Publications by authors named "Francois Guilhot"

151 Publications

Dasatinib dose optimisation based on therapeutic drug monitoring reduces pleural effusion rates in chronic myeloid leukaemia patients.

Br J Haematol 2021 Jul 30;194(2):393-402. Epub 2021 Jun 30.

Clinical Pharmacology Department, Centre Hospitalier Pellegrin, CHU de Bordeaux, Bordeaux, France.

Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17654DOI Listing
July 2021

Long-term outcome of imatinib 400 mg compared to imatinib 600 mg or imatinib 400 mg daily in combination with cytarabine or pegylated interferon alpha 2a for chronic myeloid leukaemia: results from the French SPIRIT phase III randomised trial.

Leukemia 2021 08 22;35(8):2332-2345. Epub 2021 Jan 22.

Inserm CIC 1427, Université de Paris, Paris, France.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-01117-wDOI Listing
August 2021

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Leukemia 2020 08 29;34(8):2138-2149. Epub 2020 Jun 29.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie - IBE, Ludwig-Maximilians Universität, Munich, Germany.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41375-020-0931-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387299PMC
August 2020

Low-dose tyrosine kinase inhibitors before treatment discontinuation do not impair treatment-free remission in chronic myeloid leukemia patients: Results of a retrospective study.

Cancer 2020 08 27;126(15):3438-3447. Epub 2020 May 27.

Service de Cancérologie Biologique, CHU Poitiers, Poitiers, France.

Background: Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low-dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR ).

Methods: We conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty-six patients had been managed with low-dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low-dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy.

Results: In the low-dose group, 61.5% of patients received second-generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow-up of 61.5 months, TFR at 12 months was 56.8% in the full-dose TKI group and 80.8% in the low-dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon-α.

Conclusion: This retrospective study shows that TFR was not impaired by low-dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de-escalation strategies before TKI discontinuation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.32940DOI Listing
August 2020

Model-Based Inference and Classification of Immunologic Control Mechanisms from TKI Cessation and Dose Reduction in Patients with CML.

Cancer Res 2020 06 10;80(11):2394-2406. Epub 2020 Feb 10.

Institute for Medical Informatics and Biometry, Carl Gustav Carus Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Recent clinical findings in patients with chronic myeloid leukemia (CML) suggest that the risk of molecular recurrence after stopping tyrosine kinase inhibitor (TKI) treatment substantially depends on an individual's leukemia-specific immune response. However, it is still not possible to prospectively identify patients that will remain in treatment-free remission (TFR). Here, we used an ordinary differential equation model for CML, which explicitly includes an antileukemic immunologic effect, and applied it to 21 patients with CML for whom time courses had been quantified before and after TKI cessation. Immunologic control was conceptually necessary to explain TFR as observed in about half of the patients. Fitting the model simulations to data, we identified patient-specific parameters and classified patients into three different groups according to their predicted immune system configuration ("immunologic landscapes"). While one class of patients required complete CML eradication to achieve TFR, other patients were able to control residual leukemia levels after treatment cessation. Among them were a third class of patients that maintained TFR only if an optimal balance between leukemia abundance and immunologic activation was achieved before treatment cessation. Model simulations further suggested that changes in the dynamics resulting from TKI dose reduction convey information about the patient-specific immune system and allow prediction of outcome after treatment cessation. This inference of individual immunologic configurations based on treatment alterations can also be applied to other cancer types in which the endogenous immune system supports maintenance therapy, long-term disease control, or even cure. SIGNIFICANCE: This mathematical modeling approach provides strong evidence that different immunologic configurations in patients with CML determine their response to therapy cessation and that dose reductions can help to prospectively infer different risk groups..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-19-2175DOI Listing
June 2020

Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients.

Clin Cancer Res 2019 11 10;25(22):6606-6613. Epub 2019 Jul 10.

Groupe Fi-LMC, Bergonié Institut, Bordeaux, France.

Purpose: 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.

Patients And Methods: 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.

Results: 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.

Conclusions: 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..
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/1078-0432.CCR-18-3373DOI Listing
November 2019

Ponatinib and platelets a conflict in CML.

