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• The type of donor (sibling versus MUD versus haplo) is not associated with outcomes after a clofarabine-based RIC regimen for myeloid malignancies. • Our data suggest that haploidentical donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack an MSD or a MUD. • Myelodysplastic syndrome (versus AML), high disease risk index, and older donor (≥50 years) were associated with lower OS and DFS. 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. [ABSTRACT FROM AUTHOR]

Cell surface molecules aberrantly expressed or overexpressed by myeloid leukemic cells represent potential disease-specific therapeutic targets for antibodies. MUC1 is a polymorphic glycoprotein, the cleavage of which yields two unequal chains: a large extracellular α subunit containing a tandem repeat array bound in a strong noncovalent interaction to a smaller β subunit containing the transmembrane and cytoplasmic domains. Because the α-chain can be released from the cell-bound domains of MUC1, agents directed against the α-chain will not effectively target MUC1+ cells. The MUC1 SEA (a highly conserved protein module so called from its initial identification in a sea urchin sperm protein, in enterokinase, and in agrin) domain formed by the binding of the α and β chains represents a stable structure fixed to the cell surface at all times. DMB-5F3, a partially humanized murine anti-MUC1 SEA domain monoclonal antibody, was used to examine MUC1 expression in acute myeloid leukemia (AML) and was found to bind acute myelomonocytic and monocytic leukemia (AML-M4 and AML-M5) cell lines. We also examined monocytic neoplasms freshly obtained from patients including chronic myelomonocytic leukemia and juvenile myelomonocytic leukemia, which were found to uniformly express MUC1. CD34+/lin–/CD38– or CD38+ presumed leukemic stem cell populations from CD34+ AML and CD34–CD38– or CD38+ populations from CD34– AML were also found to express MUC1, although at low percentages. Based on these studies, we generated an anti-MUC1 immunotoxin to directly gauge the cytotoxic efficacy of targeting AML-bound MUC1. Using single-chain DMB-5F3 fused to recombinant gelonin toxin, the degree of AML cytotoxicity was found to correlate with MUC1 expression. Our data support the use of an anti–MUC1 SEA module–drug conjugates to selectively target and inhibit MUC1-expressing myelomonocytic leukemic cells. [ABSTRACT FROM AUTHOR]

Event-related functional magnetic resonance imaging was used to test the involvement of the inferior prefrontal cortex in verbal working memory. Pairs of French nouns were presented to ten native French speakers who had to make semantic or grammatical gender decisions. Verbal working memory involvement was manipulated by making the categorization of the second noun optional. Decisions could be made after processing the first noun only (RELEASE condition) or after processing the two nouns (HOLD condition). Reaction times suggested faster processing for gender than for semantic category in RELEASE. Despite the absence of anatomical difference across tasks and conditions in the wide activated network, the haemodynamic response peak latencies of the inferior prefrontal cortex were significantly delayed in HOLD versus RELEASE while no such peak delay was observed in the superior temporal gyrus. Interestingly, this pattern did not interact with language tasks. This study shows that cognitive manipulation can influence haemodynamic time-course and suggests that the main cognitive process determining inferior prefrontal activation is verbal working memory rather than specific linguistic processes such as grammatical or semantic analysis. Hum. Brain Mapping 19:37–46, 2003. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A full exploration of immune responses is deserved after anti-SARS-CoV-2 vaccination and boosters, especially in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although several reports indicate successful humoral responses in such patients, the literature is scarce on cellular specific immunity. Here, both B- (antibodies) and T-cell responses were explored after one (V3 n = 40) or two (V4 n = 12) BNT162b2 mRNA vaccine boosters in 52 allo-HSCT recipients at a median of 755 days post-transplant (<1 year n = 9). Results were compared with those of 12 controls who had received only one booster (BNT162b2 n = 6; mRNA-1273 n = 6). All controls developed protective antibody levels (>250 BAU/mL) and anti-spike T-cell responses. Similarly, 81% of the patients developed protective antibody levels, without difference between V3 and V4 (82.5% vs. 75%, p = 0.63), and 85% displayed T-cell responses. The median frequency of anti-spike T cells did not differ either between controls or the whole cohort of patients, although it was significantly lower for V3 (but not V4) patients. COVID-19 infections were solely observed in individuals having received only one booster. These results indicate that four vaccine injections help to achieve a satisfactory level of both humoral and cellular immune protection in allo-HSCT patients. [ABSTRACT FROM AUTHOR]

