RESUMO
INTRODUCTION: Allogeneic Hematopoietic cell transplantation (allo-HCT) remains the only curative therapy for myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). The impact of spliceosome mutations on allo-HCT outcome is unclear and further understanding is needed to assess the implications of this class of mutations on risk of relapse, overall survival (OS) and non-relapse mortality (NRM) in order to make decision regarding timing of allo-HCT. We examined the allo-HCT outcomes of MDS/CMML patients based on their spliceosome mutation profile to understand the impact of these mutations on transplant outcomes. OBJECTIVE: To compare outcomes of MDS/CMML patients with and without spliceosome mutations undergoing allo-HCT. METHODS: This is a single institution, retrospective study of MDS/CMML patients who underwent allo-HCT with myeloablative or reduced intensity conditioning (RIC) regimen at City of Hope from January 2016 to December 2021. Among them, patients who underwent molecular mutation profiling by NGS (Next Generation Sequencing) for a set of genes known to be mutated in myeloid neoplasms are included in this analysis. We compared OS, relapse free survival, NRM and acute/chronic graft versus host disease (GVHD) incidence between the spliceosome-mutated and unmutated groups. RESULTS: We identified 258 consecutive MDS/CMML patients who underwent allo-HCT. Of these, 126 (48.8â¯%) patients had molecular profiling done among whom 57 (45.2â¯%) patients carried a spliceosome mutation. 84.9â¯% of patients had MDS and 55.6â¯% underwent a matched unrelated donor transplant. The median age for the whole cohort was 66 years (range 12-77).78.6â¯% and 73.7â¯% received RIC in the spliceosome and non-spliceosome groups, respectively. The 2-year OS for the whole cohort was 66.5â¯% (95â¯%CI 0.55-0.75) with a day 100 NRM of 7.1â¯% and 2-year cumulative incidence of relapse of 20â¯%. Grade II-IV acute GVHD at day 100 was 36.3â¯% (95â¯% CI 0.27-0.44) and any chronic GVHD at 2-years was 48.4â¯% (95â¯% CI 0.37-0.58). Patients who carried a spliceosome mutation had a significantly better 2-year survival of 83.8â¯% vs 55.9â¯% in the non-spliceosome group (P=0.002) and a better PFS of 73.7â¯% vs 50.0â¯% (P=0.007). There was no difference in the cumulative incidence of relapse at 2-years 15.9â¯% vs 18.5â¯% (P=0.59) between two groups but the spliceosome group had a significantly lower NRM at 2-years 10.4â¯% vs 31.5â¯% (P=0.009). There was no difference in incidence of acute or chronic GVHD between the two groups. CONCLUSIONS: Among patients with MDS or CMML who underwent allo-HCT, our study shows better OS for patients who have spliceosome mutations due to lower NRM compared to those carrying non- spliceosome mutations. This favorable outcome of the spliceosome-mutated patients could have implications for timing of allo-HCT, particularly for patients in the intermediate MDS prognostic risk groups.
