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Introduction: Seizures may occur in up to 30% of non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy, yet the optimal anti-seizure medication (ASM) prevention strategy has not been thoroughly investigated., Methods: Consecutive patients affected by refractory non-Hodgkin lymphoma who received anti-CD19 CAR T-cells were included. Patients were selected and assessed using similar internal protocols. ASM was started either as a primary prophylaxis (PP-group) before CAR T-cells infusion or as a pre-emptive therapy (PET-group) only upon the onset of neurotoxicity development., Results: One hundred fifty-six patients were included (PP-group = 88, PET-group = 66). Overall, neurotoxicity and severe neurotoxicity occurred in 45 (29%) and 20 (13%) patients, respectively, equally distributed between the two groups. Five patients experienced epileptic events (PET-group = 3 [4%]; PP-group = 2 [2%]). For all the PET-group patients, seizure/status epilepticus occurred in the absence of overt CAR-T-related neurotoxicity, whereas patients in the PP-group experienced brief seizures only in the context of critical neurotoxicity with progressive severe encephalopathy. ASMs were well-tolerated by all patients, even without titration. No patients developed epilepsy or required long-term ASMs., Conclusion: Our data suggest that both primary and pre-emptive anti-seizure prophylaxis are safe and effective in anti-CD19 CAR T-cell recipients. Clinical rationale suggests a possible more favourable profile of primary prophylaxis, yet no definitive conclusion of superiority between the two ASM strategies can be drawn from our study., (© 2024. The Author(s).)

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

BACKGROUNDPredicting immune effector cell-associated neurotoxicity syndrome (ICANS) in patients infused with CAR T cells is still a conundrum. This complication, thought to be consequent to CAR T cell activation, arises a few days after infusion, when circulating CAR T cells are scarce and specific CAR T cell-derived biomarkers are lacking.METHODSCAR+ extracellular vesicle (CAR+EV) release was assessed in human CD19.CAR T cells cocultured with CD19+ target cells. A prospective cohort of 100 patients with B cell lymphoma infused with approved CD19.CAR T cell products was assessed for plasma CAR+EVs as biomarkers of in vivo CD19.CAR T cell activation. Human induced pluripotent stem cell-derived (iPSC-derived) neural cells were used as a model for CAR+EV-induced neurotoxicity.RESULTSIn vitro release of CAR+EVs occurs within 1 hour after target engagement. Plasma CAR+EVs are detectable 1 hour after infusion. A concentration greater than 132.8 CAR+EVs/μL at hour +1 or greater than 224.5 CAR+EVs/μL at day +1 predicted ICANS in advance of 4 days, with a sensitivity and a specificity outperforming other ICANS predictors. ENO2+ nanoparticles were released by iPSC-derived neural cells upon CAR+EV exposure and were increased in plasma of patients with ICANS.CONCLUSIONPlasma CAR+EVs are an immediate signal of CD19.CAR T cell activation, are suitable predictors of neurotoxicity, and may be involved in ICANS pathogenesis.TRIAL REGISTRATIONNCT04892433, NCT05807789.FUNDINGLife Science Hub-Advanced Therapies (financed by Health Ministry as part of the National Plan for Complementary Investments to the National Recovery and Resilience Plan [NRRP]: E.3 Innovative health ecosystem for APC fees and immunomonitoring).

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a rare but potentially fatal complication following allogenic hematopoietic cell transplantation (allo-HCT). Timely identification of SOS/VOD to allow for prompt treatment is critical, but identifying a VOD-predictive biomarker remains challenging. Given the pivotal role of endothelial dysfunction in SOS/VOD pathophysiology, the CECinVOD study prospectively evaluated levels of circulating endothelial cells (CECs) in patients undergoing allo-HCT with a myeloablative conditioning (MAC) regimen to investigate the potential of CEC level in predicting and diagnosing SOS/VOD. A total of 150 patients from 11 Italian bone marrow transplantation units were enrolled. All participants were age >18 years and received a MAC regimen, putting them at elevated risk of developing SOS/VOD. Overall, 6 cases of SOS/VOD (4%) were recorded. CECs were detected using the Food and Drug Administration-approved CellSearch system, an immunomagnetic selection-based platform incorporating ferrofluid nanoparticles and fluorescent-labeled antibodies, and were defined as CD146+, CD105+, DAPI+, or CD45-. Blood samples were collected at the following time points: before (T0) and at the end of conditioning treatment (T1), at neutrophil engraftment (T2), and at 7 to 10 days postengraftment (T3). For patients who developed VOD, additional samples were collected at any suspected or proven VOD onset (T4) and weekly during defibrotide treatment (T5 to T8). A baseline CEC count >17/mL was associated with an elevated risk of SOS/VOD (P = .04), along with bilirubin level >1.5 mg/mL and a haploidentical donor hematopoietic stem cell source. Postconditioning regimen (T1) CEC levels were elevated (P = .02), and levels were further increased at engraftment (P < .0001). Additionally, patients developing SOS/VOD after engraftment, especially those with late-onset SOS/VOD, showed a markedly higher relative increase (>150%) in CEC count. Multivariate analysis supported these findings, along with a high Endothelial Activation and Stress Index (EASIX) score at engraftment (T2). Finally, CEC kinetics corresponded with defibrotide treatment. After the start of therapy (T4), CEC levels showed an initial increase in the first week (T5), followed by a progressive decrease during VOD treatment (T6 and T7) and a return to pre-SOS/VOD onset levels at resolution of the complication. This prospective multicenter study reveals a low incidence of SOS/VOD in high-risk patients compared to historical data, in line with recent reports. The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and its role in in the development of SOS/VOD, suggesting that CEC level can be a valuable biomarker for diagnosing SOS/VOD and identifying patients at greater risk of this complication, especially late-onset SOS/VOD. Furthermore, CEC kinetics may support treatment strategies by providing insight into the optimal timing for discontinuing defibrotide treatment., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Novelty in total body irradiation (TBI) as part of pre-transplant conditioning regimens lacked until recently, despite the developments in the field of allogeneic stem cell transplants. Long-term toxicities have been one of the major concerns associated with TBI in this setting, although the impact of TBI is not so easy to discriminate from that of chemotherapy, especially in the adult population. More recently, lower-intensity TBI and different approaches to irradiation (namely, total marrow irradiation, TMI, and total marrow and lymphoid irradiation, TMLI) were implemented to keep the benefits of irradiation and limit potential harm. TMI/TMLI is an alternative to TBI that delivers more selective irradiation, with healthy tissues being better spared and the control of the radiation dose delivery. In this review, we discussed the potential radiation-associated long-term toxicities and their management, summarized the evidence regarding the current indications of traditional TBI, and focused on the technological advances in radiotherapy that have resulted in the development of TMLI. Finally, considering the most recent published trials, we postulate how the role of radiotherapy in the setting of allografting might change in the future.