The transfer of genes encoding cytokines into tumor cells has emerged as a new strategy to increase in vivo host reactivity to a variety of tumors. Because gene transfer into tumor cells cannot be easily applied in the clinical setting, we have developed an experimental model of gene transfer into fibroblasts and examined the capacity of these engineered cells to elicit an antitumor immune response. Interleukin-12 (IL-12) is a heterodimeric cytokine with pleiotropic activities presenting strong antitumor and antimetastatic effects in murine models. A bicistronic retroviral vector was constructed that contained the cDNAs encoding both chains (p40 and p35) of murine IL-12 separated by an internal ribosomal entry site sequence. Syngeneic cutaneous fibroblasts obtained from newborn mice and transduced to secrete either IL-12 or IL-2 were injected subcutaneously with B16F0 or B16F1 melanoma cells. The time of tumor occurrence and overall survival of mice were significantly prolonged when B16F1 cells were coinjected with cytokine-producing fibroblasts compared with B16F1 alone or B16F1 together with unmanipulated fibroblasts. Systemic effects were seen in the mice injected with either IL-2- or IL-12-secreting fibroblasts, with the highest proliferation capability and interferon-γ production observed in vitro from splenocytes from recipients of IL-2-secreting fibroblasts. Injection of IL-2-secreting fibroblasts or coinjection of IL-2- and IL-12-producing fibroblasts resulted in a significant increase of survival in the B16F0 model; in some cases, complete disease eradication was observed. These results suggest that cutaneous fibroblasts represent a target of choice for gene transfer and would be useful in the treatment of minimal residual disease in humans. [ABSTRACT FROM AUTHOR]

Graft-versus host disease (GVHD) remains one of the main causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (ASCT). Prophylactic T cell depletion via antithymocyte globulin (ATG) during ASCT conditioning is one of the standards of care for GVHD prophylaxis, although the optimal dosing strategy is still unclear. Recent studies have reported that absolute lymphocyte count at the time of ATG administration could predict survivals in ASCT from unrelated donors. Here this issue was examined in 116 patients receiving peripheral blood stem cells (PBSC) ASCT with purine analog/busulfan-based conditioning regimens between 2009 and 2019 in our department. The impact of lymphopenia at the time of ATG administration was evaluated in terms of overall survival, disease-free survival and GVHD-free/relapse-free survival. After a median follow-up of 4 years, no adverse effect of a profound lymphopenia was observed on patients' outcome. Notably, a reduced dose of ATG in patients with profound lymphopenia did not translate into better survivals. This study indicates that ATG can be administered whatever the recipient's lymphocyte counts in patients receiving a PBSC purine analog/busulfan-based conditioning regimen ASCT. [ABSTRACT FROM AUTHOR]

Simple Summary: Relapse following allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) is the main reason for treatment failure. Most relapses occur during the first six months. We have observed in recent years that some patients relapse late, beyond 2 years after allograft. We sought to evaluate the frequency and the risk factors associated with these late relapses. We observed that these late relapses affect a significant number of patients, that the absence of chronic GvHD is more often associated. In addition, the intensity of the conditioning regimen does not seem to play a role and it is possible to re-treat successfully these patients. We conclude that prolonged monitoring after alloHSCT for AML is recommended. Late relapse, beyond 2 years following alloHSCT for AML, is rare. Among the 376 patients allografted for AML in our center between 1990 and 2016, 142 (38%) relapsed. The majority (68%) of relapses occurred during the first year following transplantation. Beyond 2 years after alloHSCT, relapse was observed in 26 patients, representing 6.9% of the whole transplanted cohort and 18.3% of the relapsing patients. Cytogenetics at relapse was available in 21 patients and remained for 15 of them concordant to that at diagnosis. The majority (85.7%) of the patients were in CR prior to transplant. Thirteen patients had grade 1–2 acute GvHD, while 13 other patients had grade 3–4 acute GvHD. None of these patients subsequently developed chronic GvHD. In multivariate analyses, a predictive factor of the absence of relapse 2 years after transplantation was the development of extensive chronic GVHD. Salvage therapy achieved new CR in 77% of these patients. We conclude that late relapse can affect a significant minority of patients allografted for AML, and the intensity of the conditioning regimen does not seem to have an impact on these relapses. Moreover, we were able to show that those patients can receive effective salvage therapy. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the potential impact of the kinetics of serum levels of seven cytokines during induction in acute myeloid leukemia (AML) patients. Indeed, the role of cytokines, in the pathophysiology and response to therapy of AML patients, remains under investigation. Here, we report on the impact of peripheral levels of two cytokines, the Fms‐like tyrosine kinase 3 ligand (FL) and interleukin‐6 (IL‐6), evaluated during first‐line intensive induction. A new risk stratification can be proposed, which supersedes the ELN 2017 classification to predict survivals in AML patients by examining the kinetic profile of these cytokines during the induction phase. It segregates three groups of, respectively, high‐risk, characterized by a stagnation of low FL levels, intermediate risk, with dynamic increasing FL levels and high IL‐6 at day 22, and favorable risk with increasing FL levels but low IL‐6 at day 22. [ABSTRACT FROM AUTHOR]