RESUMO
Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative treatment for most patients with hematologic malignancies. A well-matched donor (related or unrelated) remains the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we investigated outcomes of patients who underwent mismatched donor (related or unrelated) HCT with a radiation-based myeloablative conditioning MAC regimen in combination with fludarabine, and post-transplantation cyclophosphamide (PTCy) as higher-intensity graft-versus-host disease (GVHD) prophylaxis. We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT (related/haploidentical versus unrelated [MMUD]) with fractionated-total body irradiation (fTBI) plus fludarabine and PTCy as GVHD prophylaxis at City of Hope from 2015 to 2021. Diagnoses included acute lymphoblastic leukemia (46.5%), acute myelogenous leukemia (36.1%), and myelodysplastic syndrome (6.5%). The median age at HCT was 38 years, and 126 patients (81.3%) were an ethnic minority. The Hematopoietic Stem Cell Transplantation Comorbidity Index was ≥3 in 36.1% of the patients, and 29% had a Disease Risk Index (DRI) of high/very high. The donor type was haploidentical in 67.1% of cases and MMUD in 32.9%. At 2 years post-HCT, disease-free survival (DFS) was 75.4% and overall survival (OS) was 80.6% for all subjects. Donor type did not impact OS (hazard ratio [HR], .72; 95% confidence interval [CI], .35 to 1.49; P = .37) and DFS (HR, .78; 95% CI, .41 to 1.48; P = .44), but younger donors was associated with less grade III-IV acute GVHD (HR, 6.60; 95% CI, 1.80 to 24.19; P = .004) and less moderate or severe chronic GVHD (HR, 3.53; 95% CI, 1.70 to 7.34; P < .001), with a trend toward better survival (P = .099). The use of an MMUD was associated with significantly faster neutrophil recovery (median, 15 days versus 16 days; P = .014) and platelet recovery (median, 18 days versus 24 days; P = .029); however, there was no difference in GVHD outcomes between the haploidentical donor and MMUD groups. Nonrelapse mortality (HR, .86; 95% CI, .34 to 2.20; P = .76) and relapse risk (HR, .78; 95% CI, .33 to 1.85; P = .57) were comparable in the 2 groups. Patient age <40 years and low-intermediate DRI showed a DFS benefit (P = .004 and .029, respectively). High or very high DRI was the only predictor of increased relapse (HR, 2.89; 95% CI, 1.32 to 6.34; P = .008). In conclusion, fludarabine/fTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of donor relationship to the patient, provided promising results, and increased access to HCT for patients without a matched donor, especially patients from ethnic minorities and patients of mixed race.
RESUMO
The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes.
RESUMO
Outcomes for adults with relapsed/refractory (R/R) high-grade myeloid neoplasms remain poor, with allogeneic hematopoietic cell transplantation (HCT) the sole therapy likely to result in cure. We conducted the present study to determine the feasibility of early HCT-within 60 days of beginning reinduction chemotherapy-to see whether getting patients to HCT in an expeditious manner would expand the number of patients being offered this curative option. In this proof-of-principle feasibility study, we included adults age 18 to 75 years with R/R myeloid malignancies with ≥10% blood/marrow blasts at diagnosis who were eligible for a reduced-intensity HCT. Subjects received reinduction chemotherapy with cladribine, cytarabine, mitoxantrone, and filgrastim (CLAG-M) and proceeded to HCT with reduced-intensity conditioning (fludarabine/ melphalan). We enrolled 30 subjects, all of whom received CLAG-M reinduction, although only 9 underwent HCT within 60 days (<15, the predetermined threshold for feasibility "success"), with a median time to HCT of 48 days (range, 42 to 60 days). Eleven additional subjects received HCT beyond the target 60 days (off-study), with a median time to transplantation of 83 days (range, 53 to 367 days). Barriers to early HCT included infection, physician preference, lack of an HLA-matched donor, logistical delays, and disease progression, all of which may limit the real-world uptake of such early-to-transplantation protocols.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/métodos , Pessoa de Meia-Idade , Masculino , Adulto , Feminino , Idoso , Condicionamento Pré-Transplante/métodos , Citarabina/uso terapêutico , Citarabina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos de Viabilidade , Adulto Jovem , Cladribina/uso terapêutico , Cladribina/administração & dosagem , Mitoxantrona/uso terapêutico , Mitoxantrona/administração & dosagem , Recidiva , AdolescenteAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mutação , Indução de Remissão , Estaurosporina , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Tirosina Quinase 3 Semelhante a fms/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Transplante Homólogo , Resultado do TratamentoRESUMO
Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis-whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual subpopulations-including avapritinib, larotrectinib, and ruxolitinib-produced only modest tumor growth reduction in orthotopic models, systemic co-administration induced significant survival extension, making this approach a valuable contribution to the rational design of combination therapy.
