STOP second generation (2G)–tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving ...first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval CI, 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.
•First-line or subsequent dasatinib or nilotinib can be safely stopped in CML patients with deep and long-lasting molecular responses.•A suboptimal response or resistance prior to dasatinib or nilotinib is associated with significantly worse treatment-free remission.
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.
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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).
Background. Muscle depletion (MD) assessed by computed tomography (CT) has been shown to be a predictive marker in solid tumors, but has not been assessed in non-Hodgkin’s lymphomas. Despite software ...improvements, MD measurement remains highly time-consuming and cannot be used in clinical practice. Methods. This study reports the development of a Deep-Learning automatic segmentation algorithm (DLASA) to measure MD, and investigate its predictive value in a cohort of 656 diffuse large B cell lymphoma (DLBCL) patients included in the GAINED phase III prospective trial (NCT01659099). Results. After training on a series of 190 patients, the DLASA achieved a Dice coefficient of 0.97 ± 0.03. In the cohort, the median skeletal muscle index was 50.2 cm2/m2 and median muscle attenuation (MA) was 36.1 Hounsfield units (HU). No impact of sarcopenia was found on either progression free survival (PFS) or overall survival (OS). Muscular hypodensity, defined as MA below the tenth percentile according to sex, was associated with a lower OS and PFS, respectively (HR = 2.80 (95% CI 1.58–4.95), p < 0.001, and HR = 2.22 (95% CI 1.43–3.45), p < 0.001). Muscular hypodensity appears to be an independent risk factor for mortality in DLBCL and because of DLASA can be estimated in routine practice.
Background
Intravascular large B‐cell lymphoma (lVLBCL) is a very rare type of large B‐cell lymphoma.
Methods
We conducted a retrospective study on IVLBCL patients treated from 2000 to 2016 in LYSA ...cooperative group centers.
Results
Sixty‐five patients were identified in 23 centers. Median age at diagnosis was 69 years (range 23–92). Thirty‐four patients (64%) had an IPI score >3 and 40 patients (67%) had a performance status ≥2. The most frequent extra‐nodal locations were bone marrow (n = 34; 52%), central nervous system (n = 25; 39%), and skin (n = 21; 33%). Nodal involvement and endocrine system were observed in 34% (n = 22) and 18% (n = 12) of all cases, respectively. Twenty‐six patients (41%) had macrophage activation syndrome. Tumor cells were frequently CD5 positive (52%) with a non‐germinal center origin (86%). BCL2 was expressed in 87% of all samples analyzed (n = 20) and 43% of patients had a MYC/BCL2 double expression. Fifty‐six patients were treated with a regimen of chemotherapy containing rituximab, among whom 73% reached complete remission. The median progression‐free survival (PFS) and median overall survival (OS) were 29.4 months and 63.8 months, respectively. History of autoimmune disorder (Hazard ratio HR 3.3 1.4–7.8; p < 0.01), nodal involvement (HR 2.6 1.4–5.1; p < 0.01), lack of anthracycline (HR 0.1 0–0.4 for use; p < 0.001), or no intensification at first‐line regimen (p = 0.02) were associated with worse PFS. High‐dose methotrexate use was not associated with better PFS or OS.
Conclusions
Our study highlights the aggressive clinical picture of IVLBCL, in particular the frequency of macrophage activation syndrome, and the need for new therapies despite a response to R‐CHOP‐like regimen similar to non‐intravascular diffuse large B‐cell lymphomas.
Intravascular large B‐cell lymphomas in a large cohort present aggressive features and a dismal prognosis is suggested when associated with autoimmune disorders and nodal involvement.
Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final ...results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.
The Reverse Transcription Multiplex Ligation-dependent Probe Amplification (RT-MLPA) technique is a method allowing for the semi-quantitative concomitant analysis of a number of transcripts of ...interest in cells or tissues. It relies on the amplification of complementary DNA (cDNA) derived from messenger ribonucleic acid (mRNA) after binding and ligation of specific probes on adjacent regions. It is thus applicable to the relatively fragmented low-quality RNA that can be derived from formalin-fixed paraffin embedded samples (FFPE), ill adapted to other methods such as RNASeq. Adequate tagging provides specific amplicon sizes for each marker, thus becoming readily identifiable after capillary electrophoresis. Signal normalization further allows to compare relative levels of transcripts in a given run.
