In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, ...lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR
were higher with nilotinib (300 mg twice daily BID, 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily QD, 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.
Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. ...However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56
subset than had relapsing patients, while CD56
natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56
natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors,
leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies.
.
Follicular lymphoma (FL) is an indolent non-Hodgkin’s lymphoma with heterogeneous outcomes. Progression or relapse of FL within 2 years (so-called POD24) after diagnosis is associated with a poor ...outcome for patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone) in clinical trials. POD24 needs further validation before it can be used as a relevant endpoint to assess treatment efficacy. In the present retrospective monocentric study, we investigated the predictive value of POD24 in a cohort of grade 1, 2, or 3a FL patients treated in our institution (Nantes Medical University, France) and registered in our local database. We investigated the nature of treatment lines, patients’ outcomes, and the prognostic value of POD24. Between 2007 and 2016, 317 patients were included. After first-line therapy, 60 patients relapsed within 2 years (POD24-pos cohort), and 254 patients did not relapse within 2 years (PO24-neg cohort). Thirty-three patients died, and 34 patients had an aggressive transformation. The median follow-up is 59.9 months (1.6–395.5). The median PFS is 59.9 months. Overall survival (OS) at 1 year, 3 years, and 5 years is 98.4% 97.0–99.8, 95.1% 92.6–97.6, and 92.5% 89.3–95.9, respectively. The 5-year OS was statistically lower for POD24-pos patients (82% 71.9–93.5) than for POD24-neg patients (93.3% 88.98–97.8) (
p
= 10
−5
). In multivariate analyses, transformation was predictive of OS, and PS (≥ 1) was predictive of POD24. POD24 is predictive of a worse OS and may be recommended as a relevant endpoint in clinical trials and in real life in particular for patients with advanced disease.
The influence of peripheral blood stem cell (PBSC) graft cell contents after transplant with post-transplant cyclophosphamide (PTCY) remains unclear. Here, we retrospectively report on a cohort of 77 ...adults who received a Baltimore-based reduced-intensity conditioning regimen either with fludarabine (
n
= 40) or clofarabine (
n
= 37) and PTCY. With a median follow-up of 29.2 months, 2-year overall (OS), disease-free (DFS), and GVHD/relapse-free survival (GRFS) rates were 62.8%, 51%, and 36.7%, respectively. The incidence of grades 2–4 acute GVHD was significantly higher in patients transplanted with a haplodonor (
n
= 56), at 57.1% vs 19% (
p
= 0.006). PBSC graft cell contents (CD45+, CD34+, and CD3+ cells) had no impact on any outcome. Considering immune reconstitution until 1 year, only monocytes were above the normal range (as early as day + 30) during the first year post-transplant. In multivariate analysis, an older donor (> 45 years) and a high/very high disease risk index were independently associated with lower OS. A higher monocyte count (> median) at day + 90 was also associated with better OS, DFS, and GRFS. Donor/recipient CMV status matching was independently associated with GRFS. In conclusion, our data support the fact that there is no need to manipulate the graft before infusion in the particular context of PBSC/PTCY Baltimore-based allotransplant.
Discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia is feasible in clinical practice based on recently published international recommendations. Nevertheless, ...factors predictive of molecular recurrence have not been fully elucidated and long-term follow-up of patients enrolled in clinical studies are required in order to update knowledge on discontinuation attempts particularly in terms of the safety and durability of treatment-free remission (TFR). In the current study, we updated results from the STIM2 study in the light of the consensual criterion of molecular recurrence reported in different international recommendations. Among the 199 patients included in the perprotocol study, 108 patients lost a major molecular response. With a median follow-up of 40.8 months (5.5-111 months), the probability of treatment-free remission was 43.4% 36.3-50.4 at 5 years, 40.9% 32.8-47.3 at 7 years and 34.5% 25.6- 43.3 at 9 years. Molecular recurrence occurred between 0 to 6 months, 6 to 24 months and after 24 months in 75 patients (69%), 15 patients (14%) and 18 patients (17%), respectively. Notably, the kinetics of molecular recurrence differed significantly between these three subgroups with a median time from loss of MR4 (BCR::ABL1 IS≤0.01%) to loss of major molecular response of 1, 7 and 22 months, respectively. Predictive factors of molecular recurrence differed according to the time of occurrence of the molecular recurrence. Durations of imatinib treatment and deep molecular response as well as BCR::ABL1/ABL1 levels at cessation of tyrosine kinase inhibitor treatment, as quantified by reverse transcriptase droplet digital polymerase chain reaction, are involved in molecular recurrence occurring up to 24 months but not beyond. (ClinicalTrial. gov Identifier NCT#0134373).
Next-generation sequencing (NGS) is used to investigate the presence
of somatic mutations. The utility of incorporating routine
sequencing to guide diagnosis and therapeutic decisions remains
...unclear. We report the findings of an observational, multicenter study that
aimed to assess the impact of somatic mutation testing by NGS in a reallife
setting of chronic myeloid malignancies. A total of 177 patients were
enrolled, partitioned into two overlapping groups. In group A (n=94), the
indication was to search for clonal hematopoiesis, in a context of suspected
myelodysplastic syndrome or myeloproliferative neoplasia. In group B
(n=95), the theranostic impact of somatic mutations was studied. A panel
of 34 genes was used on DNA extracted from blood or bone marrow samples.
Within group A, the detection of clonal hematopoiesis supported the
diagnosis of chronic myeloid malignancies for 31 patients while the
absence of clonal hematopoiesis ruled out the suspected diagnosis in 47
patients. Within group B, NGS identified prognostically relevant somatic
mutations in 32 patients, which had a therapeutic impact in 18 cases. By
determining the presence or absence of somatic mutations, the application
of NGS in daily practice was found to be useful for an integrated final
diagnosis in 83% of the patients. Moreover, the search for somatic mutations
had a prognostic impact that led to treatment modification in 19%
of the cases. This study outlines the fact that adequate implementation of
new investigations may have a significant positive medico-economic
impact by enabling appropriate management of patients.
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