RESUMO
Background: Individualized treatment decisions for patients with multiple myeloma (MM) requires accurate risk stratification that takes into account patient-specific consequences of genetic abnormalities and tumor microenvironment on disease outcome and therapy responsiveness. Methods: Previously, SYstems Genetic Network AnaLysis (SYGNAL) of multi-omics tumor profiles from 881 MM patients generated the mmSYGNAL network, which uncovered different causal and mechanistic drivers of genetic programs associated with disease progression across MM subtypes. Here, we have trained a machine learning (ML) algorithm on activities of mmSYGNAL programs within individual patient tumor samples to develop a risk classification scheme for MM that significantly outperformed cytogenetics, International Staging System, and multi-gene biomarker panels in predicting risk of PFS across four independent patient cohorts. Results: We demonstrate that, unlike other tests, mmSYGNAL can accurately predict disease progression risk at primary diagnosis, pre- and post-transplant and even after multiple relapses, making it useful for individualized dynamic risk assessment throughout the disease trajectory. Conclusion: mmSYGNAL provides improved individualized risk stratification that accounts for a patient's distinct set of genetic abnormalities and can monitor risk longitudinally as each patient's disease characteristics change.
RESUMO
PURPOSE: The inherent genetic heterogeneity of acute myeloid leukemia (AML) has challenged the development of precise and effective therapies. The objective of this study was to elucidate the genomic basis of drug resistance or sensitivity, identify signatures for drug response prediction, and provide resources to the research community. EXPERIMENTAL DESIGN: We performed targeted sequencing, high-throughput drug screening, and single-cell genomic profiling on leukemia cell samples derived from patients with AML. Statistical approaches and machine learning models were applied to identify signatures for drug response prediction. We also integrated large public datasets to understand the co-occurring mutation patterns and further investigated the mutation profiles in the single cells. The features revealed in the co-occurring or mutual exclusivity pattern were further subjected to machine learning models. RESULTS: We detected genetic signatures associated with sensitivity or resistance to specific agents, and identified five co-occurring mutation groups. The application of single-cell genomic sequencing unveiled the co-occurrence of variants at the individual cell level, highlighting the presence of distinct subclones within patients with AML. Using the mutation pattern for drug response prediction demonstrates high accuracy in predicting sensitivity to some drug classes, such as MEK inhibitors for RAS-mutated leukemia. CONCLUSIONS: Our study highlights the importance of considering the gene mutation patterns for the prediction of drug response in AML. It provides a framework for categorizing patients with AML by mutations that enable drug sensitivity prediction.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Leucemia Mieloide Aguda , Mutação , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Análise de Célula Única/métodos , Aprendizado de Máquina , Sequenciamento de Nucleotídeos em Larga Escala , MasculinoRESUMO
E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewisx) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials.
Assuntos
Neoplasias Hematológicas , Leucemia Mieloide Aguda , Humanos , Medula Óssea/patologia , Selectina E/antagonistas & inibidores , Selectina E/metabolismo , Células Endoteliais/metabolismo , Neoplasias Hematológicas/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologiaRESUMO
SUMMARY: High-throughput screens (HTS) have been utilized to assess the efficacy of single drugs against patient tumor samples with the purpose of optimizing precision therapy, but testing the synergy of drug combinations can identify the ideal second drug to add. With novel sophisticated HTS, effective venetoclax combinations can be revealed that provide the cell state, phenotype, and molecular features of the susceptible and resistant cell populations. See related article by Eide, Kurtz et al., p. 452 (14) .
Assuntos
Leucemia Mieloide Aguda , Humanos , Avaliação Pré-Clínica de Medicamentos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
OBJECTIVES: We recently performed a single-arm phase II trial of DA-EPOCH in adults with acute lymphoblastic leukemia (ALL). We sought to compare these results to those with standard Hyper-CVAD. METHODS: We created a retrospective matched cohort of patients who received Hyper-CVAD (n = 69) at our center and otherwise met eligibility criteria for the DA-EPOCH trial (n = 53). RESULTS: Our outcomes support the use of Hyper-CVAD over DA-EPOCH in Ph- disease for both overall survival (OS; HR 0.18, p = .004) and event-free survival (EFS; HR 0.51, p = .06). In contrast, outcomes were similar in Ph+ disease (OS HR 0.97, p = .96; EFS HR 0.65, p = .21). Rates of morphologic remission and measurable residual-disease negativity were similar between the regimens. Hyper-CVAD was associated with significantly more febrile neutropenia (OR 1.9, p = .03) and a greater incidence of Grade 4 or 5 adverse events (20% vs. 6%). Average transfusions per cycle of both red blood cells (p < .001) and platelets (p < .001) were five-fold higher with Hyper-CVAD. CONCLUSIONS: Our findings support continued use of Hyper-CVAD for Ph- ALL but suggest that DA-EPOCH may be a reasonable alternative for Ph+ ALL. These data also highlight a potential role for DA-EPOCH in resource-limited settings or when more intense therapy is not feasible.