Blood 2019 04;133(14):1520-1521

INSERM Clinical Investigation Centre 1402.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2019-02-900472DOI Listing
April 2019

Sustained treatment-free remission in chronic myeloid leukaemia is associated with an increased frequency of innate CD8(+) T-cells.

Br J Haematol 2019 07 12;186(1):54-59. Epub 2019 Mar 12.

INSERM 1082, Poitiers, France.

Immunological mechanisms of treatment-free remission (TFR) in chronic myeloid leukaemia (CML) are poorly defined and, to date, no correlation between successful TFR and CD8(+) T-cell subsets has been found. We analysed a new identified human subset of CD8(+) T-cells, namely innate CD8(+) T-cells, in CML patients with TFR ≥ 2 years. We demonstrated a dramatic increase of functionally active innate CD8(+) T-cells in these patients as compared to control subjects and patients in remission under tyrosine kinase inhibitors. Moreover, we found a positive correlation between frequencies of innate CD8(+) T-cells and natural killer cells, possibly representing a new innate biomarker profile of successful TFR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15858DOI Listing
July 2019

High-dose therapy and autologous stem cell transplantation in marginal zone lymphomas: a retrospective study by the EBMT Lymphoma Working Party and FIL-GITMO.

Br J Haematol 2018 09 9;182(6):807-815. Epub 2018 Jul 9.

Ospedale degli Infermi, Biella, Italy.

The role of autologous stem cell transplantation (ASCT) in patients with marginal zone lymphoma (MZL) is debatable. This study investigated the outcome and prognostic factors affecting the outcome of patients undergoing ASCT for MZL. Eligible patients had non-transformed nodal, extra-nodal (MALT) or splenic MZL (SMZL), aged ≥18 years, who underwent a first ASCT between1994 and 2013 and were reported to the European Society for Blood and Marrow Transplantation, Fondazione Italiana Linfomi or Gruppo Italiano Trapianto Di Midollo Osseo registries. The study included 199 patients, [111 MALT lymphoma, 55 nodal MZL (NMZL) and 33 SMZL]. Median age at transplantation was 56 years. The median number of prior therapies was 2 (range 1-8), including rituximab in 71%. 95% had chemosensitive disease. 89% received a chemotherapy-based high-dose regimen. There were no significant differences in patient and transplant characteristics between the 3 histological subtypes except for a lower percentage of patients previously treated with rituximab in the MALT sub-group and more transplants performed in recent years in the other sub-groups. After a median follow-up of 5 years, 5-year cumulative incidence of relapse/progression and non-relapse mortality were 38% and 9%, respectively. Five-year event-free survival (EFS) and overall survival (OS) were 53% and 73%, respectively. Five-year cumulative incidence of second malignancies was 6%. Multivariate analysis revealed age ≥65 years was associated with a shorter EFS and OS. In addition, patients with SMZL had a shorter OS than those with MALT. ASCT may provide clinical benefit in MZL patients who have failed multiple lines of chemoimmunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.15454DOI Listing
September 2018

Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial.

Blood 2018 07 22;132(4):393-404. Epub 2018 Mar 22.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1 The pivotal phase 2 Ponatinib Ph ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1 This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-09-739086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071555PMC
July 2018

Superoxide dismutase 2 (SOD2) contributes to genetic stability of native and T315I-mutated BCR-ABL expressing leukemic cells.

Biochem Biophys Res Commun 2018 04 17;498(4):715-722. Epub 2018 Mar 17.

INSERM U935, Poitiers, Université de Poitiers, France; INSERM U935 Université Paris Sud & Service d'Hématologie, Institur Federatif d'Hématologie IFHIPS, France. Electronic address:

