RESUMO
Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.
Assuntos
Mieloma Múltiplo , Receptores de Antígenos Quiméricos , Humanos , Mieloma Múltiplo/genética , Receptores de Antígenos Quiméricos/metabolismo , Linfócitos T , Imunoterapia Adotiva , Medula Óssea/metabolismoRESUMO
Remission durability following single-antigen targeted chimeric antigen receptor (CAR) T-cells is limited by antigen modulation, which may be overcome with combinatorial targeting. Building upon our experiences targeting CD19 and CD22 in B-cell acute lymphoblastic leukemia (B-ALL), we report on our phase 1 dose-escalation study of a novel murine stem cell virus (MSCV)-CD19/CD22-4-1BB bivalent CAR T-cell (CD19.22.BBζ) for children and young adults (CAYA) with B-cell malignancies. Primary objectives included toxicity and dose finding. Secondary objectives included response rates and relapse-free survival (RFS). Biologic correlatives included laboratory investigations, CAR T-cell expansion and cytokine profiling. Twenty patients, ages 5.4 to 34.6 years, with B-ALL received CD19.22.BBζ. The complete response (CR) rate was 60% (12 of 20) in the full cohort and 71.4% (10 of 14) in CAR-naïve patients. Ten (50%) developed cytokine release syndrome (CRS), with 3 (15%) having ≥ grade 3 CRS and only 1 experiencing neurotoxicity (grade 3). The 6- and 12-month RFS in those achieving CR was 80.8% (95% confidence interval [CI]: 42.4%-94.9%) and 57.7% (95% CI: 22.1%-81.9%), respectively. Limited CAR T-cell expansion and persistence of MSCV-CD19.22.BBζ compared with EF1α-CD22.BBζ prompted laboratory investigations comparing EF1α vs MSCV promoters, which did not reveal major differences. Limited CD22 targeting with CD19.22.BBζ, as evaluated by ex vivo cytokine secretion and leukemia eradication in humanized mice, led to development of a novel bicistronic CD19.28ζ/CD22.BBζ construct with enhanced cytokine production against CD22. With demonstrated safety and efficacy of CD19.22.BBζ in a heavily pretreated CAYA B-ALL cohort, further optimization of combinatorial antigen targeting serves to overcome identified limitations (www.clinicaltrials.gov #NCT03448393).
Assuntos
Linfoma de Burkitt , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos Quiméricos , Animais , Antígenos CD19 , Síndrome da Liberação de Citocina , Citocinas , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Recidiva , Linfócitos TRESUMO
A biopsy of lymphoid tissue is currently required to diagnose Kaposi sarcoma-associated herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD). Patients showing clinical manifestations of KSHV-MCD but no pathological changes of KSHV-MCD are diagnosed as KSHV inflammatory cytokine syndrome. However, a lymph node biopsy is not always feasible to make the distinction. A pathognomonic feature of lymph nodes in KSHV-MCD is the expansion of KSHV-infected, lambda-restricted but polyclonal plasmablasts. To investigate whether these cells also reside in extra-nodal sites, effusion from 11 patients with KSHV-MCD and 19 with KSHV inflammatory cytokine syndrome was analysed by multiparametric flow cytometry. A distinct, lambda-restricted plasmablastic population (LRP) with highly consistent immunophenotype was detected in effusions in 8/11 patients with KSHV-MCD. The same population was also observed in 7/19 patients with KSHV inflammatory cytokine syndrome. The detection of LRP stratified KSHV inflammatory cytokine syndrome into two clinically distinct subgroups; those with detectable LRP closely resembled KSHV-MCD, showing similar KSHV viral load, comparable severity of thrombocytopenia and hypoalbuminaemia, and similar incidences of hepatosplenomegaly. Collectively, the detection of LRP by flow cytometry can serve as a valuable tool in diagnosing KSHV-MCD. KSHV inflammatory cytokine syndrome with LRP in effusions may represent a liquid-form of KSHV-MCD.
Assuntos
Hiperplasia do Linfonodo Gigante , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Hiperplasia do Linfonodo Gigante/patologia , Linfonodos/patologia , CitocinasRESUMO
Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829.
Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Benzamidas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/uso terapêutico , Pirazinas/uso terapêutico , Tirosina Quinase da Agamaglobulinemia/biossíntese , Tirosina Quinase da Agamaglobulinemia/genética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Esquema de Medicação , Indução Enzimática , Feminino , Cefaleia/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Leucemia Linfocítica Crônica de Células B/enzimologia , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Dor/induzido quimicamente , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/administração & dosagem , Pirazinas/efeitos adversos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Neoplásico/biossíntese , RNA Neoplásico/genética , RNA-Seq , Transcriptoma , Resultado do TratamentoRESUMO
The safety and efficacy of ibrutinib (420 mg) in chronic lymphocytic leukemia (CLL) were evaluated in a phase 2 study; 51 patients had TP53 aberration (TP53 cohort) and 35 were enrolled because of age 65 years or older (elderly cohort). Both cohorts included patients with treatment-naive (TN) and relapsed/refractory (RR) CLL. With the median follow-up of 4.8 years, 49 (57.0%) of 86 patients remain on study. Treatment was discontinued for progressive disease in 20 (23.3%) patients and for adverse events in 5 (5.8%). Atrial fibrillation occurred in 18 (20.9%) patients for a rate of 6.4 per 100 patient-years. No serious bleeding occurred. The overall response rate at 6 months, the primary study endpoint, was 95.8% for the TP53 cohort (95% confidence interval, 85.7%-99.5%) and 93.9% for the elderly cohort (95% confidence interval, 79.8%-99.3%). Depth of response improved with time: at best response, 14 (29.2%) of 48 patients in the TP53 cohort and 9 (27.3%) of 33 in the elderly cohort achieved a complete response. Median minimal residual disease (MRD) in peripheral blood was 3.8 × 10-2 at 4 years, with MRD-negative (<10-4) remissions in 5 (10.2%) patients. In the TP53 cohort, the estimated 5-year progression-free survival (PFS) was 74.4% in TN-CLL compared with 19.4% in RR-CLL (P = .0002), and overall survival (OS) was 85.3% vs 53.7%, respectively (P = .023). In the elderly cohort, the estimated 5-year PFS and OS in RR-CLL were 64.8% and 71.6%, respectively, and no event occurred in TN-CLL. Long-term administration of ibrutinib was well tolerated and provided durable disease control for most patients. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Medula Óssea/metabolismo , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Piperidinas , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Resultado do TratamentoRESUMO
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.
Assuntos
Medula Óssea/patologia , Citometria de Fluxo/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Recidiva Local de Neoplasia/patologia , Neoplasia Residual/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Imunofenotipagem , Masculino , Recidiva Local de Neoplasia/terapia , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Disease progression in patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib has been attributed to histologic transformation or acquired mutations in BTK and PLCG2. The rate of resistance and clonal composition of PD are incompletely characterized. We report on CLL patients treated with single-agent ibrutinib on an investigator-initiated phase 2 trial. With median follow-up of 34 months, 15 of 84 evaluable patients (17.9%) progressed. Relapsed/refractory disease at study entry, TP53 aberration, advanced Rai stage, and high ß-2 microglobulin were independently associated with inferior progression-free survival (P < .05 for all tests). Histologic transformation occurred in 5 patients (6.0%) and was limited to the first 15 months on ibrutinib. In contrast, progression due to CLL in 10 patients (11.9%) occurred later, diagnosed at a median 38 months on study. At progression, mutations in BTK (Cys481) and/or PLCG2 (within the autoinhibitory domain) were found in 9 patients (10.7%), in 8 of 10 patients with progressive CLL, and in 1 patient with prolymphocytic transformation. Applying high-sensitivity testing (detection limit â¼1 in 1000 cells) to stored samples, we detected mutations up to 15 months before manifestation of clinical progression (range, 2.9-15.4 months). In 5 patients (6.0%), multiple subclones carrying different mutations arose independently, leading to subclonal heterogeneity of resistant disease. For a seamless transition to alternative targeted agents, patients progressing with CLL were continued on ibrutinib for up to 3 months, with 19.8 months median survival from the time of progression. This trial was registered at www.clinicaltrials.gov as #NCT01500733.