• Only prospective series looking at FLT3L concentrations impact after allo-HSCT. • Endogenous FLT3L concentration is not a prognostic marker in this setting. • FLT3L concentration could be monitored only during induction of AML. This study was designed to assess the impact on outcomes of early soluble Fms-like tyrosine kinase 3 ligand concentrations (sFLc) in patients receiving an allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). This was a prospective monocentric study including all allo-HSCT patients included in the previous FLAM/FLAL study (Peterlin et al., 2019). Blood samples collected before the start of conditioning then post-transplant were frozen, stored and tested by ELISA. The parameters considered were hematopoietic recoveries, Leukemia Free Survival and Overall Survival, acute and chronic GVHD, grade 3 or 4 acute and/or extensive chronic GVHD-free and relapse-free survival (GRFS). Forty-one patients were included, a total of 179 samples were assayed for sFLc. There was no impact of sFLc levels (<=median vs> median) on acute and chronic GVHD incidences, LFS, OS nor GRFS. At variance with induction results for AML (Peterlin et al., 2019) endogenous sFLc do not appear to be a prognostic marker at the time of or after allo-HSCT. Even though the results are negatives, this is, to the best of our knowledge, the only prospective series specifically addressing the question of sFLc impact after allo-HSCT in acute leukemias. [ABSTRACT FROM AUTHOR]

Background: Post‐transplant cyclophosphamide (PTCY) alone as graft‐versus‐host disease (GVHD) prophylaxis may avoid/reduce short‐ and mid‐term toxicities of drugs commonly used for GVHD prophylaxis, accelerate immune reconstitution after the graft to decrease infections and facilitate the early integration of adjunct maintenance therapies to prevent relapse. Objective: A prospective phase 2 study was designed in order to assess the feasibility and safety of PTCY as a sole GVHD prophylaxis in adult patients receiving a Baltimore‐based reduced‐intensity conditioning (RIC) peripheral blood (PB) allogeneic hematopoietic stem cell transplantation (Allo‐HSCT) with a matched donor. Study design: Patients were planned to be included stepwise up to 59 evaluable PTCY recipients, in order to be able to stop the protocol in case of excessive corticosteroid resistant grade 3–4 severe acute GVHD (aGVHD). Because a high incidence of grade 2–4 aGVHD was observed after analysis of the first 27 patients, the protocol was amended to test the addition of 1 day of anti‐thymoglobulin to PTCY. In spite of this, the trial had to be stopped after 38 treated patients, because of an unacceptable rate of grade 3–4 aGVHD. Donors were matched related to 12 patients and unrelated to 26. Results: With a median follow‐up of 29.6 months, 2‐year overall, disease‐free and GVHD‐free relapse‐free (GRFS) survivals were respectively 65.4%, 62.1% and 46.9%. Cumulative incidences of grade 2–4 and 3–4 aGVHD at day 100 were 52.6% and 21.1%, respectively, while that of moderate/severe chronic(c) GVHD was 15.7% at 2 years. Addition of ATG to PTCY did influence neither aGVHD, cGVHD nor GRFS. Conclusion: Despite paradoxically good survivals, especially GRFS, this study failed to demonstrate that PTCY (± ATG) alone can be used for Baltimore‐based RIC PB Allo‐HSCT with matched donors. Other combinations should be tested to try and avoid long‐term use of immunosuppressive drugs following Allo‐HSCT in this setting. [ABSTRACT FROM AUTHOR]

This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (≥615/mm 3 ; hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (≥395/mm 3 ; HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony–stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure. [ABSTRACT FROM AUTHOR]

Double umbilical cord blood (dUCB) allogeneic transplantation after a low-dose total body irradiation, cyclophosphamide, and fludarabine (TCF)–based reduced-intensity conditioning regimen (RIC) is increasingly used in adults lacking a suitable related or unrelated donor. Currently, there are little data regarding the long-term outcome of CD3 + T cell chimerism (TCC) in this particular setting. Thirty-six adults with various hematological diseases who received dUCB allogeneic transplants conditioned with TCF were included in this retrospective study. Peripheral blood CD3 + TCC was considered until day +100 after transplantation to determine the impact of full versus mixed chimerism on long-term outcomes. Twenty-nine and 7 patients were documented with full and mixed CD3 + TCC, respectively, within the first 100 days after transplantation. With a median follow-up of 36 months, 3 year-overall survival (OS), disease-free survival (DFS), and cumulative incidence of relapse (CIR) were 61%, (95% confidence interval [CI], 43% to 75%); 50% (95% CI, 32.5% to 66%), and 28% (95% CI, 16% to 44%), respectively. In univariate analysis, a full CD3 + TCC was associated with a better 3-year DFS: 59% (95% CI, 39% to 75.5%) versus 14% (95% CI, 7% to 46%); hazard ratio (HR), .24 (.09 to .65); P = .005 and a lower CIR: 24% (95% CI, 21.5% to 57%) versus 78% (95% CI, 52% to 99%); HR, .18 (.05 to .50); P = .004. In multivariate analysis, a full CD3 + TCC remained associated with a lower CIR (HR, .17 [.028 to .99]; P = .049). CD3 + TCC has no impact on graft-versus-host disease and nonrelapse mortality in this study. In conclusion, here, full CD3 + TCC was independently associated with a lower risk of relapse in adults receiving a dUCB TCF RIC allogeneic transplantation. This highlights the need to develop immunotherapy approaches allowing for early conversion to full chimerism after this type of transplantation. [ABSTRACT FROM AUTHOR]