Accessibility to allogeneic hematopoietic cell transplantation (HCT) programs for older patients is growing constantly. We report on the clinical outcomes of a group of 701 adults aged ≥70 years, with acute myeloid leukemia (AML) in first complete remission (CR1), who received a first HCT, from HLA-matched sibling donors (MSD), 10/10 HLA-matched unrelated donors (UD), 9/10 HLA-mismatched unrelated donors (mUD) or haploidentical (Haplo) donors. The 2-year overall survival (OS) was 48.1%, leukemia-free survival (LFS) 45.3%, relapse incidence (RI) 25.2%, non-relapse mortality (NRM) 29.5% and GVHD-free, relapse-free survival (GRFS), 33.4%. Compared to MSD, patients transplanted from Haplo and UD presented lower RI (HR 0.46, 95% CI 0.25-0.8, p = 0.02 and HR 0.44, 95% CI: 0.28-0.69, p = 0.001, respectively); this translated into prolonged LFS for Haplo (HR 0.62, 95% CI: 0.39-0.99, p = 0.04). Patients transplanted from mUD exhibited the highest NRM incidence (HR 2.33, 95% CI: 1.26-4.31, p = 0.007). HCT in selected adult CR1 AML patients >70 years is feasible and could be associated with good clinical outcomes. Prospective clinical trials are warranted., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). There are no biomarkers that can consistently predict its occurrence. We aimed to evaluate whether numbers of antigen-presenting cell subsets in peripheral blood (PB) or serum chemokine concentrations are biomarkers of cGVHD occurrence. The study cohort comprised 101 consecutive patients undergoing allogeneic HSCT between January 2007 and 2011. cGVHD was diagnosed by both modified Seattle criteria and National Institutes of Health (NIH) criteria. Multicolor flow cytometry was used to determine the number of PB myeloid dendritic cells (DCs), plasmacytoid DCs, CD16 + DCs, and CD16 + and CD16 - monocytes, as well as CD4 + and CD8 + T cells, CD56 + natural killer cells, and CD19 + B cells. Serum concentrations of CXCL8, CXCL10, CCL2, CCL3, CCL4, and CCL5 were measured by a cytometry bead array assay. At a median of 60 days after enrollment, 37 patients had developed cGVHD. Patients with cGVHD and those without cGVHD had comparable clinical characteristics. However, previous acute GVHD (aGVHD) was strongly correlated with later cGVHD (57% versus 24%, respectively; P = .0024). Each potential biomarker was screened for its association with cGVHD using the Mann-Whitney U test. Biomarkers that differed significantly (P < .05) between patients with cGVHD and those without cGVHD were analyzed by receiver operating characteristic (ROC) curve analysis to select the variables predicting cGVHD with an area under the ROC curve (AUC) >.5 and a P value <.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 ≥592.650 pg/mL (hazard ratio [HR], 2.655; 95% confidence interval [CI], 1.298 to 5.433; P = .008), pDC ≥2.448/μL (HR, .286; 95% CI, .142 to .577; P < .001) and previous aGVHD (HR, 2.635; 95% CI, 1.298 to 5.347; P = .007). A risk score was derived based on the weighted coefficients of each variable (2 points each), resulting in the identification of 4 cohorts of patients (scores of 0, 2, 4, and 6). In a competing risk analysis to stratify patients at differing risk levels of cGVHD, the cumulative incidence of cGVHD was 9.7%, 34.3%, 57.7%, and 100% in patients with scores of 0, 2, 4, and 6, respectively (P < .0001). The score could nicely stratify the patients based on the risk of extensive cGVHD as well as NIH-based global and moderate to severe cGVHD. Based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of .791 (95% CI, .703 to .880; P < .001). Finally, a cutoff score ≥4 was identified as the optimal cutoff by Youden J index with a sensitivity of 57.1% and a specificity of 85.0%. A multiparameter score including a history of previous aGVHD, serum CXCL10 concentration, and number of pDCs in the PB at 3 months post-HSCT stratify patients at varying risk levels of cGVHD. However, the score needs to be validated in a much larger independent and possibly multicenter cohort of patients undergoing transplantation from different donor types and with distinct GVHD prophylaxis regimens., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing., Methods: With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%)., Results: No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients ( P  < 0.001); more active diseases at the time of SCT ( P  < 0.001); a higher prevalence of patients with either hematopoietic cell transplantation-comorbidity index ≥3 ( P  < 0.001) or a good Karnofsky performance status ( P  = 0.025); increased use of peripheral blood stem cells as graft sources ( P  < 0.001); and greater use of reduced intensity conditioning regimens ( P  = 0.013) and of haploidentical donors ( P  < 0.001). Moreover, the 2-y cumulative incidence of relapse with myeloablative doses of BU was significantly lower than that registered with reduced intensity conditioning (21% versus 31%; P  = 0.0003). This was not observed in the TREO-based group., Conclusions: Despite a higher number of risk factors in the TREO group, no significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival according to the type of alkylator, suggesting that TREO has no advantage over BU in terms of efficacy and toxicity in acute myeloid leukemia and myelodysplastic syndrome., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Infusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS., Methods: This is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation., Results: Multivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3 + CD8 + lymphocytes (38.6 % vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8 + CD45RA + CD57 + senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14 + and CD45 + myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8 + T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients., Discussion: Our data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8 + T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history., Competing Interests: PLZ: scientific advisory boards: Secura Bio BIO, Celltrion, Gilead, Janssen-Cilag, BS, Servier, Sandoz, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, ADC Therap., Incyte, Beigene; consultancy: EUSA Pharma, MSD, Novartis; speaker’s bureau: Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, TG Therap., Takeda, Roche, EUSA Pharma, Kiowa Kirin, Novartis, Incyte, Beigene. FB: scientific advisory boards and speaker fees: NEOVII, NOVARTIS, KITE, GILEAD, PFIZER, CELGENE, MSD. MB: Research Grant from NEOVII. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor GL declared a past collaboration with the author FB., (Copyright © 2023 De Matteis, Dicataldo, Casadei, Storci, Laprovitera, Arpinati, Maffini, Cortelli, Guarino, Vaglio, Naddeo, Sinigaglia, Zazzeroni, Guadagnuolo, Tomassini, Bertuccio, Messelodi, Ferracin, Bonafè, Zinzani and Bonifazi.)

Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Rabbit anti-T lymphocyte globulin (ATLG) in addition to calcineurin inhibitors and antimetabolites is a suitable strategy to prevent GVHD in several transplant settings. Randomized studies already demonstrated its efficacy in terms of GVHD prevention, although the effect on relapse remains the major concern for a wider use. Tailoring of ATLG dose on host characteristics is expected to minimize its side effects (immunological reconstitution, relapse, and infections). Here, day -6 to day +15 pharmacokinetics of active ATLG serum level was first assayed in an explorative cohort of 23 patients by testing the ability of the polyclonal serum to bind antigens on human leukocytes. Significantly lower levels of serum active ATLG were found in the patients who developed GVHD (ATLG&#95;AUC CD45 : 241.52 ± 152.16 vs. 766.63 +/- 283.52 (μg*day)/ml, p = 1.46e -5 ). Consistent results were obtained when the ATLG binding capacity was assessed on CD3+ and CD3+/CD4+ T lymphocytes (ATLG&#95;AUC CD3 : 335.83 ± 208.15 vs. 903.54 ± 378.78 (μg*day)/ml, p = 1.92e -4 ; ATLG&#95;AUC CD4 : 317.75 ± 170.70 vs. 910.54 ± 353.35 (μg*day)/ml, p = 3.78e -5 . Concomitantly, at pre-infusion time points, increased concentrations of CD69+ extracellular vesicles (EVs) were found in patients who developed GVHD (mean fold 9.01 ± 1.33; p = 2.12e -5 ). Consistent results were obtained in a validation cohort of 12 additional ATLG-treated HSCT patients. Serum CD69+ EVs were mainly represented in the nano (i.e. 100 nm in diameter) EV compartment and expressed the leukocyte marker CD45, the EV markers CD9 and CD63, and CD103, a marker of tissue-resident memory T cells. The latter are expected to set up a host pro-inflammatory cell compartment that can survive in the recipient for years after conditioning regimen and contribute to GVHD pathogenesis. In summary, high levels of CD69+ EVs are significantly correlated with an increased risk of GVHD, and they may be proposed as a tool to tailor ATLG dose for personalized GVHD prevention., Competing Interests: FB, scientific advisory boards, and speaker fees: NEOVII, NOVARTIS, KITE, GILEAD, PFIZER, CELGENE, MSD. MB, Research Grant from NEOVII. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Storci, Barbato, Ricci, Tazzari, De Matteis, Tomassini, Dicataldo, Laprovitera, Arpinati, Ursi, Maffini, Campanini, Dan, Manfroi, Santi, Ferracin, Bonafe and Bonifazi.)

Drug-induced thrombotic microangiopathy (DITMA) represents 10%-13% of all thrombotic microangiopathy (TMA) cases and about 20%-30% of secondary TMAs, just behind pregnancy-related and infection-related forms. Although the list of drugs potentially involved as causative for TMA are rapidly increasing, the scientific literature on DITMA is quite scarce (mostly as individual case reports or little case series), leading to poor knowledge of pathophysiological mechanisms and clinical management. In this review, we focused on these critical aspects regarding DITMA. We provided an updated list of TMA-associated drugs that we selected from a scientific literature review, including only those drugs with a definite or probable causal association with TMA. The list of drugs is heterogeneous and could help physicians from several different areas to be familiar with DITMA. We describe the clinical features of DITMA, presenting the full spectrum of clinical manifestations, from systemic to kidney-limited forms. We also analyze the association between signs/symptoms (i.e., malignant hypertension, thrombocytopenia) and specific DITMA causative drugs (i.e., interferon, ticlopidine). We highlighted their multiple different pathophysiological mechanisms, being frequently classified as immune-mediated (idiosyncratic) and dose-related/toxic. In particular, to clarify the role of the complement system and genetic deregulation of the related genes, we conducted a revision of the scientific literature searching for DITMA cases who underwent renal biopsy and/or genetic analysis for complement genes. We identified a complement deposition in renal biopsies in half of the patients (37/66; 57%), with some drugs associated with major deposits (i.e., gemcitabine and ramucirumab), particularly in capillary vessels (24/27; 88%), and other with absent deposits (tyrosine kinase inhibitors and intraocular anti-VEGF). We also found out that, differently from other secondary TMAs (such as pregnancy-related-TMA and malignant hypertension TMA), complement genetic pathological mutations are rarely involved in DITMA (2/122, 1.6%). These data suggest a variable non-genetic complement hyperactivation in DITMA, which probably depends on the causative drug involved. Finally, based on recent literature data, we proposed a treatment approach for DITMA, highlighting the importance of drug withdrawal and the role of therapeutic plasma-exchange (TPE), rituximab, and anti-complementary therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mazzierli, Allegretta, Maffini and Allinovi.)