Assuntos
Evolução Clonal , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B/patologia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Idoso , Transformação Celular Neoplásica , Progressão da Doença , Intervalo Livre de Doença , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/fisiopatologia , Fosfolipase C gama/genética , Piperidinas , Proteínas Tirosina Quinases/genéticaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Infecções por HIV/complicações , Linfoma não Hodgkin/tratamento farmacológico , Adulto , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/virologia , Quimioterapia Combinada , Feminino , Seguimentos , HIV/isolamento & purificação , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/virologia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Rituximab/administração & dosagem , Taxa de SobrevidaRESUMO
Immune targeting of B-cell malignancies using chimeric antigen receptors (CARs) is a promising new approach, but critical factors impacting CAR efficacy remain unclear. To test the suitability of targeting CD22 on precursor B-cell acute lymphoblastic leukemia (BCP-ALL), lymphoblasts from 111 patients with BCP-ALL were assayed for CD22 expression and all were found to be CD22-positive, with median CD22 expression levels of 3500 sites/cell. Three distinct binding domains targeting CD22 were fused to various TCR signaling domains ± an IgG heavy chain constant domain (CH2CH3) to create a series of vector constructs suitable to delineate optimal CAR configuration. CARs derived from the m971 anti-CD22 mAb, which targets a proximal CD22 epitope demonstrated superior antileukemic activity compared with those incorporating other binding domains, and addition of a 4-1BB signaling domain to CD28.CD3 constructs diminished potency, whereas increasing affinity of the anti-CD22 binding motif, and extending the CD22 binding domain away from the membrane via CH2CH3 had no effect. We conclude that second-generation m971 mAb-derived anti-CD22 CARs are promising novel therapeutics that should be tested in BCP-ALL.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Receptores de Antígenos de Linfócitos T/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Animais , Linhagem Celular Tumoral , Citocinas/metabolismo , Citotoxicidade Imunológica , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas Recombinantes de Fusão/imunologia , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Linfocítica Crônica de Células B , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/mortalidade , Masculino , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Taxa de Sobrevida , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivadosRESUMO
BACKGROUND: CD22 is a B-lineage differentiation antigen that has emerged as a leading therapeutic target in acute lymphoblastic leukemia (ALL). PROCEDURE: Properties of CD22 expression relevant to therapeutic targeting were characterized in primary samples obtained from children and young adults with relapsed and chemotherapy refractory B-precursor (pre-B) ALL. RESULTS: CD22 expression was demonstrated in all subjects (n = 163) with detection on at least 90% of blasts in 155 cases. Median antigen site density of surface CD22 was 3,470 sites/cell (range 349-19,653, n = 160). Blasts from patients with known 11q23 (MLL) rearrangement had lower site density (median 1,590 sites/cell, range 349-3,624, n = 20 versus 3,853 sites/cell, range 451-19,653, n = 140; P = <0.0001) and 6 of 21 cases had sub-populations of blasts lacking CD22 expression (22%-82% CD22 +). CD22 expression was maintained in serial studies of 73 subjects, including those treated with anti-CD22 targeted therapy. The levels of soluble CD22 in blood and marrow by ELISA were low and not expected to influence the pharmacokinetics of anti-CD22 directed agents. CONCLUSIONS: These characteristics make CD22 an excellent potential therapeutic target in patients with relapsed and chemotherapy-refractory ALL, although cases with MLL rearrangement require close study to exclude the presence of a CD22-negative blast population.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/análise , Adolescente , Adulto , Criança , Pré-Escolar , Cromossomos Humanos Par 11 , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Proteína de Leucina Linfoide-Mieloide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidoresAssuntos
Antígenos de Neoplasias/imunologia , Imunoterapia , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Criança , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Masculino , PrognósticoRESUMO
BACKGROUND: Multiparametric flow cytometry (MFC) has become a powerful tool in minimal residual disease (MRD) detection in B-lymphoblastic leukemia/lymphoma (B-ALL). In the setting of targeted immunotherapy, B-ALL MRD detection often relies on alterative gating strategies, such as the utilization of CD22 and CD24. It is important to depict the full diversity of normal cell populations included in the alternative B-cell gating methods to avoid false-positive results. We describe two CD22-positive non-neoplastic cell populations in the peripheral blood (PB), including one progenitor population of uncertain lineage and one mature B-cell population, which are immunophenotypic mimics of B-ALL. METHODS: Using MFC, we investigated the prevalence and phenotypic profiles of both CD22-positive populations in 278 blood samples from 52 patients with B-ALL; these were obtained pre- and post-treatment with CD19 and/or CD22 CAR-T therapies. We further assessed whether these two populations in the blood were exclusively associated with B-ALL or recent anticancer therapies, by performing the same analysis on patients diagnosed with other hematological malignancies but in long-term MRD remission. RESULTS: The progenitor population and mature B-cell population were detected at low levels in PB of 61.5% and 44.2% of B-ALL patients, respectively. Both cell types showed distinctive and highly consistent antigen expression patterns that are reliably distinguishable from B-ALL. Furthermore, their presence is not restricted solely to B-ALL or recent therapy. CONCLUSIONS: Our findings aid in building a complete immunophenotypic profile of normal cell populations in PB, thereby preventing misdiagnosis of B-ALL MRD and inappropriate management.