Assuntos
Doxorrubicina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudos Retrospectivos , Doxorrubicina/uso terapêutico , Ciclofosfamida/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Vincristina/uso terapêutico , DexametasonaRESUMO
PLK1 is overexpressed in acute myeloid leukemia (AML). A phase 1b trial of the PLK1 inhibitor onvansertib (ONV) combined with decitabine (DAC) demonstrated initial safety and efficacy in patients with relapsed/refractory (R/R) AML. The current study aimed to identify molecular predictors of response to ONV + DAC in R/R AML patients. A total of 44 R/R AML patients were treated with ONV + DAC and considered evaluable for efficacy. Bone marrow (BM) samples were collected at baseline for genomic and transcriptomic analysis (n = 32). A 10-gene expression signature, predictive of response to ONV + DAC, was derived from the leading-edge genes of gene set enrichment analyses (GSEA). The gene signature was evaluated in independent datasets and used to identify associated mutated genes. Twenty percent of the patients achieved complete remission, with or without hematologic count recovery (CR/CRi), and 32% exhibited a ≥50% reduction in bone marrow blasts. Patients who responded to treatment had elevated mitochondrial function and OXPHOS. The gene signature was not associated with response to DAC alone in an independent dataset. By applying the signature to the BeatAML cohort (n = 399), we identified a positive association between predicted ONV + DAC response and mutations in splicing factors (SF). In the phase 1b/2 trial, patients with SF mutations (SRSF2, SF3B1) had a higher CR/CRi rate (50%) compared to those without SF mutations (9%). PLK1 inhibition with ONV in combination with DAC could be a potential therapy in R/R AML patients, particularly those with high OXPHOS gene expression and SF mutations.
Assuntos
Leucemia Mieloide Aguda , Piperazinas , Pirazóis , Quinazolinas , Spliceossomos , Humanos , Decitabina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Protocolos de Quimioterapia Combinada AntineoplásicaRESUMO
Posttransplant lymphoproliferative disease (PTLD) is a potentially life-threatening complication of hematopoietic cell transplantation. With improvements in Epstein-Barr virus (EBV) monitoring and supportive care, PTLD incidence has decreased throughout the history of bone marrow transplantation. It is rare to develop PTLD after the first year following transplant, across all donor categories. In this case, we hope to elucidate details that may have predisposed to this unusual presentation. We present the case of a 55-year-old gentleman with acute myeloid leukemia who underwent a haploidentical transplant for consolidation and presented with fatigue, lethargy and presumed septic shock nearly 7 years after transplant.
RESUMO
We conducted a retrospective analysis of WT1-mutated acute myeloid leukemia (AML) patients who underwent allogeneic stem cell transplant. Thirty-seven patients with WT1-mutated AML were identified. Primary induction failure (40%) and early relapse rate (18%) after idarubicin/cytarabine (7 + 3) chemotherapy were observed. All patients with induction failure subsequently achieved CR with additional chemotherapy. There was no significant difference between outcomes after myeloablative vs. reduced intensity (Fludarabine/Melphalan [Flu/Mel]) conditioning regimens. RFS but not OS was significantly better in patients who received FLAG-IDA prior to transplant and/or a fludarabine-containing conditioning. In an independent ex vivo study, WT1-mutated AML samples exhibited greater sensitivity to fludarabine (p = 0.026) and melphalan (p = 0.0005) than non-WT1-mutated AML samples while there was no difference between sensitivity to cytarabine. Our data favor using a fludarabine-based induction for AML with WT1 mutation instead of 7 + 3. Fludarabine conditioning regimens for alloHCT showed better RFS but not OS.
Assuntos
Leucemia Mieloide Aguda , Melfalan , Humanos , Melfalan/uso terapêutico , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Idarubicina/uso terapêutico , Citarabina/uso terapêutico , Proteínas WT1/genéticaRESUMO
The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.