Purpose of Review: Several studies showed that age alone should not be used as an arbitrary parameter to exclude patients from allogeneic hematopoietic cell transplantation (HCT). The accessibility to allogeneic HCT programs for older patients with hematological diseases is growing up constantly. The Center for International Blood and Marrow Transplant Research has recently shown that over 30% of allogeneic HCT recipients are at least 60 years old and that nearly 4% are aged 70 or more. Historically, the use of allogeneic HCT among elderly patients has been limited by age restrictions, reflecting physicians' concerns regarding prohibitive transplant-related mortality and HCT-associated morbidity., Recent Findings: The introduction of reduced intensity/toxicity conditioning regimens has allowed transplant Centers to carry out allogeneic HCT on patients previously considered not ideal candidates. The integration of specific risk scores could lead to better capture mental and physical frailties of older patients. Older adults less frequently have available medically fit siblings, able to donate, so, unrelated donors, familial haploidentical donors or umbilical cord blood grafts could potentially abrogate such a difficulty, allowing the curative potential of allogeneic HCT., Summary: The appropriate assessing of allogeneic HCT feasibility for elderly patients should be the resonate application of different clinical and biological principles., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Disease relapse represents by far the most frequent cause of hematopoietic cell transplantation (HCT) failure. Patients with acute leukemia suffering relapse after HCT have limited conventional treatment options with little possibility of cure and represent, de facto, suitable candidates for the evaluation of novel cellular and biological-based therapies. Donor lymphocyte infusions (DLI) has been one of the first cellular therapies adopted to treat post HCT relapse of acute leukemia patients and still now, it is widely adopted in preemptive and prophylactic settings, with renewed interest for manipulated cellular products such as NK-DLI. The acquisition of novel biological insights into pathobiology of leukemia relapse are translating into the clinic, with novel combinations of target therapies and novel agents, helping delineate new therapeutical landscapes. Hypomethylating agents alone or in combination with novel drugs demonstrated their efficacy in pre-clinical models and controlled trials. FLT3 inhibitors represent an essential therapeutical instrument incorporated in post-transplant maintenance strategies. The Holy grail of allogeneic transplantation lies in the separation of graft-vs.-host disease from graft vs. tumor effects and after more than five decades, is still the most ambitious goal to reach and many ways to accomplish are on their way., Competing Interests: The authors declare that the study was conducted in the absence of any commercial or financial relationship deemed to be a potential conflict of interest., (Copyright © 2022 Maffini, Ursi, Barbato, Dicataldo, Roberto, Campanini, Dan, De Felice, De Matteis, Storci, Bonafè, Arpinati and Bonifazi.)

Measurable residual disease (MRD) assessment before allogeneic hematopoietic cell transplantation (HCT) may help physicians to identify a subgroup of patients at high risk of relapse for de novo acute myeloid leukemia (AML) but its relevance among patients affected by secondary AML (sAML) is still unknown. We assessed the impact of MRD among 318 adult patients with sAML who received an allogeneic HCT in first complete remission. At the time of HCT, a total of 208 (65%) patients achieved MRD negativity, while 110 (35%) had positive MRD. 2-year overall survival (OS) was 58.8 % (95% CI 52.2-64.9) with leukemia-free survival (LFS) of 50.0 % (95% CI 43.7-56.1), relapse incidence of 34.2% (95% CI 28.4-40.1) and non-relapse mortality (NRM) of 23.3 % (95% CI 19-27.7) for the entire cohort. In multivariate analysis, HCT recipients with KPS ≥ 90 experienced less disease recurrence (HR 0.61, 95% CI 0.4-0.94) with better LFS (HR 0.63, 95% CI 0.44-0.89) and OS (HR 0.58, 95% CI 0.39-0.86). There were no differences in major clinical endpoints between patients with MRD-positive and MRD-negative status at the time of HCT. Pre-transplantation assessment of MRD was not informative on post-HCT outcomes in this retrospective registry-based analysis among patients affected by sAML., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Multiple myeloma (MM) is a hematological disease characterized by the proliferation and accumulation of malignant plasmacells (PCs) in the bone marrow (BM). Despite widespread use of high-dose chemotherapy in combination with autologous stem cell transplantation (ASCT) and the introduction of novel agents (immunomodulatory drugs, IMiDs, and proteasome inhibitors, PIs), the prognosis of MM patients is still poor. CD38 is a multifunctional cell-surface glycoprotein with receptor and ectoenzymatic activities. The very high and homogeneous expression of CD38 on myeloma PCs makes it an attractive target for novel therapeutic strategies. Several anti-CD38 monoclonal antibodies have been, or are being, developed for the treatment of MM, including daratumumab and isatuximab. Here we provide an in-depth look atCD38 biology, the role of CD38 in MM progression and its complex interactions with the BM microenvironment, the importance of anti-CD38 monoclonal antibodies, and the main mechanisms of antibody resistance. We then review a number of multiparametric flow cytometry techniques exploiting CD38 antigen expression on PCs to diagnose and monitor the response to treatment in MM patients.

