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1.
Leuk Res ; 111: 106704, 2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34735934

RESUMO

Light-chain restricted hematogones (LCR HGs) detected by flow cytometry analysis can mimic bone marrow involvement by B-cell lymphoma. This phenomenon can present a diagnostic pitfall and negatively impact patient management, as misinterpretation may upgrade disease stage. In this study, we characterized the immunophenotype of LCR HGs with an aim to differentiate them from B-cell lymphoma. We analyzed 24 patients with LCR HGs, 12 (50 %) were kappa light chain restricted and 12 (50 %) were lambda light chain restricted. LCR HGs account for 51 % (range, 1.5%-99%) of B cells, and 0.5 % (range, 0.1%-3.7%) of total cells. In 15 patients in whom multiple specimens were analyzed, 10 (67 %) showed persistent LCR HGs in more than 1 specimen, and the duration of the light chain restriction ranged from 4 months to 2 years. Among 24 patients, 4 (16.6 %) cases were concurrently involved by B-cell lymphoma/myeloma in addition to LCR HGs. With the exception of light chain restriction, LCR HGs showed a similar immunophenotype as normal HGs and had a distinct location on the CD45/Side Scatter (SSC) plot. They were also consistently positive for CD10, CD19, CD38 (bright), CD43, and CD200. CD20 expression showed a spectrum from dim/negative to positive.

2.
Blood ; 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34724563

RESUMO

Measurable residual disease (MRD) is an important biomarker in acute myeloid leukemia (AML) that is used for prognostic, predictive, monitoring, and efficacy-response assessments. The European LeukemiaNet (ELN) MRD working party evaluates standardization and harmonization of MRD in an ongoing manner and has updated the 2018 ELN MRD recommendations based on significant developments in the field. New and revised recommendations were established during in-person and online meetings, and a two-stage Delphi poll was conducted to optimize consensus. All recommendations are graded by levels of evidence and agreement. Major changes include technical specifications for next generation sequencing (NGS)-based MRD testing and integrative assessments of MRD irrespective of technology. Other topics include use of MRD as a prognostic and surrogate endpoint for drug testing; selection of the technique, material, and appropriate time points for MRD assessment; and clinical implications of MRD assessment. In addition to technical recommendations for flow- and molecular- MRD analysis, we provide MRD thresholds and define MRD response, and detail how MRD results should be reported and combined if several techniques are used. MRD assessment in AML is complex and clinically relevant, and standardized approaches to application, interpretation, technical conduct, and reporting are of critical importance.

3.
Transplant Cell Ther ; 2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34537419

RESUMO

In the coronavirus disease 19 (COVID-19) pandemic era, the number of haploidentical hematopoietic cell transplantations (HCTs) with peripheral blood (PB) grafts increased significantly compared with HCTs with bone marrow (BM) grafts, which may be associated with adverse outcomes. We compared outcomes of HCT in BM graft and PB graft recipients age ≥18 years with hematologic malignancies who underwent T cell- replete haploidentical HCT and received graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus, and mycophenolate mofetil. Among the 264 patients, 180 (68%) received a BM graft and 84 (32%) received a PB graft. The median patient age was 50 years in both groups. The majority (n = 199; 75%) received reduced-intensity conditioning. The rate of acute leukemia or myelodysplastic syndrome was higher in the BM graft recipients compared with the PB graft recipients (85% [n = 152] versus 55% [n = 46]; P < .01). The median times to neutrophil and platelet engraftment and the incidence of grade II-IV and grade III-IV acute GVHD (aGVHD) were comparable in the 2 groups. Among the patients with grade II-IV aGVHD, the rate of steroid-refractory aGVHD was 9% (95% confidence interval [CI], 5% to 18%) in the BM group versus 32% (95% CI, 19% to 54%) in the PB group (hazard ratio [HR], 3.7, 95% CI, 1.5 to 9.3; P = .006). At 1 year post-HCT, the rate of chronic GVHD (cGVHD) was 8% (95% CI, 4% to 13%) in the BM group versus 22% (95% CI, 14% to 36%) in the PB group (HR, 3.0; 95% CI, 1.4-6.6; P = .005), and the rate of systemic therapy-requiring cGVHD was 2.5% (95% CI, 1% to 7%) versus 14% (95% CI, 7% to 27%), respectively (HR, 5.6; 95% CI, 1.7 to 18; P = .004). The PB group had a significantly higher risk of bacterial and viral infections, with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, nonrelapse mortality, or survival. Our data suggest a benefit of the use of BM grafts over PB grafts for haplo-HCT.