Our main objective was to determine new factors associated with engraftment and single-unit predominance after double umbilical cord blood (UCB) allogeneic stem-cell transplantation. Engraftment occurred in 78% of cases in this retrospective study including 77 adult patients. Three-year overall survival, disease-free survival, relapse incidence, and nonrelapse mortality were 55 ± 6%, 44 ± 6%, 33 ± 5%, and 23 ± 4%, respectively. In multivariate analysis, Human herpesvirus 6 reactivation during aplasia (hazard ratio [HR] = 2.63; 95% confidence interval [CI]: 1.64–4.17; p < 0.001), younger recipient age (<53 years) (HR = 1.97; 95% CI: 1.16–3.35; p = 0.012), and lower human leukocyte antigen matching between the two units (3 of 6 or 4 of 6) (HR = 2.09; 95% confidence interval: 1.22–3.59; p = 0.013) were the three factors independently associated with graft failure. Also, factors independently predicting the losing UCB unit were younger age of the UCB unit (odds ratio [OR] = 1.01; 95% CI: 1–1.02; p = 0.035), lower CD34 + cell dose contained in the UCB unit (≤0.8 × 10 5 /kg) (OR = 2.55; 95% CI: 1.05–6.16; p = 0.04), and presence of an ABO incompatibility between the UCB unit and the recipient (OR = 2.53; 95% CI: 1.15–5.53; p = 0.02). Thus, Human herpesvirus 6 reactivation during aplasia, lower unit-unit human leukocyte antigen matching, and younger UCB unit age, as new unfavorable predictive factors, may represent new parameters to take into account after double UCB allogeneic stem-cell transplantation in adults. These results need to be confirmed prospectively, as they may influence unit selections and patient outcomes. [ABSTRACT FROM AUTHOR]

This study analyzed changes in patients, transplantation, graft characteristics, and outcome among 827 patients who received their first allo-SCT in a single center between 1983 and 2010. In the 2001 to 2010 decade, compared with the 1983 to 1990 and 1991 to 2000 decades, patients were significantly older and presented with higher risk diseases, reduced intensity conditioning and alternative donors were used more often, and stem cell sources changed from bone marrow to peripheral blood stem cells and cord blood. In the 2001 to 2010 decade, we observed a significant decrease in nonrelapse mortality (NRM) (P = .0007 and P < .0001, respectively) and an increase in relapse incidence (P = .04 and P = .009, respectively), but overall survival (OS) was increased (P = .11 and P = .009, respectively), and there was a trend towards an increased progression-free survival (P = .30 and P = .09, respectively), as compared with the 1983 to 1990 and 1991 to 2000 decades. Chronic graft-versus-host disease (GVHD) was significantly increased, whereas grades III to IV acute GVHD remained stable. These data suggest that, despite the fact that older and higher risk patients with more comorbidities underwent transplantation in the last 10 years, NRM decreased while the incidence of relapse increased and the OS improved. [ABSTRACT FROM AUTHOR]

