Bam Conditioning Before Autologous Stem Cell Transplantation for Lymphoma: A Retrospective Study on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (sfgm-Tc)

IF 7.702International audienc

Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities.

International audienceThe prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported to be associated with a worse outcome than the traditional complex karyotype (CK). In this retrospective study of 186 AML patients older than 60 years, the prognostic influence of MK was used to further stratify elderly patients with unfavorable cytogenetics. CK was observed in 129 patients (69%), and 110 exhibited abnormalities according to the definition of MK (59%). MK(+) patients had a complete response rate significantly lower than MK(-) patients: 37% vs 64% (P = .0008), and their 2-year overall survival was also decreased at 7% vs 22% (P < .0001). In multivariate analysis, MK appeared as the major independent prognostic factor related to complete remission achievement (odds ratio = 2.3; 95% confidence interval, 1-5.4, P = .05) and survival (hazard ratio = 1.7; 95% confidence interval, 1.1-2.5, P = .008). In the subgroup of 129 CK(+) patients, survival was dramatically decreased for MK(+) patients (8% vs 28% at P = .03). These results demonstrate that MK is a major independent factor of very poor prognosis in elderly AML

Acute lymphoblastic leukemia relapsing after first-line pediatric-inspired therapy: a retrospective GRAALL study

International audienceThe outcome of adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph- ALL) relapsing after pediatric-inspired front-line therapy is ill known. Here 229 relapsing Ph- ALL younger adults (18-63 years) treated within the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/-2005 trials were considered. Salvage regimens consisted of potentially curative therapies in 194 cases, low-intensity therapies in 21, allogeneic stem cell transplant (allo-SCT) in 6 and best supportive care in 8. Overall, 77 patients received allo-SCT after relapse. The median follow-up was 3.1 years. A second complete remission (CR2) was achieved in 121 patients (53%). In multivariate analysis, only younger age \textless45 years (P=0.008) and CR1 duration 18 months (P=0.009) predicted CR2. Overall survival (OS) at 2 and 5 years was 19.3% (14-24%) and 13.3% (8-18%), respectively. In CR2 patients, disease-free survival (DFS) at 2 and 5 years was 29.0% (21-38%) and 25% (17-33%). In multivariate analysis, CR1 duration 18 months and allo-SCT after relapse were associated with longer DFS (P\textless0.009 and P=0.004, respectively) and longer OS (P=0.004 and P\textless0.0001, respectively). In conclusion, although younger adults relapsing after pediatric-inspired ALL therapies retain a poor outcome, some of them may be cured if CR1 duration 18 months and if allo-SCT can be performed in CR2. New therapies are definitely needed for these patient

Maintenance therapy with alternating azacitidine and lenalidomide in elderly fit patients with poor prognosis acute myeloid leukemia: a phase II multicentre FILO trial

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Efficacy of tyrosine kinase inhibitors in Ph-like acute lymphoblastic leukemia harboring ABL-class rearrangements