5.
Cancer ; 127(18): 3381-3389, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34138471

RESUMO

BACKGROUND: The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD + ofatumumab (hyper-CVAD + ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial. METHODS: The authors compared the outcomes of 69 patients treated with hyper-CVAD + ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups. RESULTS: The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097). CONCLUSIONS: Hyper-CVAD + ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL.

6.
Br J Haematol ; 192(6): 1054-1063, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33618432

RESUMO

Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1-mutated (NPM1mut ) AML, we identified 50 who achieved NPM1mut clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (<1%) of aberrant CD34+ myeloblasts, but immunophenotypically different from original AML blasts [herein referred to as a pre-leukaemic (PL) phenotype], was detected in 17 (49%) patients with CH, but not in any patients with complete clearance of all mutations (P = 0·0037). A PL phenotype was associated with higher mutation burden (P = 0·005). Persistent IDH2 and serine and arginine-rich splicing factor 2 (SRSF2) mutations were exclusively observed in PL+ CH+ cases (P = 0·016). Persistent dysplasia was seen exclusively in cases with a PL+ phenotype (29% vs. none; P = 0·04). The PL+ phenotype did not correlate with age, intensity of induction therapy or relapse-free survival. Post-remission CH in the setting of NPM1mut clearance is common and may result in immunophenotypic changes in myeloid progenitors. It is important to not misinterpret these cells as AML measurable residual disease (MRD).


Assuntos
Medula Óssea , Hematopoiese Clonal , Leucemia Mieloide Aguda , Mutação , Células Progenitoras Mieloides , Proteínas de Neoplasias , Proteínas Nucleares , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Células Progenitoras Mieloides/metabolismo , Células Progenitoras Mieloides/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Indução de Remissão
8.
Haematologica ; 106(4): 1047-1055, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32241840

RESUMO

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic neoplasm whose immunophenotype remains incompletely characterized, particularly in terms of distinction from reactive plasmacytoid dendritic cells (PDCs). This limitation complicates detection of low-level involvement by BPDCN as well as minimal residual disease (MRD) assessment following therapy. We conducted the current study to characterize the immunophenotype of BPDCN in a cohort of 39 patients, and compared it to reactive PDCs. We found that, in addition to CD56 expression (97%), BPDCN showed a number of aberrancies, including decreased/negative CD38 (82%), positive CD7 (64%), negative CD2 (81%), negative CD303 (56%), increased HLA-DR (69%) and decreased CD123 (78%). Although BPDCN cells were characterized by CD56 expression, reactive PDCs consistently included a CD56-positive subset, ranging 1.3%-20% (median 4.5%) of total PDCs, challenging MRD detection. These CD56+ reactive PDCs, however, were consistently positive for CD2 and CD303, brightly positive for CD38, and negative for CD7, distinctively different from BPDCN. Based on these findings, we set up a 10-color flow cytometry assay for BPDCN and validated it to a sensitivity of 0.01%. This panel was prospectively tested in 19 bone marrow samples from 7 BPDCN patients, and it effectively distinguished BPDCN cells from background reactive PDCs in all cases. In summary, by understanding the immunophenotype of reactive and neoplastic PDCs, BPDCN can be effectively detected by flow cytometry to a very low level using a panel of markers in addition to CD56, and such assay can be used for initial bone marrow workup as well as MRD detection after therapy.


Assuntos
Neoplasias Hematológicas , Neoplasias Cutâneas , Células Dendríticas , Citometria de Fluxo , Neoplasias Hematológicas/diagnóstico , Humanos , Imunofenotipagem , Neoplasia Residual
9.
Cytometry B Clin Cytom ; 100(2): 183-191, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32667737