Manganese Superoxide dismutase 2 (SOD2) plays a crucial role in antioxidant defense but there are no data suggesting its role in genetic instability in CML. We evaluated the effects of SOD2 silencing in human UT7 cell line expressing either non-mutated or T315I-mutated BCR-ABL. Array-CGH experiments detected in BCR-ABL-expressing cells silenced for SOD2 a major genetic instability within several chromosomal loci, especially in regions carrying the glypican family (duplicated) and β-defensin genes (deleted). In a large cohort of patients with chronic myeloid leukemia (CML), a significant decrease of SOD2 mRNA was observed. This reduction appeared inversely correlated with leukocytosis and Sokal score, high-risk patients showing lower SOD2 levels. The analysis of anti-oxidant gene expression analysis revealed a specific down-regulation of the expression of PRDX2 in UT7-BCR-ABL and UT7-T315I cells silenced for SOD2 expression. Gene set enrichment analysis performed between the two SOD2-dependent classes of CML patients revealed a significant enrichment of Reactive Oxygen Species (ROS) Pathway. Our data provide the first evidence for a link between SOD2 expression and genetic instability in CML. Consequently, SOD2 mRNA levels should be analyzed in prospective studies as patients with low SOD2 expression could be more prone to develop a mutator phenotype under TKI therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2018.03.023DOI Listing
April 2018

Physicians' attitude towards selection of second line therapy with nilotinib and dasatinib in chronic myeloid leukemia patients.

Health Qual Life Outcomes 2017 Oct 18;15(1):204. Epub 2017 Oct 18.

Italian Group for Adult Hematologic Diseases (GIMEMA), Data Center and Health Outcomes Research Unit, Rome, Italy.

We investigated factors that physicians consider of most importance in the selection of second line tyrosine kinase inhibitors treatments (TKIs) in chronic myeloid leukemia patients (CML).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12955-017-0788-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648464PMC
October 2017

Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study.

Haematologica 2017 08 18;102(8):1368-1377. Epub 2017 May 18.

INSERM UMRS-1160, Paris, France.

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. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2017.165001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643734PMC
August 2017

Chronic Myeloid Leukemia: Immunobiology and Novel Immunotherapeutic Approaches.

BioDrugs 2017 Jun;31(3):143-149

INSERM CIC 1402, CHU de Poitiers, Poitiers, France.

Imatinib has revolutionized the treatment and prognosis of chronic myeloid leukemia (CML) with survival rates now approaching those of the age-matched healthy population. To be able to discontinue tyrosine kinase inhibitor (TKI) treatment, it is necessary to develop complementary therapies to target minimal residual disease. Recent findings by a number of investigators in both CML mouse models and CML patients offer evidence that many factors in the leukemic microenvironment can collectively contribute to immune escape, including expansion of myeloid-derived suppressor cells, programmed death-1/programmed death-1 ligand interactions resulting in T-cell impairment, expression of soluble suppressive factors such as soluble CD25, and down-regulation of MHC molecules by CML cells. Other investigators have studied the role of cytokines on the resistance to TKIs by leukemic stem cells (LSCs) and have highlighted the implication of the JAK/STAT pathway as well as the interleukin 1 (IL-1) signaling pathway. Distinct immunologic strategies have been considered to harness the immune system or trigger LSC death to allow more CML patients to discontinue TKI treatment (so-called functional cure). Successful immunotherapy and TKI combination and the optimal timing of immunotherapy determination represent major challenges for the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40259-017-0225-6DOI Listing
June 2017

Additional cytogenetic abnormalities and variant t(9;22) at the diagnosis of childhood chronic myeloid leukemia: The experience of the International Registry for Chronic Myeloid Leukemia in Children and Adolescents.

Cancer 2017 Sep 12;123(18):3609-3616. Epub 2017 May 12.

INSERM Clinical Investigation Center 1402, Poitiers University, Poitiers, France.

Background: In the adult population with newly diagnosed chronic myeloid leukemia (CML), variant translocations are usually not considered to be impairing the prognosis, whereas some additional cytogenetic abnormalities (ACAs) are associated with a negative impact on survival. Because of the rarity of CML in the pediatric population, such abnormalities have not been investigated in a large group of children with CML.

Methods: The prognostic relevance of variant t(9;22) and ACAs at diagnosis was assessed in 301 children with CML in the chronic phase who were enrolled in the International Registry for Chronic Myeloid Leukemia in Children and Adolescents.