Patients with acute lymphoblastic leukemia (ALL) are characterized by an unfavorable outcome in the majority of adult cases. Several clinical trials have confirmed the usefulness of a pediatric-type therapy applied to adult patients. Adults present with higher risk features at diagnosis that predispose them to chemotherapy resistance and disease relapse after an initial achievement of complete remission. The recent introduction of novel immune-targeted therapies, including monoclonal antibodies (MoAbs) targeting B cell-associated antigens such as CD19 (blinatumumab) and CD22 (inotuzumab), tyrosine kinase inhibitors targeting BCR-ABL1 tyrosine kinase, bispecific antibodies and chimeric antigen receptor T- cell therapy (CAR-T), circumvent B-ALL cell chemo-refractoriness through novel mechanisms of action, potentially eradicating minimal residual disease (MRD) and enabling more patients to receive allogeneic hematopoietic stem cell transplantation and to achieve a better clinical outcome.

Previous observations have reported controversial conclusions regarding cell dose and survival endpoints after allogeneic hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis on 414 adult patients (median age 54 years, range, 18-74 years) with acute myeloid leukemia (AML) in first and second complete remission. They received a T-cell replete allogeneic HSCT from haploidentical donors, using peripheral blood stem cells, between 2006-2018. Median number of infused CD34+ was 6.58 × 10 6 /kg (range, 2.2-31.2 × 10 6 /kg). Graft-vs-host disease (GVHD) prophylaxis was post-transplant cyclophosphamide in 293 patients and anti-lymphocyte serum in 121 patients. Conditioning was myeloablative in 179 patients and reduced-intensity in 235 patients. After a median follow-up of 23.3 months (range, 12.1-41.8 months), 2-year overall survival (OS) was 64.5% (95% CI 59.3%-69.7%) with leukemia-free survival (LFS) of 57.3% (95% CI 51.8%-62.7%) and non-relapse mortality (NRM) of 23.3% (95% CI 19%-27.7%). Grades III-IV acute GVHD day+100 incidence was 14.6% while extensive chronic GVHD was 14.4% at 2-years. Thirteen (3.2%) patients experienced graft failure. We found the optimal CD34+/kg threshold defining high (n = 334) vs low cell dose (n = 80) at 4.96 × 10 6 . Recipients of >4.96 × 10 6 /kg CD34+ cells experienced less NRM (Hazard ratio [HR] 0.48; 95% CI 0.30-0.76) and prolonged LFS (HR 0.63; 95% CI 0.43-0.91) and OS (HR 0.60; 95% CI 0.40-0.88) compared to those in the lower cell dose cohort. Larger cohort studies are needed to confirm these findings., (© 2020 Wiley Periodicals, Inc.)

Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products ( off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine., (Copyright © 2020 Cerrano, Ruella, Perales, Vitale, Faraci, Giaccone, Coscia, Maloy, Sanchez-Escamilla, Elsabah, Fadul, Maffini, Pittari and Bruno.)

CD22 is a surface molecule expressed early during the ontogeny of B cells in the bone marrow and spleen, and can be found on B cells isolated from the different lymphoid compartments in humans. CD22 is expressed by most blasts from the majority (60-90%) of B-cell acute lymphoblastic leukemia (B-ALL). Current therapies in adults with newly diagnosed B-ALL are associated with complete remission (CR) rates of 50-90%. However, 30-60% of these patients relapse, and only 25-40% achieve disease-free survival of three years or more. Chemotherapy regimens for patients with refractory/relapsed B-ALL are associated with CR rates ranging from 31% to 44%. Novel immune-targeted therapies, such as blinatumomab and inotuzumab (a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin), provide potential means of circumventing chemo-refractory B-ALL cells through novel mechanisms of action. Eighty percent of inotuzumab-treated B-ALL patients may achieve a CR state. This review is focused on the biological and clinical activities of CD22 antibodies in B-ALL, and provides evidence about the potential role played by qualitative and quantitative analysis of the CD22 molecule on individual B-ALL blasts in predicting the depletion of leukemic cells, and, ultimately, leading to better clinical response rates., Competing Interests: F.L.: Served on advisory boards for Abbvie, Alexion, Pfizer. Research support from Pfizer. F.M.: Research supports from Janssen Pharmaceuticals, Celgene, Tusk Therapeutics, and Centrose. Served on advisory boards for Centrose and Tusk Therapeutics. Now for Sanofi. The other authors declare no conflict of interest.

Introduction : Human Cytomegalovirus (CMV) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Standard treatment options have for long been limited to a small number of effective drugs with significant toxicities. Areas covered : In this manuscript, the authors update a previous review summarizing recent developments in the virology lab and their possible implications for treatment strategies at bedside. In particular, the authors focused on new antiviral drugs already available and under investigation in clinical trials and innovative immunotherapeutic approaches, including adoptive T-cell therapy and vaccines. Expert opinion : Broader knowledge of CMV biology and its relationship with the host immune system is greatly contributing to the development of novel therapeutic approaches. The availability of new drugs, the improved techniques for virological testing and the more accurate patient risk stratification allow to better individualize treatment, limiting toxicity while sparing antiviral effects. The role of immunotherapy is clearly emerging and will further expand our treatment armamentarium.