RESUMO

BACKGROUND: Blood involvement by mycosis fungoides (MF)/Sézary syndrome (SS) influences prognosis and therapeutic decisions. MF/SS blood stage is currently determined by absolute CD4 + CD26- or CD4 + CD7-cell counts, which quantification method may overestimate MF/SS by including CD26- or CD7- normal CD4+ T-cells, or underestimate disease burden when MF/SS cells show incomplete loss of CD26 and/or CD7. Recently, through the standardization effort led by the International Clinical Cytometry Society (ICCS), recommendation was made to quantify MF/SS by enumerating immunophenotypically aberrant CD4+ T-cells, rather than CD26- or CD7- in isolation. METHODS: We compared these two quantitation methods in 309 MF/SS patients who had blood samples analyzed by flow cytometry immunophenotyping (FCI) over a 1-year period. RESULTS: Using the European Organization of Research and Treatment of Cancer (EORTC)/International Society for Cutaneous Lymphomas (ISCL) criteria, 221 (71.5%) patients had a blood stage corresponding to B0, 57 (18.4%) to B1, and 31 (10%) to B2. By FCI analysis, a total of 62 patients (20.0%) were found positive for MF/SS. Among EORTC B0 patients, 11/221 (5%) were positive by FCI (false negatives), and among EORTC Stage B1 patients, 35/57 (61%) were negative by FCI (false positives). Regarding patients positive for MF/SS cells by FCI, there was an overall excellent correlation (r = .999, p < .001) between the EORTC/ISCL method and FCI method; however, four (6.5%) patients would have an altered B stage between B0 and B1. CONCLUSION: The MF/SS cell quantification method using immunophenotypic aberrancies, as recommended by the ICCS, allows to distinguish MF/SS cells from background benign T-cells and enables for more accurate staging, especially among patients currently being considered to have B0 and B1 stage diseases.

10.
Blood Adv ; 4(24): 6117-6126, 2020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33351107

RESUMO

In relapsed/refractory acute myeloid leukemia (AML), the prognostic impact of complete remission (CR) and measurable residual disease (MRD) negativity is not well established. We retrospectively analyzed 141 patients with relapsed/refractory AML who received first salvage therapy and had MRD assessed by multiparameter flow cytometry at the time of response. Patients who achieved CR with full hematologic recovery as best response vs those with incomplete hematology recovery had lower cumulative incidence of relapse (P = .01) and better relapse-free survival (P = .004) but not overall survival (P = .15); a similar trend was observed in patients who achieved MRD negativity vs those who were MRD positive (P = .01, P = .05, and P = .21, respectively). By multivariate analysis, CR and MRD negativity were each independently associated with lower cumulative incidence of relapse (P = .001 and P = .003, respectively) and better relapse-free survival (P < .001 and P = .02) but not overall survival. Patients who achieved CR with MRD negativity had the lowest rates of relapse and best survival (2-year overall survival rate, 37%), which was driven largely by lower rates of early relapse and an increased ability in this group to undergo hematopoietic stem cell transplantation (HSCT); however, post-HSCT outcomes were similar regardless of response to salvage chemotherapy. Overall, in patients with relapsed/refractory AML, CR with MRD negativity was associated with the best outcomes, supporting it as the optimal response in this setting.


Assuntos
Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual , Prognóstico , Indução de Remissão , Estudos Retrospectivos
11.
Hum Pathol ; 98: 1-9, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32032618

RESUMO

Anaplastic large cell lymphoma (ALCL) is a T-cell neoplasm characterized by uniformly strong CD30 expression and common absence of T-cell markers. Most ALCL cases express CD4, but a small subset of ALCL cases has been reported to express CD8. Little is known about the clinicopathologic and prognostic features of CD8+ ALCL. In this study, CD8 was assessed in 158 patients with systemic ALCL: CD8 was positive in 13 of 67 (19%) ALK+ and 13 of 91 (14%) ALK-negative neoplasms. In ALK+ ALCL, the CD8+ subgroup more often showed a noncommon morphologic pattern (69% vs 13%, P = .0001) and was more often positive for CD2 (100% vs 45%, P = .001), CD3 (92% vs 24%, P = .0001), and CD7 (100% vs. 39%, P = .002), but less frequently positive for CD25 (50% vs. 100%, P = .02). Patients with ALK+ ALCL and CD8+ neoplasms also had a higher relapse rate (82% vs 48%, P = .05) and more often underwent stem cell transplant (73% vs 36%, P = .04). CD8 expression did not correlate with patient overall survival or progression-free survival regardless of ALK status (all P > 0.05). We conclude that CD8+ ALCL cases appear to be biologically different from the more common CD8-negative ALCL cases. Our data suggest that CD8 positivity in ALK+ ALCL helps to identify a subset of patients more prone to relapse or more in need of stem cell transplant during their clinical course, although there was no impact on survival in this cohort.