Assuntos
Leucemia de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Humanos , Neoplasia Residual/patologia , Citometria de Fluxo/métodos , Antígenos CD19 , Linfócitos B/patologia , Leucemia de Células B/patologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Antígeno CD24RESUMO
Primary effusion lymphoma (PEL), an aggressive non-Hodgkin lymphoma caused by Kaposi sarcoma-associated herpesvirus (KSHV), lacks standard therapy and has a median survival of 10-22 months with combination chemotherapy. PEL is a tumor of plasmablast-like B cells generally expressing CD38, the target of daratumumab (Dara). Initially, we assessed PEL cells from eight patients and established that each expressed high levels of CD38 by flow cytometry. PEL cell lines were also evaluated and most had high CD38 expression. We then assessed Dara's effects on complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) of PEL cell lines as well as its clinical benefits on two patients with PEL. Despite high CD38 expression, Dara did not induce CDC of PEL cell lines, due in part to high levels of the complement-inhibitory proteins, CD55 and CD59. However, Dara induced significant and dose-dependent increases in ADCC, particularly in those lines with high CD38 levels. Two FDA-approved drugs, all trans-retinoic acid (ATRA) and pomalidomide (Pom), significantly increased surface CD38 levels in low-CD38 expressing PEL cell lines, resulting in increased Dara-induced ADCC. Two patients with refractory PEL were treated with Dara alone or in combination with Pom. One patient with leptomeningeal PEL had a complete response to Dara and Pom combination treatment. Others had improvement in performance status and resolution of malignant ascites with Dara alone. Together, these data support the use of Dara monotherapy or in combination with ATRA or Pom as a potential therapeutic option for PEL.
Assuntos
Anticorpos Monoclonais , Linfoma de Efusão Primária , Humanos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Imunológica , Linfoma de Efusão Primária/imunologia , Linfoma de Efusão Primária/terapia , Tretinoína/farmacologia , Tretinoína/uso terapêuticoRESUMO
Hairy cell leukemia (HCL), similar to its variant HCLv, is a B-cell malignancy associated with decreased humoral immunity. We prospectively monitored the largest cohort of patients with HCL/HCLv to date (n = 503) for COVID-19 by symptoms, antibody, and polymerase chain reaction (PCR) and/or antigen positivity. Fifty percent (253 of 503) of the patients with HCL/HCLv (238 HCL and 15 HCLv) had evidence of COVID-19, with 210 (83%) testing positive by PCR or rapid-antigen test. Of the 43 patients without positive tests, all had nucleocapsid antibodies indicating COVID-19 exposure, 7 recalled no symptoms, and 36 had mild symptoms. Of the 210 who tested positive, 23, 46, 129, and 12 cases occurred in 2020, 2021, 2022, and 2023, respectively. Among them, 175 began treatment for HCL/HCLv 0.4 to 429 (median, 66) months before, and 132 had their last dose of anti-CD20 monoclonal antibody 0.2 to 229 (median, 63) months before. Two patients died, including a young woman who began rituximab 2 months after first-line cladribine before vaccine availability. Nearly all patients with HCL/HCLv recovered uneventfully from COVID-19 including those without vaccination or those with significant immunosuppression and recent treatment. However, decreased normal B cells from HCL or treatment was associated with lower spike antibody levels as a response to COVID-19 (P = .0094) and longer recovery time (P = .0036). Thus, in a large cohort of patients with HCL/HCLv and in the first to determine relationships between COVID-19 outcome and immune markers, mortality was relatively low (â¼1%), sequelae were uncommon, and recovery from COVID-19 was longer if normal B cells were low after recent treatment. The trials are registered at www.clinicaltrials.gov as #NCT01087333 and #NCT04362865.