Results: Overall, 19 children (6.3%) presented with additional cytogenetic findings at diagnosis: 5 children (1.7%) had a variant t(9;22) translocation, 13 children (4.3%) had ACAs, and 1 had both. At 3 years, for children with a classic translocation, children with ACAs, and children with a variant t(9;22) translocation who were treated with imatinib as frontline therapy, the probability of progression-free survival (PFS) was 95% (95% confidence interval [CI], 91%-97%), 100%, and 75% (95% CI, 13%-96%), respectively, and the probability of overall survival (OS) was 98% (95% CI, 95%-100%), 100% (95% CI, 43%-98%), and 75% (95% CI, 13%-96%), respectively. No statistical difference was observed between the patients with classic cytogenetic findings and those with additional chromosomal abnormalities in terms of PFS and OS.

Conclusions: In contrast to adults with CML, additional chromosomal abnormalities observed at diagnosis do not seem to have a significant prognostic impact. Cancer 2017;123:3609-16. © 2017 American Cancer Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.30767DOI Listing
September 2017

Age-related health care disparities in multiple myeloma.

Hematol Oncol 2018 Feb 21;36(1):224-231. Epub 2017 Apr 21.

INSERM CIC 1402, CHU, Poitiers, France.

Age is a well-known factor in solid tumours linked to lower adherence to guidelines. Scarce data exist for haematologic malignancies such as multiple myeloma (MM). The aim of the study was to investigate the relationships among age, adherence to guidelines in MM, and overall survival (OS).The Poitou-Charentes cancer registry has exhaustively registered incident cases of MM from 2008 to 2010. Diagnosis, staging, prognosis, and first-line treatment were compared to the international guidelines. Three hundred and sixty-seven patients aged 36 to 93 years were included. Compliance to diagnostic procedure was 98%, staging 62%, prognosis 30%, and first-line treatment 89%. Cytogenetic analysis was compliant in 37%. Younger age was the strongest factor associated with compliant provision of care (odds ratio 14.4 [6.1-33.8] for <66 years and 2.3 [0.9-6.1] for 66-74 years; P < .0001). The second independent factor was active versus smouldering myeloma (odds ratio 3.5 [1.6-7.3]; P = .0009). Adherence to guidelines is related with OS in multivariate analysis hazard ratio: 1.6 [1.0-2.5]; P = .03. Age is linked with inadequate provision of care in myeloma, particularly prognosis and first-line treatment. Compliance to guidelines seems to be related to OS taking into account the main prognostic factors. Future guidelines should stress the point that age and frailty need to be taken into account in myeloma care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hon.2422DOI Listing
February 2018

Long-Term Outcomes of Imatinib Treatment for Chronic Myeloid Leukemia.

N Engl J Med 2017 03;376(10):917-927

From Abteilung Hämatologie-Onkologie, Universitätsklinikum Jena, Jena, Germany (A.H.); the Department of Medicine, University of Chicago, Chicago (R.A.L.); INSERM Centre d'Investigation Clinique 1402, Centre Hospitalier Universitaire de Poitiers, Poitiers, France (F.G.); Fred Hutchinson Cancer Research Center, Seattle (J.P.R.); Centre for Cancer Biology, SA Pathology, University of South Australia and University of Adelaide (S.B.), and the South Australian Health and Medical Research Institute and University of Adelaide (T.P.H.), Adelaide, SA, Australia; University of Bologna, Bologna, Italy (M.B.); the University of Utah Huntsman Cancer Institute, Salt Lake City (M.W.D.); the Hematology Department, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona (F.C.); Novartis, Basel, Switzerland (S.F., C.-E.O., H.D.M.); M.D. Anderson Cancer Center, Houston (H.K.); the University of Newcastle, Newcastle, United Kingdom (S.G.O.); and Knight Cancer Institute, Oregon Health and Science University and Howard Hughes Medical Institute, Portland (B.J.D.).

Background: Imatinib, a selective BCR-ABL1 kinase inhibitor, improved the prognosis for patients with chronic myeloid leukemia (CML). We conducted efficacy and safety analyses on the basis of more than 10 years of follow-up in patients with CML who were treated with imatinib as initial therapy.

Methods: In this open-label, multicenter trial with crossover design, we randomly assigned patients with newly diagnosed CML in the chronic phase to receive either imatinib or interferon alfa plus cytarabine. Long-term analyses included overall survival, response to treatment, and serious adverse events.