Abstract: Recent advances in allogeneic stem cell transplantation (allo-HSCT) have included the advent of reduced-intensity conditioning (RIC) regimens to decrease the toxicity of myeloablative allo-SCT and the use of double umbilical cord blood (dUCB) units as a graft source in adults lacking a suitable donor. The FB2A2 regimen (fludarabine 30 mg/kg/day for 5-6 days + i.v. busulfan 3.6 mg/kg/day for 2 days + rabbit antithymocyte globulin 2.5 mg/kg/day for 2 days) supported by peripheral blood stem cells (PBSCs) and the TCF regimen (fludarabine 200 mg/m² for 5 days + cyclophosphamide 50 mg/kg for 1 day + low-dose [2 Gy] total body irradiation) supported by dUCB units are currently the most widely used RIC regimens in many centers and could be considered standard of care in adults eligible for an RIC allo-SCT. Here we compared, retrospectively, the outcomes of adults patients who received the FB2A2-PBSC RIC regimen (n = 52; median age, 59 years; median follow-up, 19 months) and those who received the dUCB-TCF RIC regimen (n = 39; median age, 56 years; median follow-up, 20 months) for allo-SCT between January 2007 and November 2010. There were no significant between-group differences in patient and disease characteristics. Cumulative incidences of engraftment, acute grade II-IV and chronic graft-versus-host disease were similar in the 2 groups. The median time to platelet recovery, incidence of early death (before day +100), and 2-year nonrelapse mortality were significantly higher in the dUCB-TCF group (38 days versus 0 days [P <.0001]; 20.5% versus 4% [P = .05], and 26.5% versus 6% [P = .02], respectively). The groups did not differ in terms of 2-year overall survival (62% for FB2A2-PBSC versus 61% for dUCB-TCF), disease-free survival (59% versus 50.5%), or relapse incidence (35.5% versus 23%). In multivariate analysis, the presence of a lymphoid disorder was associated with a significantly higher 2-year overall survival (hazard ratio, 0.42; 95% confidence interval, 0.20-0.87; P = .02), whereas patients receiving a FB2A2-PBSC allo-SCT had a significantly lower 2-year nonrelapse mortality (hazard ratio, 0.24; 95% confidence interval, 0.1-0.7; P = .01). There were no factors associated with higher 2-year disease-free survival or lower relapse incidence. This study suggests that the dUCB-TCF regimen provides a valid alternative in adults lacking a suitable donor and eligible for RIC allo-SCT. Prospective and randomized studies are warranted to establish the definitive role of dUCB RIC allo-SCT in adults. In addition, strategies for decreasing nonrelapse mortality after dUCB RIC allo-SCT are urgently needed. [Copyright &y& Elsevier]

Background: Three different scoring systems have been developed to assess pre‐transplant comorbidity in allogeneic hematopoietic stem cell transplantation (Allo‐HSCT): the Hematopoietic Cell Transplantation‐Specific Comorbidity Index, the Comorbidity/Age index, and the Augmented Comorbidity/Age index. All were devised to predict overall survival (OS) and disease‐free survival (DFS) survivals and non‐relapse mortality (NRM) in patients receiving HLA‐matched Allo‐HSCT, but their performance has scarcely been studied in the haploidentical Allo‐HSCT setting with post‐transplant cyclophosphamide, a procedure in constant expansion worldwide. Methods: To address this issue, their impact on survivals and NRM was examined in a cohort of 223 patients treated with haploidentical Allo‐HSCT in four different centers. Results: With a median follow‐up of 35.6 months, 3‐year OS, DFS, and NRM were 48.1% ± 4%, 46.3% ± 4%, and 30.0% ± 3%, respectively. No impact was found for any of the three comorbidity scores in univariate analysis. In multivariate analyses, the only three factors associated with lower OS were DRI (p < 0.001), an older age of recipients (≥55 years old, p = 0.02) and of donors (≥40 years old, p = 0.005). Older donor age was also associated with lower DFS and higher NRM. Conclusion: The comorbidity scores do not predict survivals nor NRM in haploidentical Allo‐HSCT with PTCY, suggesting that pre‐transplant comorbidities should not be a contra‐indication to this procedure. [ABSTRACT FROM AUTHOR]

KIR are mainly expressed on NK cells and to a lesser extent on T lymphocytes. Although the KIR NK cell repertoire was well explored in haploidentical Hematopoietic Stem Cell Transplantation (HSCT), KIR T cell compartment remains to be investigated in this context. In this study, the investigation of NK receptors on T lymphocytes during immune reconstitution after T-cell-replete haploidentical HSCT with Post-Transplant Cyclophosphamide (PTCy) has shown a significant increase of KIR2DL2/3+ T cell frequency at day 25. This was especially observed at day 30 in recipients who relapsed. IL-15 but not IL-12 increased in vitro KIR+ T cell expansion suggesting that the raised IL-15 serum concentration observed after PTCy in haploidentical HSCT might increase KIR+ T cell frequency. Moreover, investigations from healthy blood donors showed a higher inhibiting effect of KIR2DL3 on CMV specific T cell response against allogeneic than autologous C1+ target cells. The association of KIR+ T cell subset with relapse may suggest that inhibitory KIR2DL2/3 limit anti-leukemic effect of specific T lymphocytes at this early step of immune reconstitution. Further phenotypic and mechanistic investigations on this cell subset from a broader cohort of HSCT recipients should clarify its potential implication in relapse occurrence. Our results demonstrate that KIR-HLA interactions known to modulate NK cell functions also modulate T cell immune responses in the context of allogeneic HSCT. [ABSTRACT FROM AUTHOR]

