Key Points• T SCM lymphocytes are preferentially generated from naive precursors in vivo early after haploidentical HSCT.• T SCM represent relevant novel players in the diversification of immunological memory after haploidentical HSCT.Memory stem T cells (T SCM ) have been proposed as key determinants of immunologic memory. However, their exact contribution to a mounting immune response, as well as the mechanisms and timing of their in vivo generation, are poorly understood. We longitudinally tracked T SCM dynamics in patients undergoing haploidentical hematopoietic stem cell transplantation (HSCT), thereby providing novel hints on the contribution of this subset to posttransplant immune reconstitution in humans. We found that donor-derived T SCM are highly enriched early after HSCT. We showed at the antigenspecific and clonal level that T SCM lymphocytes can differentiate directly from naive precursors infused within the graft and that the extent of T SCM generation might correlate with interleukin 7 serum levels. In vivo fate mapping through T-cell receptor sequencing allowed defining the in vivo differentiation landscapes of human naive T cells, supporting the notion that progenies of single naive cells embrace disparate fates in vivo and highlighting T SCM as relevant novel players in the diversification of immunological memory after allogeneic HSCT. (Blood. 2015;125(18):2865-2874

Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

IntroductionCNS dissemination in patients with aggressive non-Hodgkin lymphoma (NHL) is a relatively rare but often fatal complication that occurs in the different subtypes of NHL with a frequency of 5% (ie, diffuse large B-cell lymphoma [DLBCL]) to 30% 1 (ie, Burkitt lymphoma [BL] and B-cell lymphoblastic lymphoma [B-LL]). Many CNS events occur early after diagnosis (4.7-9 months), during therapy, or shortly after completion of treatment, suggesting that initial CNS involvement could have been undetected in most cases. Prophylactic treatment likely reduces the incidence of CNS relapse, but may increase the toxicity of systemic chemotherapy; furthermore, the incidence of CNS dissemination is not high enough to suggest the use of prophylaxis treatment in all patients affected by aggressive NHL. Therefore, CNS prophylaxis is usually incorporated into protocols for the treatment of B-LL and BL, but it is not systematically warranted in patients with DLBCL. Therefore, the identification of patient subgroups for which CNS prophylaxis may be useful is important, especially for DLBCL patients who have no well-defined risk factors for CNS relapse. Risk models for DLBCL have been developed, but are mainly derived from analyses of retrospective studies. [2][3][4][5] An increased risk of CNS dissemination is associated with involvement of the BM and certain extranodal sites such as testis, paranasal sinuses, orbits, and paravertebral masses. Moreover, patients with a high to intermediate or high risk according to the International Prognostic Index (IPI), particularly those with high serum levels of lactate dehydrogenase (LDH) and involvement of more than 1 extranodal organ, are much more prone to develop CNS involvement than others and should receive CNS prophylaxis. 6 Nevertheless, CNS risk predictors and related prognostic scores have been identified in retrospective and heterogeneous series, including different lymphoma categories; however, resulting scores show a low sensitivity in predicting CNS involvement.The diagnosis of CNS dissemination is frequently suspected by the presence of related signs or symptoms and confirmed by examination of cerebrospinal fluid (CSF) and neuroimaging techniques. The diagnostic standard conventional cytology (CC) examination of CSF is considered as having low sensitivity and low specificity, with reported falsenegative rates of 20%-60%. 7 This has been ascribed to the paucity of neoplastic cells in the CSF of patients with minimal disease and to the presence of confounding reactive lymphocytes. Therefore, patients with low tumor burden in the CSF, who are more likely to benefit from CNS treatment, are actually more commonly exposed to false-negative [8][9][10][11][12][13][14] However, it is still unknown whether detecting occult leptomeningeal involvement and consequently changing treatment may improve outcome in these patients.In the present study, we compared prospectively FCM analysis versus CC examination of baseline samples of CSF to detect occult leptomeningeal disease in patie...

Use of the TRS could lead to substantial saving by improving the cost-effectiveness of the autologous blood donation programme.

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Autologous hematopoietic stem cell transplantation (ASCT) is a curative option alternative to allogeneic transplantation for patients with acute myeloid leukemia (AML). Relapse after ASCT can be due to contamination with leukemic blasts of autologous peripheral blood stem cells (PBSCs) collected by leukapheresis (LK). Identification and quantification of a minimal residual disease (MRD) marker in PBSCs could be relevant in determining the relapse risk after ASCT. High levels of the WT1 gene transcript in bone marrow of AML patients after treatment completion predict disease relapse. We evaluated WT1 transcript levels in autologous PBSC from LK used for ASCT in 30 consecutive AML patients in complete remission (CR) and established a correlation with clinical outcome. At diagnosis, all patients had WT1 overexpression. All patients were in morphological and genetic CR at the time of PBSC collection and before ASCT. Real-time quantitative PCR of WT1 was performed in samples of each LK, using TaqMan technology on RNA from mononucleated cells. The median WT1 transcript level in the PBSC graft (WT1-LK) of patients who relapsed was significantly higher than of those who did not relapse after transplantation (P <.0001). We defined a cut-off level of 80 WT1-LK copies/ABL 10e4 copies to discriminate between positive and negative PBSC grafts. The cut-off level was strongly associated with disease recurrence, DFS and OS. Our study represents the largest series of patients evaluating WT1 as a marker of MRD in PBSC LK products using a completely standardized real-time WT1-reverse transcriptase-PCR based assay. These data, if confirmed by prospective study, will help to determine an individual patient's adapted postremission allocation strategy.

Plerixafor and G-CSF combination mobilizes hematopoietic stem and progenitors cells with a distinct transcriptional profile and a reduced in vivo homing capacity compared to plerixafor alone For decades, bone marrow (BM) has been the preferred source of hematopoietic stem and progenitor cells (HSPCs) for transplants following myeloablative conditioning. At present, mobilized peripheral blood stem cells are commonly used for transplantation, particularly in the autologous setting.