Results: The median follow-up was 10.9 years. Given the high rate of crossover among patients who had been randomly assigned to receive interferon alfa plus cytarabine (65.6%) and the short duration of therapy before crossover in these patients (median, 0.8 years), the current analyses focused on patients who had been randomly assigned to receive imatinib. Among the patients in the imatinib group, the estimated overall survival rate at 10 years was 83.3%. Approximately half the patients (48.3%) who had been randomly assigned to imatinib completed study treatment with imatinib, and 82.8% had a complete cytogenetic response. Serious adverse events that were considered by the investigators to be related to imatinib were uncommon and most frequently occurred during the first year of treatment.

Conclusions: Almost 11 years of follow-up showed that the efficacy of imatinib persisted over time and that long-term administration of imatinib was not associated with unacceptable cumulative or late toxic effects. (Funded by Novartis Pharmaceuticals; IRIS ClinicalTrials.gov numbers, NCT00006343 and NCT00333840 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1609324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5901965PMC
March 2017

The Hypothesis of the Human iNKT/Innate CD8(+) T-Cell Axis Applied to Cancer: Evidence for a Deficiency in Chronic Myeloid Leukemia.

Front Immunol 2016 16;7:688. Epub 2017 Jan 16.

INSERM 1082, Poitiers, France; Service d'Immunologie et Inflammation, Poitiers, France; CHU de Poitiers, Poitiers, France; Université de Poitiers, Poitiers, France.

We recently identified a new human subset of NK-like [KIR/NKG2A(+)] CD8(+) T cells with a marked/memory phenotype, high Eomesodermin expression, potent antigen-independent cytotoxic activity, and the capacity to generate IFN-γ rapidly after exposure to pro-inflammatory cytokines. These features support the hypothesis that this new member of the innate T cell family in humans, hereafter referred to as innate CD8(+) T cells, has a role in cancer immune surveillance analogous to invariant natural killer T (iNKT) cells. Here, we report the first quantitative and functional analysis of innate CD8(+) T cells in a physiopathological context in humans, namely chronic myeloid leukemia (CML), a well-characterized myeloproliferative disorder. We have chosen CML based on our previous report that IL-4 production by iNKT cells was deficient in CML patients at diagnosis and considering the recent evidence in mice that IL-4 promotes the generation/differentiation of innate CD8(+) T cells. We found that the pool of innate CD8(+) T cells was severely reduced in the blood of CML patients at diagnosis. Moreover, like iNKT and NK cells, innate CD8(+) T cells were functionally impaired, as attested by their loss of antigen-independent cytotoxic activity and IFN-γ production in response to innate-like stimulation with IL-12 + IL-18. Remarkably, as previously reported for IL-4 production by iNKT cells, both quantitative and functional deficiencies of innate CD8(+) T cells were at least partially corrected in patients having achieved complete cytogenetic remission following tyrosine kinase inhibitor therapy. Finally, direct correlation between the functional potential of innate CD8(+) T and iNKT cells was found when considering all healthy donors and CML patients in diagnosis and remission, in accordance with the iNKT cell-dependent generation of innate CD8(+) T cells reported in mice. All in all, our data demonstrate that CML is associated with deficiencies of innate CD8(+) T cells that are restored upon remission, thereby suggesting their possible contribution to disease control. More generally, our study strongly supports the existence of an innate iNKT/innate CD8(+) T-cell axis in humans and reveals its potential contribution to the restoration of tumor immune surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2016.00688DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5237805PMC
January 2017

Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia.

J Clin Oncol 2017 Jan 31;35(3):298-305. Epub 2016 Oct 31.