Cellular therapies are a rapidly evolving approach to treat cancer in the light of their unique mechanism of action that potentially overcomes drug resistance and induces durable remissions. Modalities of adoptive cell therapy include gene-modified T cells expressing novel T cell receptors or chimeric antigen receptors (CAR) that modify the immune system to recognize tumor cells and carry out potent anti-tumor effector functions. CAR T cells have shown very promising clinical results and several trials are being conducted worldwide to establish their role in cancer treatment. Most successful results have been observed in lymphoproliferative disorders with the use of CD19-directed CAR T cells, which led to their commercial approval by FDA. In this review, we provide a comprehensive overview of the current role of CAR T cell therapies in hematological malignancies and solid tumors, their associated toxicities and potential future developments in the armamentarium for cancer treatment.

The majority of adult patients affected by B-cell acute lymphoblastic leukemia (B-ALL) will relapse after an initial response, while approximately 20% will display primary resistant disease. Patients suffering from relapsed/refractory B-ALL have a very poor outcome. Allogeneic hematopoietic cell transplantation (HCT) still represents the only curative approach, but is not so frequently feasible, because of patient's fitness, donor availability, and the ability to achieve a remission prior to HCT. The estimated remission rates with conventional cytotoxic agents are around 30%, but they are short-lived. These disappointing results led to the introduction of new immunologic-based treatments-blinatumomab and inotuzumab. They produced a substantial improvement in terms of response rates, with the ability, in most cases, to induce a minimal residual disease (MRD)-negative status. Similarly, T cells engineered to express a CD19-specific chimeric antigen receptor (CAR-T) have yielded sensational results among patients with relapsed/refractory B-ALL, with unexpectedly high MRD-negative complete remissions rates. However, the first studies looking at long-term outcomes after CAR-T infusions told us that a significant fraction of such responses are not durable, and may benefit from a consolidation approach such as an allogeneic HCT., Competing Interests: There are no conflicts of interest to report., (© 2019 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.)

We previously reported initial results in 102 multiple myeloma (MM) patients treated with sequential high-dose melphalan and autologous hematopoietic cell transplantation followed by 200 cGy total body irradiation with or without fludarabine 90 mg/m 2 and allogeneic hematopoietic cell transplantation. Here we present long-term clinical outcomes among the 102 initial patients and among 142 additional patients, with a median follow up of 8.3 (range 1.0-18.1) years. Donors included human leukocyte antigen identical siblings (n=179) and HLA-matched unrelated donors (n=65). A total of 209 patients (86%) received tandem autologous-allogeneic upfront, while thirty-five patients (14%) had failed a previous autologous hematopoietic cell transplantation before the planned autologous-allogeneic transplantation. Thirty-one patients received maintenance treatment at a median of 86 days (range, 61-150) after allogeneic transplantation. Five-year rates of overall survival (OS) and progression-free survival (PFS) were 54% and 31%, respectively. Ten-year OS and PFS were 41% and 19%, respectively. Overall non-relapse mortality was 2% at 100 days and 14% at five years. Patients with induction-refractory disease and those with high-risk biological features experienced shorter OS and PFS. A total of 152 patients experienced disease relapse and 117 of those received salvage treatment. Eighty-three of the 117 patients achieved a clinical response, and for those, the median duration of survival after relapse was 7.8 years. Moreover, a subset of patients who became negative for minimal residual disease (MRD) by flow cytometry experienced a significantly lower relapse rate as compared with MRD-positive patients ( P =0.03). Our study showed that the graft- versus -myeloma effect after non-myeloablative allografting allowed long-term disease control in standard and high-risk patient subsets. Ultra-high-risk patients did not appear to benefit from tandem autologous/allogeneic hematopoietic cell transplantation because of early disease relapse. Incorporation of newer anti-MM agents into the initial induction treatments before tandem hematopoietic cell transplantation and during maintenance might improve outcomes of ultra-high-risk patients. Clinical trials included in this study are registered at: clinicaltrials.gov identifiers: 00075478, 00005799, 01251575, 00078858, 00105001, 00027820, 00089011, 00003196, 00006251, 00793572, 00054353, 00014235, 00003954., (Copyright © 2019 Ferrata Storti Foundation.)

Haplo-identical transplants (Haplo-Tx) are an important alternative for patients with hematological malignancies who lack a HLA-identical donor. Seventy-one T-replete Haplo-Tx were performed in 70 high-risk patients at our center; 22/70 (31%) patients with refractory/relapsed leukemia received sequential salvage therapy (SeqTh) with high-dose chemotherapy followed by Haplo-Tx during the chemotherapy-induced neutropenia. Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant cyclophosphamide (days + 3 and + 4) with tacrolimus and mycophenolic acid. After a median follow-up of 29.2 months, 3-year overall survival (OS) and event-free survival (EFS) were 43.8 and 40.2%, while 3-year cumulative incidences (CIs) of non-relapse mortality (NRM) and relapse (RI) were 27 and 33%. Day 100 and day 400 CI of grade III-IV acute and moderate-severe chronic GVHD were 11 and 15%. Three-year RI was significantly lower in patients in complete remission (CR) versus those not in CR at the time of transplant (21.5 vs. 48%, p = 0.009) and in patients who received PBSC as compared to BM (22 vs. 45%, p = 0.009). In patients treated with SeqTh, 3-year OS was 19%, while 3-year RI and NRM were 52 and 28% at a median follow-up of 50 months. Overall, Haplo-Tx was feasible in heavily pretreated high-risk patients without a suitable HLA-identical donor.