Assuntos
Leucemia Mieloide Aguda , Mitoxantrona , Adulto , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos , Leucemia Mieloide Aguda/diagnóstico , Mitoxantrona/uso terapêutico , Sorafenibe/uso terapêutico , Pessoa de Meia-IdadeRESUMO
Cytokine release syndrome (CRS) is a common complication after haploidentical hematopoietic cell transplantation (HaploHCT). Severe CRS after haploHCT leads to higher risk of non-relapse mortality (NRM) and worse overall survival (OS). Tocilizumab (TOCI) is an interleukin-6 receptor inhibitor and is commonly used as first-line for CRS management after chimeric antigen receptor T cell therapy, but the impact of TOCI administration for CRS management on Haplo HCT outcomes is not known. In this single center retrospective analysis, we compared HCT outcomes in patients treated with or without TOCI for CRS management after HaploHCT with post-transplantation cyclophosphamide- (PTCy-) based graft-versus-host disease (GvHD) prophylaxis. Of the 115 patients eligible patients who underwent HaploHCT at City of Hope between 2019 to 2021 and developed CRS, we identified 11 patients who received tocilizumab for CRS management (TOCI). These patients were matched with 21 patients who developed CRS but did not receive tocilizumab (NO-TOCI) based on age at the time of HCT (≤64 years or >65 years or older), conditioning intensity (myeloablative versus reduced-intensity/nonmyeloablative), and CRS grading (1, 2, versus 3-4). Instead of 22 controls, we chose 21 patients because there was only 1 control matched with 1 TOCI treatment patient in 1 stratum. With only 11 patients in receiving tocilizumab for CRS treatment, matching with 21 patients who developed CRS but did not receive tocilizumab, we had 80% power to detect big differences (hazard ratio [HR] = 3.4 or higher) in transplantation outcomes using a 2-sided 0.05 test. The power would be reduced to about 20% to 30% if the difference was moderate (HR = 2.0) using the same test. No CRS-related deaths were recorded in either group. Median time to neutrophil engraftment was 21 days (range 16-43) in TOCI and 18 days (range 14-23) in NO-TOCI group (HR = 0.55; 95% confidence interval [CI] = 0.28-1.06, P = .08). Median time to platelet engraftment was 34 days (range 20-81) in TOCI and 28 days (range 12-94) in NO-TOCI group (HR = 0.56; 95% CI = 0.25-1.22, P = .19). Cumulative incidences of day 100 acute GvHD grades II-IV (P = .97) and grades III-IV (P = .47) were similar between the 2 groups. However, cumulative incidence of chronic GvHD at 1 year was significantly higher in patients receiving TOCI (64% versus 24%; P = .05). Rates of NRM (P = .66), relapse (P = .83), disease-free survival (P = .86), and overall survival (P = .73) were similar at 1 year after HCT between the 2 groups. Tocilizumab administration for CRS management after HaploHCT appears to be safe with no short-term adverse effect and no effect on relapse rate. However, the significantly higher cumulative incidence of chronic GvHD, negates the high efficacy of PTCy on GvHD prophylaxis in this patient population. Therefore using tocilizumab for CRS management in the HaploHCT population with PTCy maybe kept only for patients with severe CRS. The impact on such approach on long term outcome in HaploHCT with PTCy will need to be evaluated in a larger retrospective study or a prospective manner.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Pessoa de Meia-Idade , Ciclofosfamida/uso terapêutico , Ciclofosfamida/farmacologia , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/tratamento farmacológico , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Estudos Prospectivos , Estudos Retrospectivos , Condicionamento Pré-Transplante/efeitos adversos , IdosoRESUMO
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is associated with a poor response to standard chemotherapy. However, outcomes with novel antibody and cellular therapies in relapsed/refractory (r/r) Ph-like ALL are largely unknown. We conducted a single-center retrospective analysis of adult patients (n = 96) with r/r B-ALL and fusions associated with Ph-like who received novel salvage therapies. Patients were treated with 149 individual novel regimens (blinatumomab = 83, inotuzumab ozogamicin [InO] = 36, and CD19CAR T cells = 30). The median age at first novel salvage therapy was 36 years (range; 18-71). Ph-like fusions were IGH::CRLF2 (n = 48), P2RY8::CRLF2 (n = 26), JAK2 (n = 9), ABL-class (n = 8), EPOR::IGH (n = 4) and ETV6::NTRK2 (n = 1). CD19CAR T cells were administered later in the course of therapy compared to blinatumomab and InO (p < .001) and more frequently in recipients who relapsed after allogeneic hematopoietic cell transplantation (alloHCT) (p = .002). Blinatumomab was administered at an older age compared to InO and CAR T-cells (p = .004). The complete remission (CR)/CR with incomplete hematologic recovery (CRi) rates were 63%, 72%, and 90% following blinatumomab, InO and CD19CAR, respectively, among which 50%, 50%, and 44% of responders underwent consolidation with alloHCT, respectively. In multivariable analysis, the type of novel therapy (p = .044) and pretreatment marrow blasts (p = .006) predicted the CR/CRi rate, while the Ph-like fusion subtype (p = .016), pretreatment marrow blasts (p = .022) and post-response consolidation with alloHCT (p < .001) influenced event-free survival. In conclusion, novel therapies are effective in inducing high remission rates in patients with r/r Ph-like ALL and successfully transitioning the responders to alloHCT.