Gabriel Etienne and François-Xavier Mahon, Institut Bergonié, Bordeaux; Joëlle Guilhot and François Guilhot, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire (CHU) de Poitiers, Poitiers; Delphine Rea, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP); Bruno Varet, Hôpital Necker, AP-HP et Université Paris Descartes, Paris; Françoise Rigal-Huguet, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse; Franck Nicolini, Centre Hospitalier Lyon Sud, Pierre Bénite; Aude Charbonnier, Institut Paoli Calmette, Marseille; Agnès Guerci-Bresler, CHU Brabois Vandoeuvre, Nancy; Laurence Legros, Hôpital de l'Archet, Centre Hospitalier Universitaire de Nice, Nice; Martine Gardembas, CHU d'Angers, Angers; Viviane Dubruille, CHU Hôtel-Dieu, Nantes; Michel Tulliez, Hôpital Henri Mondor, Créteil; Marie-Pierre Noel, Hôpital Claude Huriez, Centre Hospitalier Regional Universitaire de Lille, Lille; Jean-Christophe Ianotto, CHU Morvan, Brest; Bruno Villemagne, Centre Hospitalier Départemental La Roche-Sur-Yon, La Roche-Sur-Yon; Martin Carré, Hôpital Albert Michallon, CHU de Grenoble, Grenoble; Philippe Rousselot, Hôpital André Mignot, Le Chesnay; and François-Xavier Mahon, CHU de Bordeaux, INSERM U1218, Bordeaux, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.68.2914DOI Listing
January 2017

Pioglitazone together with imatinib in chronic myeloid leukemia: A proof of concept study.

Cancer 2017 05 27;123(10):1791-1799. Epub 2016 Dec 27.

CEA, Institute of Emerging Diseases and Innovative Therapies, University Paris-Sud UMR 007, Fontenay-aux-Roses, France.

Background: We recently reported that peroxisome proliferator-activated receptor γ agonists target chronic myeloid leukemia (CML) quiescent stem cells in vitro by decreasing transcription of STAT5. Here in the ACTIM phase 2 clinical trial, we asked whether pioglitazone add-on therapy to imatinib would impact CML residual disease, as assessed by BCR-ABL1 transcript quantification.

Methods: CML patients were eligible if treated with imatinib for at least 2 years at a stable daily dose, having yielded major molecular response (MMR) but not having achieved molecular response 4.5 (MR ) defined by BCR-ABL1/ABL1 RNA levels ≤ 0.0032%. After inclusion, patients started pioglitazone at a dosage of 30 to 45 mg/day in addition to imatinib. The primary objective was to evaluate the cumulative incidence of patients having progressed from MMR to MR over 12 months.

Results: Twenty-four patients were included (age range, 24-79 years). No pharmacological interaction was observed between the drugs. The main adverse events were weight gain in 12 patients and a mean decrease of 0.4 g/dL in hemoglobin concentration. The cumulative incidence of MR was 56% (95% confidence interval, 37%-76%) by 12 months, despite a wide range of therapy duration (1.9-15.5 months), and 88% of 17 evaluable patients who were still on imatinib reached MR by 48 months. The cumulative incidence of MMR to MR spontaneous conversions over 12 months was estimated to be 23% with imatinib alone in a parallel cohort of patients.

Conclusion: Pioglitazone in combination with imatinib was well tolerated and yielded a favorable 56% rate. These results provide a proof of concept needing confirmation within a randomized clinical trial (EudraCT 2009-011675-79). Cancer 2017;123:1791-1799. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.30490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434901PMC
May 2017

Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study.

Blood 2017 02 8;129(7):846-854. Epub 2016 Dec 8.

Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Bordeaux, France.

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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-09-742205DOI Listing
February 2017

Beyond tyrosine kinase inhibitors: Combinations and other agents.

Best Pract Res Clin Haematol 2016 09 20;29(3):271-283. Epub 2016 Oct 20.

Inserm CIC 1402, CHU de Poitiers, Poitiers, France. Electronic address:

The modern therapeutic strategy for patients with chronic myeloid leukemia (CML) has been successfully altered by first and subsequently second generation tyrosine kinase inhibitors. However, despite high rate of molecular response, minimal residual disease persists in the majority of patients. Thus other approaches are warranted in order to eliminate the leukemia stem cells. Targeting CML stem cells could be of clinical benefit and a number of new agents are currently tested in phase I/II trials. Also immunological approaches with vaccination strategies and combination of tyrosine kinase inhibitors with various form of interferons are actively ongoing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.beha.2016.10.017DOI Listing
September 2016

The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia.

J Pathol 2016 11 29;240(3):262-268. Epub 2016 Sep 29.

INSERM U1082, Poitiers, France.