We evaluated the potential correlation of the hematopoietic cell transplantation comorbidity index (HCT-CI) with the risk of developing post-transplant invasive fungal infections (IFIs). Between January 2009 and March 2015, 312 consecutive patients who received a first allograft entered the study. Low/intermediate HCT-CI risk score (0-2) was observed in 172/312 (55%), whereas high HCT-CI score (≥3) was seen in 140/312 (45%). Overall, 51/312 (16%) patients experienced IFI, defined as possible in 19 (6%), probable in 27 (9%), and proven in 5 (2%). Cumulative incidence of probable-proven IFI at 1 year was 8.5% with a significant higher incidence in patients with high HCT-CI (12%) vs. those with low-intermediate HCT-CI (5%; p = 0.006). There was a strong trend for a higher incidence of baseline severe pulmonary comorbidity in patients who developed probable-proven IFI (p = 0.051). One-year cumulative incidence of non-relapse mortality was higher in patients with IFI vs. those without, 49 and 16% (p < 0.001). By multivariate analysis, disease status at transplant and high HCT-CI, when combined with acute GVHD, were independently associated with the risk of post-transplant IFI. This study shows that a high HCT-CI predicts the risk of developing IFI and may indicate the need of mold-active antifungal prophylaxis in high-risk patients.

Acute graft-vs-host disease (GVHD) is a serious complication after allografting. We carried out an exploratory study to investigate a potential correlation of surface antigens on extracellular vesicles (EVs) and acute GVHD. EVs were extracted from serum samples from 41 multiple myeloma patients who underwent allografting. EVs were characterized by flow cytometry using a panel of 13 antibodies against specific membrane proteins that were reported to be predictive of acute GVHD. We observed a correlation between three potential biomarkers expressed on EV surface and acute GVHD onset by both logistic regression analysis and Cox proportional hazard model. In our study, CD146 (MCAM-1) was correlated with an increased risk-by almost 60%-of developing GVHD, whereas CD31 and CD140-α (PECAM-1 and PDGFR-α) with a decreased risk-by almost 40 and 60%, respectively. These biomarkers also showed a significant change in signal level from baseline to the onset of acute GVHD. Our novel study encourages future investigations into the potential correlation between EVs and acute GVHD. Larger prospective multicenter studies are currently in progress.

Before the introduction of "new drugs," we designed a trial in which 162 newly diagnosed myeloma patients were biologically randomized to receive either an autologous stem cell transplant (auto-SCT) followed by a nonmyeloablative allogeneic stem cell transplant (allo-SCT) or a double auto-SCT. Fifty-eight patients in the allo-SCT arm and 46 in the double auto-SCT arm completed the assigned treatment. At a median follow-up of 12.3 years from allo-SCT and 12.1 years from second auto-SCT, median overall survival (OS) was 11.4 in the allo-SCT arm and 3.9 years in the auto-SCT -arm (P = .007), whereas event-free survival was 3.6 and 1.5 years (P < .001), respectively. A subset of allo-SCT patients showed persistent molecular remission. Two-year cumulative incidence of chronic graft-versus-host disease was 67.2%. At 5 years, 39% of these patients were alive, disease-free, and off immunosuppression; 36.6% had relapsed and 12.2% were still on immunosuppression. Thirty-three of 58 patients (allo-SCT arm) and 39 of 46 (auto-SCT arm) relapsed at least once and were rescued with new drugs. In the allo-SCT arm, 2 patients in biochemical relapse did not reach clinical criteria for treatment. Overall 28 (90%) were treated with new drugs and 14 (45%) received donor lymphocyte infusions (DLIs). In 28 of 31 patients (90%) DLIs were given with new drugs. Median OS from first relapse was 7.5 years in the allo-SCT arm and 2 years in the auto-SCT arm (P = .01). Patients who received DLI showed significantly longer OS (hazard ratio, .38; P = .042) as compared with auto-SCT patients. This difference was slightly lower when only allo-SCT patients who did not receive DLIs were considered (hazard ratio, .56; P = .154). In summary, long-term disease-free survival and survival outcomes after treating relapse with new drugs with or without DLIs were better in allo-SCT patients., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Neurologic complications after hematopoietic stem cell transplantation are frequently life-threatening, and their clinical management can be highly challenging. A wide spectrum of causative factors-including drug-related toxicities; infections sustained by virus, bacteria, or invasive molds; metabolic encephalopathy; cerebrovascular disorders; immune-mediated disorders; and disease recurrence-may lead to potentially lethal complications. Moreover, given that some neurologic complications are not uncommonly diagnosed post mortem, their overall incidence is likely to be underestimated. Their prompt recognition and timely treatment are of paramount importance to reduce the risk for transplantation-related death., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is potentially curative in a variety of hematological malignancies. Graft-vs.-host disease (GvHD) remains a life-threatening complication. Standard treatment is high-dose (HD) corticosteroids. Steroid-refractory (SR) GvHD is associated with poor prognosis. At present, second-line treatment is ill-defined and includes a number of agents. Novel insights into the pathophysiology of acute GvHD (aGvHD) highlight the relevant role of the host inflammatory response governed by several kinase families, including Janus kinases (JAK)1/2. Ruxolitinib, a JAK1/2 inhibitor approved for intermediate-2/high-risk myelofibrosis, was recently employed in SR-GvHD with encouraging overall response rates. Clinical experience however remains limited., Case Presentation: A 51-year-old male with refractory anemia with excess blast type-2 underwent a myeloablative allogeneic HSCT from a 9/10 HLA-matched unrelated donor after conditioning with busulfan and cyclophosphamide. GvHD prophylaxis consisted of cyclosporine, methotrexate, and thymoglobulin. CD34(+) cells/kg infused were 8.69 × 10(6) kg. On day 29, the patient developed overall grade IV aGvHD with biopsy proven stage IV gastrointestinal (GI) GvHD refractory to HD corticosteroids. Patient conditions rapidly deteriorated and became critical despite the addition of mycophenolate mofetil and budesonide. On day 33, Ruxolitinib was started, and on day 39 the patient clinical conditions gradually improved. Complete resolution of aGvHD was also confirmed by histology on day 54., Conclusions: At 5 months from HSCT, the patient is well and in continuous hematological complete remission without flare of GvHD. Ruxolitinib was discontinued on day 156. Ruxolitinib is feasible and effective in SR-aGvHD though large prospective clinical trials are warranted.