Here we report on the application of this method to explore the tumoral and microenvironmental, i.e. intrinsic and extrinsic, transcriptome of mantle cell lymphoma (MCL). Data were obtained from i)bone marrow (BM) and lymph nodes (LN) from normal individuals, ii)BM and LN from MCL patients at diagnosis (n=33) and iii)BM and LN from relapsing MCL patients (n=19). Samples were either frozen BM and frozen of FFPE LN. mRNAs were extracted and reverse-transcripted in cDNA before being processed for MLPA investigating for 17 transcripts of interest. The latter explored the intrinsic tumoral expression of CCND1, SOX11 and MKI67. The extrinsic parameters of the microenvironment investigated concerned the monocyte/macrophage compartment (CD14, CD163), T-cells (CD3E/CD3, CD8A/CD8), NK cells (CD94), the costimulation molecule CD40-ligand (CD40LG/CD40L) and immune-checkpoint molecules (CD152/CTLA4, PDC1/PD1, CD274/PDL1, PDCD1LG2/PDL2, INDO1/IDO) as well as cytokines (CSF1/MCSF , IL10, TGFB1).
The samples studied were 39 MCL LN, 20 MCL BM, 10 non-tumoral LN and 9 normal BM.
RT-MLPA readily differentiated MCL samples from non-tumoral samples by showing high levels of CCND1 and SOX11 transcripts in patients. Extrinsic markers expression, analyzed in principal component analysis (PCA) clearly segregated diseased and normal LN, while the difference was less clear in BM. Macrophage markers transcript levels were lower in patients' LN which also showed a down regulation of global T- and NK-cells yet increased levels of CD8 transcripts. PDL1 expression was higher in MCL BM compared to controls.
LN from MCL patients with aggressive characteristics displayed lower CCND1 but higher MKI67 transcripts than other MCL patients' samples. These aggressive forms were found to be significantly associated with high CD14 transcripts in LN and high CD163 in BM. In addition, blastoid morphology was significantly associated with high CD14 (p=.005) and CD163 transcript levels in LN. Regarding T-cells, MCL aggressive forms had significantly lower amounts of CD3E transcripts, yet increased CD8 expression.
LN from patients with a high proliferative index displayed higher levels of CD8 but also of CTLA-4, PD-1 and PDL1, suggesting that these T-cells are exhausted.
A significant upregulation of the levels of CCND1 transcripts was observed in relapse LN. Conversely, CD163, CD3E, CD40L and CD94 levels were lower in relapsed samples compared to diagnosis, which could reflect immune depletion secondary to immuno-chemotherapy.
This study confirms, in an original transcriptomic approach, the great heterogeneity of the MCL microenvironment. Besides being a useful tool at diagnosis, RT-MLPA successfully allowed for a concomitant approach of a large number of transcripts and thus a precise evaluation of intrinsic prognostic and extrinsic features of MCL. Important, yet seldom described, modulations of T-cells, NK cells, macrophages and cytokines were observed, with different profiles segregating MCL with aggressive morphology and those with resistance to treatment.
No relevant conflicts of interest to declare.
Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. ...A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.
We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.
A total of 218 patients with
chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1-64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in
levels defined as molecular recurrence. The molecular recurrence-free survival was 52% 95% confidence interval (CI), 45%-59% at 6 months, and 50% (95% CI, 43%-57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of
in 175 of 218 patients at imatinib cessation. To apply positive
ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%
. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%
) were the two identified predictive factors of molecular recurrence, with
= 0.0366 (HR, 0.635; 95% CI, 0.415-0.972 and
= 0.008 (HR, 0.556; 95% CI, 0.360-0.858), respectively.
We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with
chronic phase CML.
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