Assuntos
Antígenos CD7/análise , Biomarcadores Tumorais/análise , Complexo CD3/análise , Linfócitos T CD8-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/análise , Linfoma Anaplásico de Células Grandes/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/genética , Linfócitos T CD8-Positivos/patologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Rearranjo Gênico , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patologia , Linfoma Anaplásico de Células Grandes/terapia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Fatores de Tempo , Adulto Jovem
12.
Cytometry B Clin Cytom ; 98(1): 36-42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31211490

RESUMO

B-cell progenitors (hematogones) are markedly decreased or completely absent in the bone marrows of myelodysplastic syndromes (MDS), and the finding is considered as an important feature in MDS flow cytometry immunophenotyping. We studied CD34+ hematogones as a proportion of total CD34+ cells in 160 treatment naïve low grade primary MDS patients, consecutively collected over a two-year period. While confirming that the median CD34 + hematogones was significantly decreased (1.08%, 0%, to 67.86%), we observed variably preserved CD34 + hematogones in some MDS patients. Using a 5% cutoff, a total of 46 (29%) MDS patients had ≥5% CD34 + hematogones, significantly overrepresented by MDS with ring sideroblasts (RS) (MDS-RS) (18/40, 45%, vs. 28/120, 23%, P = 0.015). While we did not observe unique features among MDS-RS, mutations were noticeably absent in a significant number of MDS without RS (37% vs. 14%, P = 0.013), including TP53 mutations (0% vs.16.5%, P = 0.021) if ≥5% CD34 + hematogones were present. Although the follow up was short (18.5 months, 0 to 151.0), a better overall survival was observed in MDS with ≥5% CD34 + hematogones, either as a group (P = 0.008) or among patients with no RS (P = 0.028). In multivariate analysis, reduced hematogones remained to be significant hazard (P = 0.015). In summary, preserved CD34 + hematogones (≥5%) are seen in over a quarter of primary low-grade MDS and these cases are overrepresented by MDS with RS or MDS with no detectable mutations. The finding is new, and this phenomenon may in part attribute to preservation of B-cell differentiation of CD34+ progenitors, and it is associated with a better prognosis in low grade MDS patients. © 2019 International Clinical Cytometry Society.


Assuntos
Antígenos CD34/metabolismo , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia , Células Precursoras de Linfócitos B/metabolismo , Células Precursoras de Linfócitos B/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Medula Óssea/patologia , Feminino , Citometria de Fluxo/métodos , Humanos , Imunofenotipagem/métodos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
13.
Blood ; 134(22): 1951-1959, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31537528

RESUMO

Patients with chronic lymphocytic leukemia (CLL) who achieve blood or bone marrow (BM) undetectable minimal residual disease (U-MRD) status after first-line fludarabine, cyclophosphamide, and rituximab (FCR) have prolonged progression-free survival (PFS), when assessed by an assay with sensitivity 10-4 (MRD4). Despite reaching U-MRD4, many patients, especially those with unmutated IGHV, subsequently relapse, suggesting residual disease <10-4 threshold and the need for more sensitive MRD evaluation. MRD evaluation by next-generation sequencing (NGS) has a sensitivity of 10-6 (MRD6). To better assess the depth of remission following first-line FCR treatment, we used NGS (Adaptive Biotechnologies Corporation) to assess MRD in 62 patients, all of whom had BM U-MRD by multicolor flow cytometry (sensitivity 10-4) at end-of-FCR treatment. Samples from these patients included 57 BM samples, 29 peripheral blood mononuclear cell (PBMC) samples, and 32 plasma samples. Only 27.4% of the 62 patients had U-MRD by NGS. Rate of U-MRD by NGS was lowest in BM (25%), compared with PBMC (55%) or plasma (75%). No patient with U-MRD by NGS in BM or PBMC was MRD+ in plasma. Patients with mutated IGHV were more likely to have U-MRD by NGS at the end of treatment (EOT; 41% vs 13%, P = .02) than those with unmutated IGHV. Median follow-up was 81.6 months. Patients with U-MRD at EOT had superior PFS vs MRD+ patients, regardless of sample type assessed (BM, P = .02, median not reached [NR] vs 67 months; PBMC, P = .02, median NR vs 74 months). More sensitive MRD6 testing increases prognostic discrimination over MRD4 testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Imunoterapia , Leucemia Linfocítica Crônica de Células B , Idoso , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/sangue , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Valor Preditivo dos Testes , Rituximab/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados
14.
Br J Haematol ; 186(4): 538-548, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31115909