CD1d-restricted invariant natural killer T (iNKT) cells are believed to play a key role in cancer immune surveillance, and are functionally deficient in patients with chronic myeloid leukaemia (CML). Herein, we have hypothesized that this defect might originate from BCR-ABL-dependent dysfunctions in myeloid dendritic cells (mDCs). Indeed, flow cytometry and confocal microscopy revealed that cell surface expression of CD1d was downregulated in CML mDCs, relative to healthy donor (HD) controls. The decreased cell surface display of CD1d could not be ascribed to defective mDC differentiation, as attested by normal expression of HLA-DR and the CD86 maturation marker. On the other hand, reduced membrane expression was not associated with decreased intracytoplasmic levels of CD1d or its mRNA transcripts, consistent with intracellular retention. In vitro treatment of CML mDCs with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 partially restored both cell surface CD1d expression and CD1d-mediated antigen presentation, whereas it had no effect on HD mDCs. An inhibitor of BCR-ABL tyrosine kinase (TK), imatinib mesylate (IM), had no such activity. Similar recovery of CD1d expression occurred with fasudil, another ROCK inhibitor that is commonly used in clinical trials. Our data support the conclusion that BCR-ABL-dependent ROCK, but not TK, is involved in CD1d downregulation. We propose that ROCK, which is most likely activated by the DH/PH domain of BCR-ABL, mediates iNKT-cell immune subversion in CML patients by downregulating CD1d expression on CML mDCs. Our study reveals the ROCK-mDC axis as a new potential target to restore immune surveillance in patients with CML, offering new therapeutic perspectives for CML treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/path.4779DOI Listing
November 2016

Cytogenetics in CML: more important than you think.

Blood 2016 06;127(22):2661-2

INSERM CLINICAL INVESTIGATION CENTRE 1402.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-04-708206DOI Listing
June 2016

Cross-Intolerance With Dasatinib Among Imatinib-Intolerant Patients With Chronic Phase Chronic Myeloid Leukemia.

Clin Lymphoma Myeloma Leuk 2016 06 29;16(6):341-349.e1. Epub 2016 Mar 29.

Department of Oncology, Hematology, and Cell Therapy, Centre Hospitalier Universitaire de Poitiers, Clinical Investigation Center, Inserm 0802, Poitiers, France.

Background: BCR-ABL inhibitors have improved the prognosis of patients with chronic myeloid leukemia (CML). However, imatinib, the first approved BCR-ABL inhibitor, must be discontinued in many patients because of resistance or intolerance.

Patients And Methods: The present retrospective, pooled analysis of phase II and III data explored the extent of cross-intolerance between imatinib and dasatinib, a second-generation BCR-ABL inhibitor, in 271 CML imatinib-intolerant patients.

Results: Overall, 47 patients (17%) had cross-intolerance to dasatinib, determined by recurrence of grade 3 or 4 adverse events (AEs). Of the 228 patients who discontinued imatinib because of nonhematologic intolerance, 10 (4%) experienced the same severe nonhematologic AEs with dasatinib, with 4 of these patients (2%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients who discontinued imatinib because of hematologic intolerance, 37 (86%) experienced a recurrence of grade 3 or 4 hematologic AEs with dasatinib, with 8 patients (19%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients taking dasatinib at the optimized dose of 100 mg/d, 1 (2%) discontinued therapy because of recurrence of nonhematologic AEs and 3 (7%) because of recurrence of hematologic AEs. With a median treatment duration of 22 months, the estimated rates of progression-free survival and overall survival at 2 years were greater for patients with nonhematologic versus hematologic intolerance to imatinib who switched to dasatinib (progression-free survival, 94% vs. 68%, respectively; overall survival, 98% vs. 88%, respectively).

Conclusion: Dasatinib could be an appropriate treatment option for imatinib-intolerant patients with CML, with cross-intolerance resulting in discontinuation in a few patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clml.2016.03.004DOI Listing
June 2016

Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial.

Lancet Oncol 2016 05 12;17(5):612-21. Epub 2016 Apr 12.

Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.

Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.

Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.

Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.

Funding: ARIAD Pharmaceuticals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)00080-2DOI Listing
May 2016
-->