Cleavage of the MUC1 glycoprotein yields two subunits, an extracellular alpha-subunit bound to a smaller transmembrane beta-subunit. Monoclonal antibodies (mAbs) directed against the MUC1 alpha–beta junction comprising the SEA domain, a stable cell-surface moiety, were generated. Sequencing of all seven anti-SEA domain mAbs showed that they clustered into four groups and sequences of all groups are presented here. mAb DMB5F3 with picomolar affinity for the MUC1 SEA target was selected for further evaluation. Immunohistochemical staining of a series of malignancies with DMB5F3 including lung, prostate, breast, colon, and pancreatic carcinomas revealed qualitative and qualitative differences between MUC1 expression on normal versus malignant cells: DMB5F3 strongly stained malignant cells in a near-circumferential pattern, whereas MUC1 in normal pancreatic and breast tissue showed only weak apical positivity of ductal/acinar cells. Humanized chimeric DMB5F3 linked to ZZ-PE38 (ZZ IgG-binding protein fused to Pseudomonas exotoxin) induced vigorous cytotoxicity of MUC1+ malignant cells in vitro. The intensity of cell killing correlated with the level of MUC1 expression by the target cell, suggesting a MUC1 expression threshold for cell killing. MUC1+ Colo357 pancreatic cancer cells xenotransplanted into nude and SCID mice models were treated with the chDMB5F3:ZZ-PE38 immunocomplex. In both transplant models, chDMB5F3:ZZ-PE38 exhibited significant in vivo anti-tumor activity, suppressing up to 90% of tumor volume in the SCID model compared with concomitant controls. The efficacy of chDMB5F3:ZZ-PE38 immunotoxin in mediating tumor killing both in vitro and in vivo strongly suggests a clinical role for anti-MUC1 SEA antibody in the treatment of MUC1-expressing malignancies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) is the main cause of late nonrelapse mortality and morbidity after allogeneic stem cell transplantation (allo-SCT), To improve such patients' outcomes, we conducted a phase 2, prospective, multicenter trial to test the efficacy of the addition of rituximab to corticosteroids (CSs) and cyclosporine A (CsA) as first-line therapy for newly diagnosed cGVHD after allo-SCT. Twenty-four patients (median age, 47 years) with mild (n = 2), moderate (n = 7), or severe (n = 15) cGVHD were included. All patients received rituximab 375 mg/m² weekly for 4 weeks, followed by a second course 1 month later for patients with partial response. Twenty of 24 patients (83%) were in response at 1 year. Furthermore, among 19 evaluable patients, 14 (74%) were off CSs. The estimated 1-year overall survival was 83%, and the 1-year cumulative incidence of nonrelapse mortality was 14%. One patient died of progressive multifocal leukoencephalopathy. Although PD-L1hi naive B cells were significantly decreased at diagnosis of cGVHD, they increased after anti-CD20 B-cell depletion. In contrast, activated ICOShl PD-1hi circulating T follicular helper (Tfh) cells decreased after rituximab treatment. Overall, the addition of rituximab to corticosteroid and CsA appeared to be sa_e and effective for first-line treatment of cGVHD. Furthermore, our data suggest that this efficacy may be in part related to an effect on PD-L1hi B cells and Tfh cells. This study was registered at www.clinicaltrials.gov as identifier NCT01135641. [ABSTRACT FROM AUTHOR]

Late complications (LC) and quality of life (QOL) were analyzed in 110 adult patients who underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) and were alive for more than 2 years after allo-SCT. Overall survival of these patients was 93% (95% confidence interval [CI], 88% to 99%) and 81% (95% CI, 71% to 94%) at 5 and 10 years, respectively. The primary cause of death was a recurrence of primary malignancy. With a median follow-up of 4.6 years (range, 2 to 12.1), chronic graft-versus-host disease (cGVHD) was the most prevalent late effect, with a cumulative incidence of 66% (95% CI, 57% to 74%) at 10 years. Cardiovascular complications were the most prevalent LC with a cumulative incidence of 47% (95% CI, 35% to 59%), followed by pulmonary complications with a cumulative incidence of 33% (95% CI, 21% to 46%) and renal impairment with a cumulative incidence of 34% (95% CI, 25% to 43%) at 10 years. Secondary malignancies occurred with a cumulative incidence of 11% (95% CI, 5% to 20%) at 10 years. In this series, 61 patients (55%) responded to QOL survey. With the use of European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30 and Functional Assessment of Cancer Therapy–Bone Marrow Transplant questionnaires, most of the patients reported good to excellent QOL and patients with cGVHD had significantly lower QOL than patients without cGVHD. In conclusion, QOL after RIC is comparable to that seen after myeloablative conditioning, while the natural history of LC after RIC appears to be different from that described in the standard myeloablative setting, warranting further research in this field. [ABSTRACT FROM AUTHOR]