Assuntos
Antineoplásicos , COVID-19 , Leucemia de Células Pilosas , Feminino , Humanos , Leucemia de Células Pilosas/tratamento farmacológico , Cladribina/uso terapêutico , Antineoplásicos/uso terapêutico , Rituximab/uso terapêuticoRESUMO
Outcomes for post-chimeric antigen receptor (CAR) T cell therapy (CART) relapse are poor. The utilization of a unique CAR T cell construct for post-CART failure is increasing, but this approach is not well described. In this study, with CART-A the first unique CAR T cell construct received and CART-B the second, the primary objective was to characterize outcomes following CART-B. Secondary objectives included evaluating safety and toxicity with sequential CART infusions; investigating the impact of potential factors, such as antigen modulation and interval therapy, on CART-B response; and characterizing long-term outcomes in patients receiving multiple CARTs. This was a retrospective review (NCT03827343) of children and young adults with B cell acute lymphoblastic leukemia (B-ALL) undergoing CART therapy who received at least 2 unique CART constructs, excluding interim CART reinfusions of the same product. Of 135 patients, 61 (45.1%) received 2 unique CART constructs, including 13 who received >2 CARTs over time. Patients included in this analysis received 14 distinct CARTs targeting CD19 and/or CD22. The median age at CART-A was 12.6 years (range, 3.3 to 30.4 years). The median time from CART-A to CART-B was 302 days (range, 53 to 1183 days). CART-B targeted a different antigen than CART-A in 48 patients (78.7%), owing primarily to loss of CART-A antigen target. The rate of complete remission (CR) was lower with CART-B (65.5%; 40 of 61) than with CART-A (88.5%; 54 of 61; P = .0043); 35 of 40 (87.5%) CART-B responders had CART-B targeting a different antigen than CART-A. Among the 21 patients with a partial response or nonresponse to CART-B, 8 (38.1%) received CART-B with the same antigen target as CART-A. Of 40 patients with CART-B complete response (CR), 29 (72.5%) relapsed. For the 21 patients with evaluable data, the relapse immunophenotype was antigennegative in 3 (14.3%), antigendim in 7 (33.3%), antigenpositive in 10 (47.6%), and lineage switch in 1 (4.8%). The median relapse-free survival following CART-B CR was 9.4 months (95% confidence interval [CI], 6.1 to 13.2 months), and overall survival was 15.0 months (95% CI, 13.0 to 22.7 months). Given the limited salvage options for post-CART relapse, identifying optimizing strategies for CART-B is critical. We raise awareness about the emerging use of CART for post-CART failure and highlight clinical implications accompanying this paradigm shift.
Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos Quiméricos , Criança , Adulto Jovem , Humanos , Pré-Escolar , Adolescente , Adulto , Receptores de Antígenos Quiméricos/uso terapêutico , Linfócitos T , Terapia de Salvação , Imunoterapia Adotiva/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , RecidivaRESUMO
Relapse following chimeric antigen receptor (CAR) T-cell therapy directed against CD19 for relapsed/refractory B-acute lymphoblastic leukemia (r/r B-ALL) remains a significant challenge. Three main patterns of relapse predominate: CD19 positive (CD19pos) relapse, CD19 negative (CD19neg) relapse, and lineage switch (LS). Development and validation of risk factors that predict relapse phenotype could help define potential pre- or post-CAR T-cell infusion interventions aimed at decreasing relapse. Our group sought to extensively characterize preinfusion risk factors associated with the development of each relapse pattern via a multicenter, retrospective review of children and young adults with r/r B-ALL treated with a murine-based CD19-CAR construct. Of 420 patients treated with CAR, 166 (39.5%) relapsed, including 83 (50%) CD19pos, 68 (41%) CD19neg, and 12 (7.2%) LS relapses. A greater cumulative number of prior complete remissions was associated with CD19pos relapses, whereas high preinfusion disease burden, prior blinatumomab nonresponse, older age, and 4-1BB CAR construct were associated with CD19neg relapses. The presence of a KMT2A rearrangement was the only preinfusion risk factor associated with LS. The median overall survival following a post-CAR relapse was 11.9 months (95% CI, 9-17) and was particularly dismal in patients experiencing an LS, with no long-term survivors following this pattern of relapse. Given the poor outcomes for those with post-CAR relapse, study of relapse prevention strategies, such as consolidative hematopoietic stem cell transplantation, is critical and warrants further investigation on prospective clinical trials.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Animais , Camundongos , Antígenos CD19 , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Prospectivos , Recidiva , Linfócitos TRESUMO
Prolonged myelosuppression after chimeric antigen receptor (CAR) T-cell therapy is common and poorly understood. A retrospective analysis of 43 patients was conducted to investigate factors contributing to CAR T-cell-related cytopenias. Thirty-five patients were evaluable for analysis of delayed cytopenias occurring after initial hematologic recovery. Time to hematologic recovery (TTHR) was defined as number of days after CAR T-cell infusion for recovery to hemoglobin ≥8.0 g/dL, platelets ≥50.0 k/µL, and neutrophil count ≥1.0 k/µL without transfusions or growth factors for 7 days. Baseline percent bone marrow (BM) malignancy involvement correlated with TTHR (p = .0047). Patients with grades 3-4 cytokine-release syndrome (CRS) had longer TTHR than those with grades 0-2 CRS (p = .0479). Patients who developed prolonged or delayed cytopenias after anti-BCMA CAR T cells had a higher percentage of BM aspirate CAR+ cells at 2 months (n = 10; p = .0159).
Assuntos
Anemia , Leucopenia , Trombocitopenia , Anemia/etiologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Linfócitos T , Trombocitopenia/etiologiaRESUMO
PURPOSE: Children's Oncology Group trial AALL1621 was conducted to prospectively determine the safety and efficacy of inotuzumab ozogamicin (InO) in pediatric and adolescent patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). PATIENTS AND METHODS: This single-arm phase II trial enrolled patients age 1-21 years with R/R CD22-positive B-ALL. In cycle 1, InO dosing was 0.8 mg/m2 intravenously on day 1 and 0.5 mg/m2 on days 8 and 15 of a 28-day cycle with response evaluation at day 28. Using a two-stage design, the trial was continuously monitored for dose-limiting toxicities and sinusoidal obstruction syndrome (SOS). CD22 expression was retrospectively evaluated by central flow cytometry. RESULTS: Forty-eight patients were evaluable for response and toxicity; 19 had complete response (CR) and nine CR with incomplete count recovery (CRi) after cycle 1 (CR/CRi rate: 58.3%; two-sided 90% CI, 46.5 to 69.3). Twenty-seven of 28 patients with CR or CRi had minimal residual disease measured by flow cytometry; 18 (66.7%) had minimal residual disease < 0.01%. Seven of 28 patients (25%) with CR or CRi had delayed count recovery past day 42 in cycle 1. Three (6.3%) patients had grade 3 ALT elevation and one patient had grade 3 hyperbilirubinemia in cycle 1. Of 21 patients undergoing hematopoietic stem-cell transplantation after InO, 6 (28.6%) developed grade 3 SOS. Partial CD22 expression and lower CD22 site density were associated with lower likelihood of response to InO. CONCLUSION: InO is effective and well tolerated in heavily pretreated children and adolescents with R/R CD22-positive B-ALL. SOS after hematopoietic stem-cell transplantation and prolonged cytopenias were notable. CD22 modulation was identified as a mechanism of resistance. Expanded study of InO combined with chemotherapy is underway.