RESUMO

The differential immunophenotypic characteristics of early T precursor (ETP) acute lymphoblastic leukaemia/lymphoma (ALL) remain incompletely characterized. The study group (n = 142) included 106 (74·7%) men and 36 (25·3%) women with a median age of 34·9 years (range, 2-79) at diagnosis. Patients were subtyped by flow cytometry immunophenotyping as follows: 33 (23·2%) ETP; 32 (22·5%) early non-ETP; 60 (42·2%) thymic; and 17 (12·1%) mature. Excepting definitional markers, there was a significant differential expression of the markers CD2, CD10, CD33 and TdT between ETP-ALL and non-ETP-ALL. Positive CD33 expression (≥20% of leukaemic blasts) was detected in 21/33 (63%) ETP-ALL compared with 17/95 (17·9%) non-ETP-ALL (P < 0·001). Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro. An 11-marker T-ALL immunophenotype score discriminated reliably between ETP and non-ETP ALL. Longitudinal analysis of ETP-ALL cases in this study demonstrated that the immunophenotype may be occasionally dynamic but is largely stable over the disease course. In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted.


Assuntos
Imunofenotipagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Adulto , Idoso , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Biomarcadores , Linhagem Celular , Feminino , Citometria de Fluxo , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasia Residual/diagnóstico , Neoplasia Residual/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Prognóstico , Modelos de Riscos Proporcionais , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Adulto Jovem
16.
Haematologica ; 104(4): 749-755, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30361418

RESUMO

The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of patients with acute lymphoblastic leukemia/lymphoma and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA-alkylating payload. CD123 expression on leukemic blasts was surveyed using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 patients with B acute lymphoblastic leukemia/lymphoma and 30 with T acute lymphoblastic leukemia/lymphoma. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma than in T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% versus 13/30, 43.3%; P<0.0001), and within B acute lymphoblastic leukemia/lymphoma CD123 expression was more prevalent in Philadelphia chromosome-positive patients than in Philadelphia chromosome-negative patients (96.6% versus 86.3%; P=0.033). In T acute lymphoblastic leukemia/lymphoma, 12/13 (92.3%) patients with CD123-positive blasts had either early T precursor (ETP) or early non-ETP immunophenotype. IMGN632 was highly cytotoxic to B acute lymphoblastic leukemia/lymphoma cell lines, with half maximal inhibitory concentrations (IC50) between 0.6 and 20 pM. In five of eight patients' samples, low picomolar concentrations of IMGN632 eliminated more than 90% of the B acute lymphoblastic leukemia/lymphoma blast population, sparing normal lymphocytes. In conclusion, CD123 expression is prevalent across acute lymphoblastic leukemia/lymphoma subtypes, and the CD123-targeted antibody-drug conjugate IMGN632 demonstrates promising selective activity in preclinical models of B acute lymphoblastic leukemia/lymphoma.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Sistemas de Liberação de Medicamentos , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Imunoconjugados/farmacologia , Subunidade alfa de Receptor de Interleucina-3 , Proteínas de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-3/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-3/biossíntese , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia
17.
Cancer Discov ; 9(3): 370-383, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30409776

RESUMO

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve (n = 25) and HMA-pretreated (n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4+ Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3+ bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Antígeno CTLA-4/metabolismo , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Terapia de Salvação , Resultado do Tratamento , Adulto Jovem
18.
Haematologica ; 104(2): 305-311, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30171025

RESUMO

Persistence of IDH1 or IDH2 mutations in remission bone marrow specimens of patients with acute myeloid leukemia has been observed, but the clinical impact of these mutations is not well known. In this study, we evaluated 80 acute myeloid leukemia patients with known IDH1 R132 or IDH2 R140/R172 mutations and assessed their bone marrow at the time of remission to determine the potential impact of persistent IDH1/2 mutations. Approximately 40% of acute myeloid leukemia patients given standard treatment in this cohort had persistent mutations in IDH1/2 Patients with an IDH1/2 mutation had an increased risk of relapse after 1 year of follow-up compared to patients without a detectable IDH1/2 mutation (59% versus 24%; P<0.01). However, a persistent mutation was not associated with a shorter time to relapse. High IDH1/2 mutation burden (mutant allelic frequency ≥10%) did not correlate with relapse rate (77% versus 86% for patients with a low burden, i.e., mutant allelic frequency <10%; P=0.66). Persistent mutations were also observed in NPM1, DNMT3A and FLT3 during remission, but IDH1/2 mutations remained significant in predicting relapse by multivariate analysis. Flow cytometry was comparable and complementary to next-generation sequencing-based assay for predicting relapse. Monitoring for persistent IDH1/2 mutations in patients with acute myeloid leukemia in remission can provide information that could be used to justify early interventions, with the hope of facilitating longer remissions and better outcomes in these patients.