We studied the impact of a set of immune cells contained within granulocyte colonystimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n = 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P=.007). In multivariate analysis, the iNKT dose was the only parameter with a significant impact on GPFS (hazard ratio50.48; 95% confidence interval, 0.27-0.85; P=.01). The incidences of severe grade III to IV acuteGVHD and National Institutes of Health grade 2 to 3 chronic GVHD (12% and 16%, respectively) were low and associated with the use of antithymocyte globulin in 91% of patients. No difference in GVHD incidence was reported according to the iNKT dose. In conclusion, a higher dose of iNKTs within the graft is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content to improve allo-SCT outcome. (Blood. 2016;127(14):1828-1835) [ABSTRACT FROM AUTHOR]

The rapidly increasing use of allogeneic stem cell transplantation (allo-SCT) emphasizes the need for identifying variables predictive of its outcome. Plasmacytoid dendritic cells (pDCs) play a major role in establishing immune competence and in several autoimmune diseases. Thus, we investigated whether pDCs might influence the outcome of patients after allo-SCT in 79 consecutive patients who underwent this procedure. pDCs were identified in the blood of patients at day 100 after allo-SCT by staining peripheral blood mononuclear cells for surface markers and intracellular cytokines and analyzing them on a flow cytometer. We found the pDC level at day 100 was not influenced by patient or graft characteristics, and only the absence of previous grades II to IV acute graft-versus-host disease was significantly associated with higher levels of blood pDCs after allo-SCT (OR, .67; 95% CI, .54 to .83; P = .0004). Using the median value of pDCs at day 100 to divide the patients into 2 distinct groups, we observed that a low pDC level was correlated with a worse overall survival (55% versus 86%, P = .007). In a multivariate analysis, only low pDC level (OR, 3.41; 95% CI, 1.19 to 9.79; P = .02) and older patient age (OR, 5.16; 95% CI, 1.15 to 23.14; P = .03) were significantly predictive of increased risk of death. We conclude that monitoring of pDC may be useful for patient management and may have a significant impact on the probability of a favorable outcome of allo-SCT. [ABSTRACT FROM AUTHOR]

The aim of this phase 2 study was to evaluate the efficacy and safety of trastuzumab, a humanized monoclonal antibody targeted against the human epidermal growth factor receptor 2 (HER2), for adult patients with relapsed/refractory HER2-positive B-ALL. Fifteen patients, with a median age of 62 years, received trastuzumab according to the schedule approved for breast cancer patients (ie, 4 mg/kg intravenous loading dose followed by 2 mg/kg weekly). The overall response rate was 13% with 2 patients achieving partial response and partial remission cytolytic response, respectively. Two other patients were documented with blast clearance. Only 1 reversible grade 3 cardiac toxic event occurred. This phase 2 study showed that trastuzumab monotherapy can allow for some responses in a very high-risk refractory/relapsed HER2-positive adult B-ALL population. Combination of trastuzumab with chemotherapy or other therapeutic monoclonal antibodies should be tested in the future. [ABSTRACT FROM AUTHOR]

This retrospective report compared the results of a reduced-intensity conditioning (RIC) regimen including fludarabine (Flu), and very low-dose oral busulfan (BU) (4 mg/kg total dose) in combination with antithymocyte globulin (ATG) (Flu/ATG/BU) to the classical Flu and low-dose total body irradiation (TBI) (2 Gy) regimen (Flu/TBI) in patients with lymphoid malignancies. With a median follow-up of 42 months, the cumulative incidence of transplant-related mortality (TRM) was 22% in the Flu/ATG/BU group versus 41% in the Flu/TBI group (P = .09). Grade 3-4 acute graft-versus-host disease (aGVHD) and extensive chronic GVHD (cGVHD) incidents were 15% versus 44% (P = .006), and 12% versus 58% (P = .0003), in the Flu/ATG/BU group versus the Flu/TBI group, respectively. The Kaplan-Meier estimate of overall survival (OS) at 2 years was comparable between both groups (71%; 95% confidence interval [CI] 58%-86%, in the Flu/ATG/BU group vs 60%; 95% CI 44%-83%, in the Flu/TBI group, P = .20). The estimate of progression-free survival (PFS) was 63% (95% CI 50%-80%) in the Flu/ATG/BU group versus 52% (95% CI, 36%-76%) in the Flu/TBI group (P = .18), suggesting that reduced-intensity conditioning (RIC) based on Flu, very low-dose BU, and ATG has the potential to induce long-term remissions in patients with lymphoid malignancies. [ABSTRACT FROM AUTHOR]