Assuntos
Anticorpos Biespecíficos , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Estudos Retrospectivos , Inotuzumab Ozogamicina/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Indução de Remissão , Anticorpos Biespecíficos/uso terapêuticoRESUMO
Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.
Assuntos
Doxorrubicina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Humanos , Vincristina/efeitos adversos , Prednisona/efeitos adversos , Etoposídeo/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Rituximab/efeitos adversosRESUMO
Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication that can be observed after allogeneic hematopoietic cell transplantation (HCT). Inotuzumab ozogamicin is an anti-CD22 monoclonal antibody-drug conjugate that has demonstrated high efficacy in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) but is associated with an increased risk of SOS in HCT recipients. Here we aimed to examine the incidence and outcomes of SOS in 47 adult patients with R/R ALL who received inotuzumab therapy and subsequently underwent HCT at our institution. All patients received prophylactic therapy with ursodiol, and continuous low-dose heparin also was administered to patients receiving myeloablative conditioning (MAC). SOS occurred in 12 patients (26%) post-HCT, at a median onset of 11 days (range, 3 to 41 days). SOS was graded as very severe in 50% (n = 6), severe in 25% (n = 3), and mild in 25% (n = 3). All patients diagnosed with SOS received treatment with defibrotide for a median of 21 days (range, 3 to 34 days), with resolution of SOS occurring in 8 patients (67%). Mortality from SOS was 33% (n = 4) and occurred at a median of 10 days from diagnosis (range, 3 to 31 days) in patients graded as very severe (n = 3) or severe (n = 1). There were no significant differences between patients who developed SOS and those who did not develop SOS in the median time from the last dose of inotuzumab to transplantation (46 days versus 53 days; P = .37), use of an MAC regimen (42% versus 49%; P = .75), number of lines of therapy prior to inotuzumab (P = .79), median number of administered cycles of inotuzumab (2 versus 2; P = .14), or receipt of inotuzumab as the last therapy prior to HCT (67% versus 66%; P = 1.0). Sirolimus-based graft-versus-host disease (GVHD) prophylaxis was used more frequently in the SOS group (75% versus 29%; P < .01), but there was no between-group difference in the peak sirolimus level (P = .81) or the median time to peak sirolimus level (7 days versus 3.5 days; P = .39). In univariable analysis, only the use of sirolimus-based GVHD prophylaxis was significantly associated with an increased risk of SOS (hazard ratio [HR], 7.50; 95% confidence interval [CI], 1.7 to 33.6; P < .01). In the SOS group, the 100-day mortality rate was 33% (n = 4), and median overall survival (OS) post-HCT was 4.3 months (range, 0.2 to 57.2 months). In the group without SOS, the 100-day mortality rate was 14% (n = 5) and the median OS post-HCT was 10.7 months (range, .52 to 39.6 months). In this study cohort, SOS was prevalent in HCT recipients who had been treated with inotuzumab prior to transplantation, and sirolimus-based GVHD prophylaxis was a risk factor for SOS in inotuzumab recipients.