Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce ...trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×10
/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.
Blinatumomab is a bispecific T-cell engager approved for B-cell precursor acute lymphoblastic leukemia (B-ALL) with persistent minimal residual disease (MRD) or in relapse. The prognostic impact of ...tumor load has been suggested before other immunotherapies but remains poorly explored before blinatumomab. We retrospectively analyzed the outcome of 73 patients who received blinatumomab either in first complete remission (CR) with MRD+ (N=35) or at relapse (N=38). Among MRD+ patients, 91% had a MRD >0.01% before blinatumomab, and 89% achieved a complete MRD response after blinatumomab. High preblinatumomab MRD levels were associated with shorter RFS (p=0.049) and OS (p=0.011). At 3 years, OS was 33%, 58% and 86% for pre-blinatumomab MRD >1%, between 0.1-1%, and.
Class I Human Leukocyte Antigen (HLA) evolutionary divergence (HED) is a metric which reflects immunopeptidome diversity and has been associated with immune checkpoint inhibitor responses in solid ...tumors. Its impact and interest in allogeneic hematopoietic stem cell transplantation (HCT) have not yet been thoroughly studied. This study analyzed the clinical and immune impact of class I and II HED in 492 acute myeloid leukemia (AML) recipients undergoing HCT. The overall cohort was divided into a training (n=338) and a testing (n=132) set. Univariate cox screening found a positive impact of a high class I HED and a negative impact of a high class II HED on both disease-free (DFS) and overall survival (OS). These results were combined in a unique marker, class I/class II HED ratio, and assessed in the testing cohort. The final multivariate cox model confirmed the positive impact of a high
low class I/class II HED ratio on both DFS (Hazard Ratio (HR) 0.41 95% CI 0.2-0.83; p=0.01) and OS (HR 0.34 0.19-0.59; p<0.001), independently of HLA matching and other HCT parameters. No significant association was found between the ratio and graft-versus-host disease (GvHD) nor with neutrophil and platelet recovery. A high class I HED was associated with a tendency for an increase in NK, CD8 T-cell, and B cell recovery at 12 months. These results introduce HED as an original and independent prognosis marker reflecting immunopeptidome diversity and alloreactivity after HCT.
Torque teno virus (TTV) has been proposed as a surrogate biomarker of T-cell function in allogeneic-haematopoietic-stem-cell transplantation (allo-HSCT). Conflicting data exists regarding the value ...of TTV to assess the degree of immunosuppression. The aim of the present study was to investigate the correlation between TTV viral load and immune function. Using samples from a prospective cohort composed of healthy-volunteers (HV) and allo-HSCT recipients at 6 months post-transplantation, we assessed the correlation between TTV viraemia and immune cell counts or T-cell proliferation capacity post-phytohaemagglutinin stimulation. TTV viraemia was detected in 68% of HV (
= 80) and 100% of allo-HSCT recipients (
= 41;
< 0.001); it was significantly higher in allo-HSCT recipients (3.9 vs. 2.1 Log copies/mL,
< 0.001). There was no correlation between T-cell function and CD3
T-cell count (rho: 0.002) suggesting that T-cell count can normalise without full functional recovery. Furthermore, no significant correlation was observed between TTV viraemia and absolute total/subset lymphocyte counts (rho: <0.13). The highest correlation was observed between TTV viral load and T-cell proliferation capacity (rho: -0.39). We therefore report an inverse correlation between T-cell function and TTV viraemia that is independent of T-cell count. Monitoring of TTV viraemia could be a fast suitable option to objectively assess the competence of immune function in at-risk populations.
T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors ...at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.
Although the outcome in younger adults with acute myeloid leukemia (AML) has improved, the benefit associated with standard intensive chemotherapy in older patients remains debatable. In this study, ...we investigated the incidence and the prognostic significance of genetic characteristics according to treatment intensity in patients aged 60 years or older. On the 495 patients of our cohort,
(25.2%),
(23.7%) and
(16.8%) were the most frequent molecular mutations found at diagnosis. In this elderly population, intensive chemotherapy seemed to be a suitable option in terms of early death and survival, except for normal karyotype (NK)
patients and those aged over 70 within the adverse cytogenetic/molecular risk group. The
mutation was systematically associated with an unfavorable outcome, independently of the ratio. NK
genotype tends to confer a good prognosis in patients treated intensively. Regarding minimal residual disease prognostic value, overall survival was significantly better for patients achieving a 4 log
reduction (median OS: 24.4 vs. 12.8 months,
= 0.013) but did not reach statistical significance for progression free survival. This retrospective study highlights that intensive chemotherapy may not be the most appropriate option for each elderly patient and that molecular markers may help treatment intensity decision-making.
Minimal residual disease (MRD) is now a powerful surrogate marker to assess the response to chemotherapy in acute myeloid leukemia (AML).
mutation has been associated with adverse outcomes. In this ...study, we aimed to investigate the impact of
status on NPM1 MRD predictive value for survival in a retrospective cohort of AML patients aged over 60 years old treated intensively. A total of 138 patients treated for
-mutated AML in two French institutions were analyzed retrospectively.
status did not influence the probability of having a ≥ 4log MRD1 reduction after induction. Only 20.4% of
patients reached ≥ 4log MRD1 reduction compared to 47.5% in
wt cases. A 4log reduction of
MRD was associated with a better outcome, even in
mutated patients, independent of the allelic ratio.
negative patients who reached a 4log reduction had a superior outcome to those who did not (HR = 0.23;
< 0.001). However, postinduction
MRD1 reduction was not predictive of OS and LFS in
mut patients. These results confirm that post-induction
MRD1 is a reliable tool to assess disease outcome in elderly AML patients. However, the presence of
also identifies a subgroup of patients at high risk of relapse.
Ninety-four adults with newly diagnosed or relapsed/refractory acute myeloid leukemia (AML) were treated with fractionated doses of gemtuzumab ozogamicin (GO) at one-single French center over ten ...years. We attempted to define predictive factors for response and survival. The overall response rate was 70% (86% in newly diagnosed and 65% in relapsed/refractory AML). Mortality during induction was 6%. Disease-free survival (DFS) and overall survival at three years after GO treatment was 36% and 31%, respectively. Median DFS in relapsed/refractory patients was eight months with a 3-year DFS at 34%. Among remitters, allogeneic hematopoietic stem cell transplantation (HSCT) can be performed in 28 cases (42%), including two patients in first-line therapy and 26 in further line. In relapsed/refractory patients undergoing allogeneic HSCT after responding to GO therapy, the median DFS was not reached. Incidences of transplant-related mortality, grade ≥ 3 acute graft-versus-host (GvH) disease, and extensive chronic GvH disease were 11%, 14%, and 25%, respectively. No sinusoidal obstruction syndromes were reported among allografted patients as among the other patients in the studied cohort. GO-based chemotherapy is a viable option for the treatment of relapsed/refractory AML patients and is a feasible schedule as a bridge to allogeneic transplant.
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