous system (CNS) studies included routine lumbar punctures performed for disease evaluation pretherapy and posttherapy and a baseline brain MRI. Brief cognitive evaluations, assessing 4 domains (attention, working memory, cognitive flexibility, and processing speed), were administered preinfusion and postinfusion. A newly developed CAR-T-specific neurological symptom checklist (NSC) was completed by caregivers at 3 designated time-points. Serial serum cytokine levels were compared with neurotoxicity symptoms and severity. The majority of the first 22 consecutively treated subjects (ages, 7-30) demonstrated stable or improved cognitive test scores following therapy and no irreversible neurotoxicity, despite CAR-T-related antileukemic response, cytokine release syndrome, and trafficking of CAR-T cells to the CSF. The NSC allowed us to document the type and timing of symptoms and explore the etiology of neurotoxicity associated with CD22 CAR-T therapy. Cytokine profiling demonstrated that more concerning symptoms of neurotoxicity, such as hallucination and disorientation, were significantly associated with higher serum cytokine levels, supporting the hypothesis of inflammation-driven neurotoxicity. Systematic assessments of neurotoxicity were feasible in acutely ill children and young adults and served to characterize and monitor the symptoms associated with CAR-T therapy. We recommend these evaluations be incorporated into future immunotherapy protocols.


Assuntos
Encéfalo/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Imunoterapia Adotiva/métodos , Síndromes Neurotóxicas/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Coluna Vertebral/patologia , Adolescente , Adulto , Criança , Confusão , Citocinas/sangue , Resistencia a Medicamentos Antineoplásicos , Feminino , Alucinações , Humanos , Imunoterapia Adotiva/efeitos adversos , Imagem por Ressonância Magnética , Masculino , Testes de Estado Mental e Demência , Síndromes Neurotóxicas/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Estudos Prospectivos , Recidiva , Adulto Jovem
19.
Biol Blood Marrow Transplant ; 24(10): 2040-2046, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29933069

RESUMO

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison.


Assuntos
Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Condicionamento Pré-Transplante , Doadores não Relacionados , Proteínas WT1/sangue , Adolescente , Adulto , Aloenxertos , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Neoplasia Residual , Transplante Homólogo
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