This single-center retrospective study analyzed 85 consecutive patients who underwent allogeneic stem cell transplantation (allo-SCT) with the aim to assess whether there is a correlation between exposure to cyclosporine-A (CsA; as measured by CsA concentrations during the first month after allo-SCT) and the risk for developing severe grade III-IV acute graft-versus-host disease (aGVHD). The median concentrations of CsA in the blood at 1, 2, 3, and 4 weeks after allo-SCT were 348 (range: 172-733), 284 (range: 137-535), 274 (range: 107-649), and 247 (range: 37-695) ng/mL, respectively. Overall, grade II-IV aGVHD occurred in 36 patients (42%) at a median of 29 (range: 6-100) days after allo-SCT. The incidence of grade III-IV aGVHD (n = 20) was 23% (95% confidence interval [CI], 14%-32%). In univariate analysis, patients receiving allo-SCT from an HLA-matched unrelated donor had a higher risk of grade III-IV aGVHD, and patients having the lowest CsA concentration in the first and second weeks after allo-SCT had a significantly higher risk of grade III-IV aGVHD. In a multivariate logistic regression analysis, a higher CsA concentration measured during the first week following graft infusion was the strongest parameter significantly associated with a reduced risk of severe grade II-IV aGVHD (P = .012; relative risk [RR] = 0.24; 95% CI, 0.08-0.73). Of note, when adjusted by donor type, CsA concentration in week 1 remained significantly associated with risk of severe grade II-IV aGVHD (P = .014). We conclude that precise monitoring of CsA concentrations and adjustment of CsA dose early after allo-SCT may be effective to prevent onset of severe aGVHD. [Copyright &y& Elsevier]

Unrelated umbilical cord blood (UCB) is being increasingly used as an alternative stem cell source for allogeneic stem cell transplantation (allo-SCT). This retrospective study assessed infectious complications occurring in adult patients after UCB transplantation (UCBT). 31 patients received a single (n=4) or double UCBT (n=27) with a median dose of 4.7×107 nucleated cells/kg (range: 2.4-7.7). Patients received either a reduced-intensity conditioning (RIC; n=23) or a standard myeloablative (MA) regimen (n=8). The cumulative incidence of neutrophil recovery was 90%. Neutrophil recovery was achieved at a median time of 24 (range: 8-60) days after UCBT. The cumulative incidences of bacterial, fungal, and parasitic infections were, respectively, 16%, 10%, and 6%. Bloodstream infections were neither lethal nor required any intensive care therapy. Similarly, invasive fungal infections and parasitic infections did not cause any death in those patients with sustained engraftment. Although the cumulative incidence of cytomegalovirus (CMV) recurrence was 21%, no CMV disease was observed. With a median follow-up of 10 (range: 3-30) months, 10 patients have died (relapse, n=5; nonrelapse mortality, [NRM] n=5). Overall, the cumulative incidence of infectious-related mortality (IRM) was 8%. In conclusion, this data suggests that UCBT can be performed in adult patients with hematologic malignancies with an acceptable incidence of IRM provided a sufficient dose of nucleated cells is infused to the patient. [Copyright &y& Elsevier]

Natural killer (NK) cells are key cytotoxic effectors against malignant cells. Polygenic and polymorphic Killer cell Immunoglobulin-like Receptor (KIR) and HLA genes participate in the structural and functional formation of the NK cell repertoire. In this study, we extensively investigated the anti-leukemic potential of NK cell subsets, taking into account these genetic parameters and cytomegalovirus (CMV) status. Hierarchical clustering analysis of NK cell subsets based on NKG2A, KIR, CD57 and NKG2C markers from 68 blood donors identified donor clusters characterized by a specific phenotypic NK cell repertoire linked to a particular immunogenetic KIR and HLA profile and CMV status. On the functional side, acute lymphoblastic leukemia (ALL) was better recognized by NK cells than acute myeloid leukemia (AML). However, a broad inter-individual disparity of NK cell responses exists against the same leukemic target, highlighting bad and good NK responders. The most effective NK cell subsets against different ALLs expressed NKG2A and represented the most frequent subset in the NK cell repertoire. In contrast, minority CD57+ or/and KIR+ NK cell subsets were more efficient against AML. Overall, our data may help to optimize the selection of hematopoietic stem cell donors on the basis of immunogenetic KIR/HLA for ALL patients and identify the best NK cell candidates in immunotherapy for AML. [ABSTRACT FROM AUTHOR]

We describe 4 cases of zygomycosis that occurred after prolonged use of voriconazole in severely immunocompromised patients with hematologic disease. An invasive infection was present in 3 patients who died soon after the diagnosis at 12, 13, and 45 days. Physicians should be mindful of this potential risk after treatment with voriconazole. [ABSTRACT FROM AUTHOR]