Assuntos
Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Mutação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imunofenotipagem , Isocitrato Desidrogenase/metabolismo , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Tirosina Quinase 3 Semelhante a fms/genética
19.
Lancet Haematol ; 5(9): e411-e421, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30115541

RESUMO

BACKGROUND: Front-line therapy for elderly or unfit patients with acute myeloid leukaemia (AML) remains unsatisfactory with poor outcomes and excessive toxicity. We studied a new low-intensity regimen of cladribine combined with low-dose cytarabine alternating with decitabine, aimed at improving outcomes in this population. Based on our previous experience, we hypothesised that this combination would be safe and more effective than current approaches with hypomethylating agents. METHODS: In this single-arm, open-label, single-centre phase 2 study, we enrolled patients aged 60 years or older with previously untreated AML or high-risk myelodysplastic syndrome who had adequate organ function and an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were treated with cladribine plus low-dose cytarabine for two 28-day cycles alternating with decitabine for two 28-day cycles, for up to 18 cycles. Induction therapy (cycle 1) consisted of cladribine 5 mg/m2 intravenously over 1-2 h on days 1-5 and cytarabine 20 mg subcutaneously twice daily on days 1-10. Patients who had remission during this induction regimen moved on to consolidation therapy (cladribine 5 mg/m2 intravenously over 1-2 h on days 1-3 and cytarabine 20 mg twice daily on days 1-10, alternating with decitabine 20 mg/m2 intravenously on days 1-5). The primary outcome measure was disease-free survival. Secondary outcomes were overall survival, proportion of patients achieving complete response, proportion of patients achieving response, toxicity, and induction mortality. All treated patients were included in the analyses. This trial is ongoing and is registered with ClinicalTrials.gov, number NCT01515527. FINDINGS: Between Feb 17, 2012, and July 6, 2017, 118 patients were enrolled and treated, among whom 48 (41%) had an adverse karyotype, 20 (17%) had therapy-related AML, 18 (15%) had treated secondary AML, and 20 (17%) had TP53 mutations. Median disease-free survival was 10·8 months (IQR 5·4-25·9). 80 (68%) patients achieved objective response: 69 (58%) achieved a complete response and 11 (9%) patients had complete response with incomplete count recovery. The median overall survival was 13·8 months (6·9-28·6). The regimen was well tolerated, with one (1%) death within the first 4 weeks and eight (7%) deaths within the first 8 weeks. The most common non-haematological adverse events of grade 3 or worse were infection (88 [75%] patients), elevated total bilirubin (26 [22%] patients), rash (13 [11%] patients), and nausea (13 [11%] patients). INTERPRETATION: The combination of cladribine and low-dose cytarabine alternating with decitabine appears to be a safe and highly effective regimen for the treatment of elderly or unfit patients with newly diagnosed AML. Further testing of this regimen is warranted, and could help to provide a new, effective option for reduced-intensity therapy in this population. FUNDING: Part supported by the National Institutes of Health.


Assuntos
Azacitidina/análogos & derivados , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/uso terapêutico , Decitabina , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida
20.
Ann Hematol ; 97(10): 1775-1783, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29872884

RESUMO

Chromosome translocation t(16;21)(q24;q22)/RUNX1-RUNX1T3 is an infrequent but recurrent chromosomal abnormality identified in myeloid neoplasms, with only 25 cases have been reported to date. Here, we report eight cases (six women and two men) of myeloid neoplasms associated with t(16;21)(q24;q22): five with therapy-related myeloid neoplasms, two with relapsed acute myeloid leukemia (AML), and one with blast phase of chronic myeloid leukemia. Morphologic and immunophenotypic features include granulocytic dysplasia, blasts with prominent perinuclear hof, large orange-pink granules, long and slim Auer rods, and aberrant expression of CD19. Six patients received AML-based regimens, and five achieved complete remission after initial induction therapy. Our study suggests that myeloid neoplasm with t(16;21)/RUNX1-RUNX1T1 resembles AML with t(8;21)(q22;q22)/RUNX1-RUNX1T1, in regard to morphology, immunophenotype, and response to therapy. Therefore, the clinical management of AML with t(8;21) may provide the best model for patients with myeloid neoplasms with t(16;21).


Assuntos
Cromossomos Humanos Par 16/genética , Cromossomos Humanos Par 21/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Proteínas Repressoras/genética , Translocação Genética , Proteínas Supressoras de Tumor/genética , Adulto , Idoso , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Mimetismo Molecular , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/patologia
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