Background
Blinatumomab is a CD19 BiTE (bispecific T‐cell engager) immuno‐oncology therapy that mediates the lysis of cells expressing CD19.
Methods
A pooled analysis of long‐term follow‐up data from ...2 phase 2 studies that evaluated blinatumomab in heavily pretreated adults with Philadelphia chromosome–negative, relapsed/refractory B‐cell precursor acute lymphoblastic leukemia was conducted.
Results
A total of 259 patients were included in the analysis. The median overall survival (OS) among all patients, regardless of response, was 7.5 months (95% confidence interval CI, 5.5‐8.5 months); the median follow‐up time for OS was 36.0 months (range, 0.3‐60.8 months). The median relapse‐free survival (RFS) among patients who achieved a complete remission (CR) or complete remission with partial hematologic recovery (CRh) in the first 2 cycles (n = 123) was 7.7 months (95% CI, 6.2‐10.0 months); the median follow‐up time for RFS was 35.0 months (range, 9.5‐59.5 months). OS and RFS plateaued with 3‐year rates of 17.7% and 23.4%, respectively. The cumulative incidence function of the time to relapse, with death not due to relapse considered a competing risk, for patients who achieved a CR/CRh within 2 cycles of treatment also plateaued with a 3‐year relapse rate of 59.3%. For patients who achieved a CR/CRh with blinatumomab followed by allogeneic hematopoietic stem cell transplantation while in continuous CR, the median OS was 18.1 months (95% CI, 10.3‐30.0 months) with a 3‐year survival rate of 37.2%.
Conclusions
These data suggest that long‐term survival is possible after blinatumomab therapy.
Lay Summary
Immuno‐oncology therapies such as blinatumomab activate the patient's own immune system to kill cancer cells.
This study combined follow‐up data from 2 blinatumomab‐related clinical trials to evaluate long‐term survival in patients with relapsed and/or refractory B‐cell precursor acute lymphoblastic leukemia at high risk for unfavorable outcomes.
Among patients who achieved a deep response with blinatumomab, one‐third lived 3 years or longer. These findings suggest that long‐term survival is possible after treatment with blinatumomab.
Patients achieving remission after blinatumomab can have a durable response. The survival plateau indicates a high probability of a cure in those patients responding to blinatumomab and alive after 3 years.
Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse ...transcriptase–polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10−3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.
•Among adults with MRD-positive ALL in hematologic remission after chemotherapy, 78% achieved a complete MRD response with blinatumomab.•Complete MRD response after blinatumomab treatment in this population was associated with significantly improved OS.
Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present ...retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosome– and BCR-ABL–negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n = 224) was 42%. After failure of first salvage (n = 82), the CR rate after second salvage was 33%. In relapse after SCT (n = 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT, and age. Overall survival appeared superior compared with previously published studies, likely because of the high rate of SCT in the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. The study is registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991.
Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational ...bispecific T cell-engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort.
Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs).
Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically.
The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.
The bispecific T-cell engager blinatumomab targeting CD19 can induce complete remission in relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, some patients ...ultimately relapse with loss of CD19 antigen on leukemic cells, which has been established as a novel mechanism to escape CD19-specific immunotherapies. Here, we provide evidence that CD19-negative (CD19–) relapse after CD19-directed therapy in BCP-ALL may be a result of the selection of preexisting CD19– malignant progenitor cells. We present 2 BCR-ABL1 fusion–positive BCP-ALL patients with CD19– myeloid lineage relapse after blinatumomab therapy and show BCR-ABL1 positivity in their hematopoietic stem cell (HSC)/progenitor/myeloid compartments at initial diagnosis by fluorescence in situ hybridization after cell sorting. By using the same approach with 25 additional diagnostic samples from patients with BCR-ABL1–positive BCP-ALL, we identified HSC involvement in 40% of the patients. Patients (6 of 8) with major BCR-ABL1 transcript encoding P210BCR-ABL1 mainly showed HSC involvement, whereas in most of the patients (9 of 12) with minor BCR-ABL1 transcript encoding P190BCR-ABL1, only the CD19+ leukemia compartments were BCR-ABL1 positive (P = .02). Our data are of clinical importance, because they indicate that both CD19+ cells and CD19– precursors should be targeted to avoid CD19– relapses in patients with BCR-ABL1–positive ALL.
•BCR-ABL1–positive cells outside the B-lineage compartment are found in 40% of adult patients with BCR-ABL1–positive BCP-ALL.•Selection of preexisting CD19– subclones is a potential source of tumor escape after CD19-targeted therapies in adult Philadelphia chromosome–positive ALL.
Background.Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, ...but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking. Methods.In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated. Results.Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P > .05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P > .05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group. Conclusions.In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine ...whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval CI, 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio HR, 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.
•Midostaurin plus intensive chemotherapy can be safely administered in older FLT3-ITD-positive patients with AML.•Compared with historical controls, midostaurin significantly improved event-free survival in older and younger FLT3-ITD positive patients with AML.
The tet oncogene family member 2 (TET2) gene was recently identified to be mutated in myeloid disorders including acute myeloid leukemia (AML). To date, there is increasing evidence for a functional ...role of TET2 mutations (TET2(mut)) in AML. Thus, we explored the frequency, gene-expression pattern, and clinical impact of TET2(mut) in a large cohort of patients with AML in the context of other AML-associated aberrations.
Samples from 783 younger adult patients with AML were analyzed for the presence of TET2(mut) (coding exons 3 to 11), and results were correlated with data from molecular genetic analyses, gene-expression profiling, and clinical outcome.
In total, 66 TET2(mut) were found in 60 patients (60 of 783 patients; 7.6%), including missense (n = 37), frameshift (n = 16), and nonsense (n = 13) mutations, which, with one exception, were all heterozygous. TET2(mut) were not correlated with distinct clinical features or genetic alterations, except for isocitrate dehydrogenase mutations (IDH(mut)) that were almost mutually exclusive with TET2(mut) (P < .001). TET2(mut) were characterized by only a weak gene-expression pattern, which, nevertheless, reflected TET2(mut)-associated biology. TET2(mut) did not impact the response to induction therapy and clinical outcome; the combination of patients who exhibited TET2(mut) and/or IDH(mut) revealed shorter overall survival (P = .03), although this association was not independent from known risk factors.
TET2(mut) were identified in 7.6% of younger adult patients with AML and did not impact the response to therapy and survival. Mutations were mutually exclusive with IDH(mut), which supported recent data on a common mechanism of action that might obscure the impact of TET2(mut) if compared against all other patients with AML.
In people living with HIV (PLWH), a decade-long antiretroviral therapy (ART) poses new challenges regarding physical and mental health. The aim of this cross-sectional study is to investigate the ...health-related quality of life (HRQOL) in adult HIV-infected patients with viral suppression and an ART exposure for at least 5 years in three German HIV centers. Patients were evaluated by the ACTG Augmented Symptoms Distress Module (ASDM) and the SF-12 Health Survey. Among 894 patients, symptom-related distress was highly prevalent. The most common symptoms were fatigue, insomnia, sadness and depression, sexual dysfunction, and changes in body appearance. In the multivariate analysis, ART duration, age and depression were significantly associated with a higher overall symptom summary score. Self-reported mean SF-12 scores were lower for mental health and younger patients compared to the standard random sample of a healthy German population. Depression and occupational status were significantly related to a lower physical component summary score, by contrast older age was associated with higher scores in the mental component summary, implying more favorable mental health status. In this large group of PLWH, the degree of symptom-related distress was high. Mental and physical health should be considered an integral part of ongoing HIV care.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
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