Philadelphia(Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of B-precursor ALL characterized by a gene expression profile (GEP) similar to Ph-positive ALL but lacking the specific BCR-ABL1 fusion gene.1,2 Several pediatric and adult groups have reported on the poor baseline features of Ph-like ALL including a high white blood cells count (WBC) at diagnosis and a frequent association with IKZF1 intragenic deletion. Patients with Ph-like ALL are at higher risk of induction failure or high post-induction minimal residual disease (MRD) levels.3\u20135 This poor early response translates into inferior outcome in terms of event-free survival (EFS) and overall survival (OS) as compared to other B-ALL patients. Ph-like ALL was recognized as a provisional entity by the 2016 WHO classification but strict and unequivocal diagnostic criteria have not been established yet.6 Ph-like ALL are characterized by a multitude of oncogenic events that lead to the aberrant activation of cytokine receptors or signaling factors, the most frequent beeing rearrangements of CRLF2, fusions and mutations of JAK kinases and fusions involving ABL-class kinases (ABL1, ABL2, CSF1R or PDGFRB).7 As expected, Ph-like cells harboring ABL-class rearrangements have shown sensitivity to tyrosine kinase inhibitors (TKIs) such as imatinib and dasatinib in vitro or in patient-derived xenograft (PDX).8\u201310 In addition, we and others have reported single experiences of clinical benefit of TKI treatment in early resistant patients.11,12 In an attempt to enable targeted therapy in B-ALL patients with poor response to chemotherapy, we have developped an integrative diagnostic strategy to identify Ph-like alterations in newly diagnosed or relapsing patients in a timely manner. Here, we report on the characteristics, response and outcome of 24 patients with B-ALL harboring ABL-class fusions who could be treated with a combination of TKI and chemotherapy, either during frontline treatment (N=19) or at relapse (N=5). Patients were initially enrolled in or treated according to pediatric FRALLE/CAALL/EORTC (NCT02716233; NCT01185886) or adult GRAALL/EWALL trials (NCT00327678; NCT02617004) in french clinical centers. Cytogenetic analyses were performed locally according to standard recommendations. Molecular analyses were performed centrally and evolved over time with the introduction of new techniques, up to the current algorithm shown in Supplementary Figure 1. Briefly, fusion transcripts are searched for using an in-house multiplexed method (derived from 13) and cases negative for classifying alterations are subjected to RNA-sequencing for detection of alternative fusions. Of the 24 patients reported here, 12 had fusions involving ABL1, including NUP214-ABL1 (n=6), ETV6-ABL1 (n=3) and other partners in single cases (RCSD1, RANBP2 and LSM14A) (Figure 1A). Nine cases had a PDGFRB rearrangement, including EBF1-PDGFRB (n=6) and other partners in single cases (NUMA1, ETV6 and ATF7IP). ZC3HAV1-ABL2 and MEF2D-CSF1R fusions were identified in single cases, and a patient with a ZMYM2-FGFR1 fusion (not strictly ABL-class) was also included in the present cohort. The resulting cohort (Table 1) included 16 males and 8 females and median age at diagnosis was 24 years (range 5-72). Two patients were previously reported (#1,24).11,14 As expected, patients had baseline characteristics and early response to treatment associated with a poor prognosis. Median WBC was 30x109/L (range 4-570x109/L). Intragenic IKZF1 deletions were detected in 11 out of 24 patients (46%). A poor response to prednisone prephase ( 651 G/L blasts in peripheral blood at day 8) was observed in 14 out of 22 evaluable patients (64%). After induction therapy, only 16 out of 24 (67%) of patients reached complete remission, all with detectable minimal residual disease (MRD), including 7 with MRD 6510-2, and only one with MRD &lt;10-4 (Table 1, Figure 1B). In 19 patients, the ABL-class fusion was identified at initial diagnosis work-up and TKI was introduced during frontline treatment, within the first month of consolidation or salvage for most of them (n=14). In 5 patients, the Ph-like status was diagnosed at relapse and TKI was introduced in association with salvage therapy. In this retrospective study, the choice of TKI, TKI dosage, and combination was up to the physician choice. Fourteen patients were exposed to imatinib, 9 to dasatinib, one to ponatinib. Three patients were switched from imatinib to dasatinib during frontline treatment (Table 1). Among the 19 patients treated with TKI frontline, 7 out of 8 primary refractory patients subsequently achieved CR, one after a switch to dasatinib (#10). One patient died early of sepsis in a context of uncontrolled disease (#16). One patient was lost of sight after salvage until she relapsed (#13). In 14 out of 18 patients (78%), a MRD level below 10-4 was achieved within a median time of 2.5 months (range 1.4-14.8) (Figure 1B). Allogeneic hematopoietic stem cell transplant (HSCT) was performed in 9 patients, of whom 3 with a sibling donor (SIB), 4 with a matched unrelated donor (MUD), and 2 with a haploidentical donor (Haplo). All patients were in CR before HSCT and 6/9 (67%) had undetectable MRD. One patient was additionally exposed to blinatumomab in combination to dasatinib in bridge to HSCT. After a median follow-up of 36 months (range 8-73), 12 patients were alive in first CR. Six patients relapsed, 3 patients received an alternative TKI, including one in association to inotuzumab. The median remission duration and OS were not reached. At 3 years, EFS was 55% (95%CI: 27-76) and OS was 77% (95%CI: 50-91) (Figure 1C-D). The 5 patients who were treated with TKI at relapse achieved CR, including two patients who had refractory disease to several lines of treatment (#22,24). A MRD level below 10-4 was achieved in 3 patients of whom two could proceed to HSCT (1 Haplo, 1 MUD) and remained alive in remission. The three other patients further relapsed and died of progressive disease after exposition to second-line TKIs (dasatinib, n=2; ponatinib, n=1). The efficacy of TKIs in Ph-like ALL has been suggested by several case reports.11,12,15\u201317 In a large pediatric and adult cohort, Roberts et al. mentioned 11 patients with Ph-like ALL and slow response or failure to induction who achieved rapid responses upon TKI or ruxolitinib therapy.3 In frontline patients, the 3-year OS of 77% we observe compares favorably with retrospective survival rates of Ph-like adult patients treated without TKI. In the GMALL group experience in 19 adult patients with Ph-like ALL and a median age of 31 years old (range 16-59), the 5-year OS was 22%.19 In the MDACC experience, the 5-year survival of 56 Ph-like adult patients with a median age of 33.5 years (range 15-71) treated with either Hyper-CVAD or augmented BFM was 23%.7 Of note, these series included all Ph-like ALL cases characterized by GEP, and no specific subgroup analysis was performed in patients with ABL-class fusion genes. In conclusion, we report the largest cohort of patients with ABL-class kinase rearrangement exposed to TKI frontline or at relapse, and show promising MRD response and outcome similar to those observed in early trials of imatinib combined with chemotherapy in Ph-positive ALL.18 Prospective screening strategies are feasible and should be generalized to identify these high-risk patients and to propose early TKI-based intervention. In future studies, several questions remain to be adressed including the choice of TKI according to the fusion transcript, whether these patients should benefit from recently approved blinatumomab19, and finally, the benefit of HSCT in patients who achieve good MRD response upon targeted therapy