Despite a remarkable reduction in the past decades, cytomegalovirus (CMV) disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients remains a feared complication, still associated with significant morbidity and mortality. Today, first line treatment of CMV infection/reactivation is still based on dated antiviral compounds Ganciclovir (GCV), Foscarnet (FOS) and Cidofovir (CDF) with their burdensome weight of side effects. Maribavir (MBV), Letermovir (LMV) and Brincidofovir (BDF) are three new promising anti-CMV drugs without myelosuppressive properties or renal toxic effects that are under investigation in randomized phase II and III trials. Adoptive T-cell therapy (ATCT) in CMV infection possesses a strong rationale, demonstrated by several proof of concept studies; its feasibility is currently under investigation by clinical trials. ATCT from third-party and naïve donors could meet the needs of HSCT recipients of seronegative donors and cord blood grafts. In selected patients such as recipients of T-cell depleted grafts, ATCT, based on CMV-specific host T-cells reconstitution kinetics, would be of value in the prophylactic and/or preemptive CMV treatment. Vaccine-immunotherapy has the difficult task to reduce the incidence of CMV reactivation/infection in highly immunocompromised HSCT patients. Newer notions on CMV biology may represent the base to flush out the Troll of transplantation.

We report the clinical outcomes of 83 patients with acute lymphoblastic leukemia (median age, 46 years; range, 18-75 years) treated at our institution between 1999 and 2011. Treatment refers to clinical trials open for accrual at the time of diagnosis or to institutional guidelines. Upfront allografting was considered for younger high-risk patients. Seventy-eight of 83 (94%) patients achieved complete remission after induction, although 53% of them eventually relapsed. Forty of 70 patients younger than 61 years underwent allografting. The median follow-up was 7.4 years (range, 0.2-15.0 years). Overall, the 5-year overall survival (OS) and event-free survival (EFS) were 40% and 39%, respectively. In patients undergoing transplantation, OS and EFS at 5 years were both 53%, whereas in a nontransplantation setting, both OS and EFS were 35% at 5 years (P = .044 for both OS and EFS). By multivariate analysis, the independent predictors of OS and EFS were age and leukocytosis in the overall population and allografting in young patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Several studies provided evidence of a consistent antileukemic effect induced by cytomegalovirus (CMV) replication in acute myeloid leukemia (AML) patients receiving allogeneic hematopoietic stem cell transplantation (HSCT), however the use of antithymocyte globulin (ATG) as graft-versus-host disease prophylaxis, may potentially abrogate the protective effect of CMV infection. To address this issue, we retrospectively analyzed the risk of relapse in a cohort of 101 patients with AML who received grafts from an unrelated donor after a conditioning regimen including ATG. The cumulative incidence of CMV reactivation, evaluated by RT qPCR, was 59% at 12 months, and 93% of CMV reactivations occurred within the first 100 days post HSCT. The 5-year cumulative incidence of relapse in patients with CMV reactivation was 29% compared with 37% for patients without CMV reactivation, and the only factor associated with a reduced 5-year cumulative incidence of relapse was the disease status at HSCT (P < 0.001). In the multivariable model adverse cytogenetics (HR 2.42, 95% CI 1.02-5.72; P = 0.044) and acute GVHD (HR 3.36, 95% CI 1.32-8.54; P =  0.011) were independent risk factors for reducing overall survival (OS), while the presence of chronic GVHD was associated with a better OS (HR 0.37, 95% CI 0.15-0.89; P = 0.027). CMV replication was not an independent risk factor for OS (HR 1.06, 95% CI 0.07-15.75; P = 0.965). In Conclusion, the results of present study suggest that relapse prevention in patients with AML receiving T-cell depleted HSCT using ATG do not benefit from CMV reactivation., (© 2015 Wiley Periodicals, Inc.)

Immunophenotypic remission (IR) is a strong prognostic factor in myeloma patients. The combination of IR and conventional CR was retrospectively evaluated in 66 patients after allografting. IR was defined as the absence of monoclonal plasma cells in BM aspirates by multiparameter flow cytometry. Conditioning was non-myeloablative in 55 patients; reduced-intensity in 10 and myeloablative in 1 patient. The allograft was given upfront in 35/66 (53%) patients. After a median follow-up of 7.1 years, 24 patients achieved both CR and IR (CR/IR group), 21 achieved IR but not CR with persistence of a urine/serum M-component (no CR/IR group) and 21 did not achieve either CR or IR (no CR/no IR group). Median OS and EFS were 'not reached' and 59 months in the CR/IR group; 64 and 16 months in the no CR/IR; and 36 and 6 months in the no CR/no IR, respectively (P<0.001). Cumulative incidence of extramedullary disease was 4.4% in the CR/IR, 38.1% in the no CR/IR and 14.3% in the no CR/no IR groups, respectively, at 4 years (P<0.001). IR was a valid tool to monitor residual disease after allografting, and allowed definition of a cohort of patients at higher incidence of extramedullary relapse.

We present a case of Trichoderma fungemia with pulmonary involvement in a multiple myeloma patient, who was severely immunocompromised and heavily treated with high-dose melphalan, and underwent autologous hematopoietic cell transplantation. This is the first report, to our knowledge, of proven Trichoderma fungemia, defined by published criteria, successfully treated with voriconazole., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)