Humoral immune depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma.

Rituximab maintenance (RM) after autologous stem cell transplantation (ASCT) is standard-of-care for young patients with mantle cell lymphoma (MCL). RM may enhance post-transplantation immune depression and risk of infections. We compared infection incidence and immune consequences of RM versus observation in transplanted MCL patients. All randomized patients included in the LyMa trial were eligible. The following parameters were collected prospectively: occurrence of fever, infection, hospitalization, neutropenia, hypogammaglobulinemia, CD4 lymphopenia and γ globulin (Ig) substitution. The post-ASCT period was divided into four periods in order to assess the possible effects of RM or ASCT on immune status. Each arm included 120 patients. Concerning infection incidence and all biological parameters, there was no difference between the two arms during the first year post ASCT. After this period, RM patients were more exposed to fever (P=0.03), infections (P=0.001), hypogammaglobulinemia (P=0.0001) and Ig substitution (P<0.0001). Incidences of hospitalization, neutropenia and CD4 lymphopenia were not different between the two arms. The number of rituximab injections was correlated with infections and hypogammaglobulinemia, P<0.0001 and P=0.001; but was not correlated with neutropenia and CD4 lymphopenia. Ig substitution did not modify infection incidence. Patients who presented hypogammaglobulinemia <6 g/L or <4 g/L had longer 3-years progression-free survival (PFS), this applies to RM patients (P=0.012 and P=0.03) and to the global cohort (P=0.008 and P=0.003). Hypogammaglobulinemia did not influence overall survival. Occurrence of infectious event, neutropenia and CD4 lymphopenia did neither influence PFS nor overall survival. Post-ASCT RM in MCL patients causes sustained hypogammaglobulinemia, which is independently correlated with improved PFS.

Deauville Scores 4 or 5 Assessed by Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Early Post-Allotransplant Is Highly Predictive of Relapse in Lymphoma Patients.

The impact of early fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET-CT) status on survival after allogeneic transplantation for lymphoma is poorly reported. This retrospective study included all adult Hodgkin lymphoma (HL) or non-Hodgkin lymphoma(NHL) patients (>18 years old) who benefited from FDG PET-CT before (within 1 month) and/or early (+3 months and within +6 to 9 months) after allogeneic stem cell transplantation in our institution between 2005 and 2015 and who were still without documented progression or relapse at the time of the FDG PET-CT. All FDG PET-CT were reviewed by a nuclear medicine expert in hematology and restaged according to the Deauville scale. FDG-PET CT was considered positive when the uptake was higher than liver background (Deauville score ≥ 4). The primary objective was to study the impact of pre- and post-transplant FDG PET-CT on lymphoma-free survival (LFS) and overall survival (OS). Inclusion criteria were fulfilled for 103 patients (69 men; median age, 51.6 years old; range, 22 to 67). Diagnoses were high-grade NHL (n = 47), low-grade NHL (n = 6), T cell lymphoma (n = 34), and HL (n = 16). More than half of the patients were in complete remission at the time of transplant (n = 56). A reduced-intensity conditioning regimen was applied in most cases (n = 90). With a median follow-up of 49.5 months (range, 6 to 140.5) for alive patients, median 3-year OS and LFS were, respectively, 81% (range, 71% to 87%) and 65% (range, 54% to 74%) for the entire cohort. In multivariate analysis, positive FDG PET-CT at 3 months was the strongest independent factor significantly associated with poorer LFS (hazard ratio, 9.22; 95% confidence interval, 1.88 to 645.2; P = .006). FDG PET-CT positivity at 3 months appears to be highly predictive of LFS in patients after allogeneic transplantation and may help to guide strategies to prevent relapse. These results need to be validated prospectively.

Influence of Donor Type (Sibling versus Matched Unrelated Donor versus Haploidentical Donor) on Outcomes after Clofarabine-Based Reduced-Intensity Conditioning Allograft for Myeloid Malignancies.