One-day prevalence of asymptomatic carriage of toxigenic and non-toxigenic Clostridioides difficile in 10 French hospitals

International audienceBackground: Asymptomatic faecal carriage of Clostridioides difficile has been widely evaluated, but its prevalence across a wide range of clinical departments and related risk factors are not well described. The objectives of the PORTADIFF study were to evaluate the prevalence and identifying risk factors leading to asymptomatic carriage of both toxigenic and non-toxigenic C. difficile.Methods: The PORTADIFF study was a 1-day prevalence study carried out in 10 different French hospitals. Adult patients, who agreed to participate, were included in this study and provided a fresh stool sample. C. difficile strains isolated from carriage were characterized by polymerase chain reaction (PCR) detection of tcdA, tcdB, cdtA and cdtB, and PCR ribotyping.Results: In total, 721 patients were included in this study. The median age was 73 years (range 18-101 years) and the male/female ratio was 1.06. C. difficile (either toxigenic or non-toxigenic strains) was isolated from 79 (11%) patients; 42 (5.8%) strains were toxigenic. The prevalence rates of asymptomatic carriage ranged from 5% on surgical wards to 19% on long-term care wards. The main risk factors associated with asymptomatic carriage were antibiotic treatment within the preceding 3 months (81.8% vs 53.7%; P<0.01), hospitalization within the preceding 2 months (55.8% vs 33%; P<0.01), cumulative duration of hospital stay before study inclusion (mean 50.1 vs 34.5 days; P<0.047), and hospitalization on a ward with high global incidence of C. difficile infection.Conclusion: Eleven percent of hospitalized patients were asymptomatic carriers of toxigenic or non-toxigenic C. difficile, and may constitute a potential reservoir of C. difficile strains

Lomustine is beneficial to older AML with ELN2017 adverse risk profile and intermediate karyotype: a FILO study

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