Clofarabine-based reduced-intensity conditioning (RIC) regimens are well-established schedules for allograft in patients with myeloid malignancies. A retrospective study was conducted including all adults allografted in our department with such a regimen and disease with the aim to assess whether or not the donor type (matched sibling [MSD], matched unrelated [MUD], or haploidentical [haplo]) impacted outcomes. Between October 2009 and February 2018, 118 patients met the inclusion criteria. Thirty-six, 55, and 27 patients received a graft from an MSD, MUD, or haplo donor, respectively. Peripheral blood stem cells (PBSCs) were the source of graft for all patients. The median age of the entire cohort was 62 years (range, 20 to 73), and the median follow-up was 31 months (range, 4.5 to 106). All patients engrafted except 1 haplo recipient. Neutrophils (>.5 × 109/L) and platelets (50 × 109/L) recoveries were significantly delayed in the haplo group (P = .0003 and P < .0001) compared with MSD and MUD. Acute grades II to IV or III to IV graft-versus-host disease (GVHD) incidences were similar between the 3 groups as well as the incidence of moderate or severe chronic GVHD. Also, similar 2-year overall survival (OS; 64.7% versus 73.9% versus 60.2%, P = .39), disease-free survival (DFS; 57.7% versus 70.9% versus and 53.6%, P = .1), and GVHD relapse-free survival (37.9% versus 54.3% versus 38.9%, P = .23) were observed between MSD versus MUD versus haplo groups. The same was true when considering only acute myeloid leukemia (AML) cases. In multivariate analysis the type of donor remained independent of outcomes in this series, whereas myelodysplastic syndrome (versus AML), high disease risk index, and older donor (≥50 years) were associated with lower OS and DFS. These data suggest that haplo donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack an MSD or a MUD.

Combined inhibition of CTPS1 and ATR is a metabolic vulnerability in p53-deficient myeloma cells.

In multiple myeloma, as in B-cell malignancies, mono- and especially bi-allelic TP53 gene inactivation is a high-risk factor for treatment resistance, and there are currently no therapies specifically targeting p53 deficiency. In this study, we evaluated if the loss of cell cycle control in p53-deficient myeloma cells would confer a metabolically actionable vulnerability. We show that CTP synthase 1 (CTPS1), which encodes a CTP synthesis rate-limiting enzyme essential for DNA and RNA synthesis in lymphoid cells, is overexpressed in samples from myeloma patients displaying a high proliferation rate (high MKI67 expression) or a low p53 score (synonymous with TP53 deletion and/or mutation). This overexpression of CTPS1 was associated with reduced survival in two cohorts. Using scRNA-seq analysis in 24 patient samples, we further demonstrate that myeloma cells in the S or G2/M phase display high CTPS1 expression. Pharmacological inhibition of CTPS1 by STP-B induced cell cycle arrest in early S phase in isogenic NCI-H929 or XG7 TP53 +/+, TP53 -/-, and TP53 R175H/R175H cells and in a TP53 -/R123STOP patient sample. The functional annotation of transcriptional changes in 10 STP-B-treated myeloma cell lines revealed a decrease in protein translation and confirmed the blockade of cells into the S phase. The pharmacological inhibition of ATR, which governs the intrinsic S/G2 checkpoint, in STP-B-induced S-phase arrested cells synergistically induced cell death in TP53 +/+, TP53 -/-, and TP53 R175H/R175H isogenic cell lines (Bliss score >15). This combination induced replicative stress and caspase-mediated cell death and was highly effective in resistant/refractory patient samples with TP53 deletion and/or mutation and in TP53 -/- NCI-H929 xenografted NOD-scid IL2Rgamma mice. Our in vitro, ex vivo, and in vivo data provide the rationale for combined CTPS1 and ATR inhibition for the treatment of p53-deficient patients.

Aggressive, early resistant and relapsed mantle cell lymphoma distinct extrinsic microenvironment highlighted by transcriptome analysis.

Immunotherapy strategies relying on innate or adaptive immune components are increasingly used in onco-haematology. However, little is known about the infiltrated lymph nodes (LN) or bone marrow (BM) landscape of mantle cell lymphoma (MCL). The original transcriptomic approach of reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) was applied here to explore the expression of 24 genes of interest in MCL at diagnosis (21 LN and 15 BM) or relapse (18 LN). This allowed us to identify that at baseline, samples from MCL patients with an aggressive morphology (i.e. blastoid or pleomorphic) or a high proliferative profile, displayed significantly higher monocyte/macrophage-associated transcripts (CD14 and CD163) in LN and BM. Regarding T-cells, aggressive MCL forms had significantly lower amounts of LN CD3E transcripts, yet an increased expression of cytotoxic markers in LN (CD8) and BM (CD94). A very high-risk group with early treatment resistance displayed, at diagnosis, high proliferation (KI67) and high macrophages and cytotoxic transcript levels. Post-immunochemotherapy relapsed samples revealed lower levels of T- and natural killer-cells markers, while monocyte/macrophage markers remained similar to diagnosis. This study suggests that rapid analysis of MCL microenvironment transcriptome signatures by RT-MLPA could allow for an early distinction of patient subgroups candidates for adapted treatment strategies.