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Natural killer cells are an important part of the innate immune system mediating robust responses to virus-infected and malignant cells without needing prior antigen priming. NK cells have always been thought to be short-lived and with no antigen specificity; however, recent data support the presence of NK cell memory including in the hapten-specific contact hypersensitivity model and in certain viral infections. The memory-like features can also be generated by short-term activation of both murine and human NK cells with cytokine combination of IL-12, IL-15 and IL-18, imparting increased longevity and enhanced anticancer functionality. Preclinical studies and very early clinical trials demonstrate safety and very promising clinical activity of these cytokine-induced memory-like (CIML) NK cells, making them an attractive cell type for developing novel adoptive cellular immunotherapy strategies. Furthermore, efforts are on to arm them with novel gene constructs for enhanced tumor targeting and function. [ABSTRACT FROM AUTHOR]

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 µg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are innate lymphoid cells important for host defense against pathogens and mediate antitumor immunity. Cytokine receptors transduce important signals that regulate proliferation, survival, activation status, and trigger effector functions. Here, we review the roles of major cytokines that regulate human NK cell development, survival, and function, including IL-2, IL-12, IL-15, IL-18, and IL-21, and their translation to the clinic as immunotherapy agents. We highlight a recent development in NK cell biology, the identification of innate NK cell memory, and focus on cytokine-induced memory-like (CIML) NK cells that result from a brief, combined activation with IL-12, IL-15, and IL-18. This activation results in long lived NK cells that exhibit enhanced functionality when they encounter a secondary stimulation and provides a new approach to enableNK cells for enhanced responsiveness to infection and cancer. An improved understanding of the cellular and molecular aspects of cytokine-cytokine receptor signals has led to a resurgence of interest in the clinical use of cytokines that sustain and/or activate NK cell antitumor potential. In the future, such strategies will be combined with negative regulatory signal blockade and enhanced recognition to comprehensively enhance NK cells for immunotherapy. [ABSTRACT FROM AUTHOR]

The Fc receptor CD16 is present on essentially all CD56dim peripheral blood natural killer (NK) cells. Upon recognition of antibody-coated cells it delivers a potent signal to NK cells, which eliminate targets through direct killing and cytokine production. Here we investigated the regulation of CD16 surface expression after NK cell activation. Cytokine activation and target cell stimulation led to marked decreases in CD16 expression. Activation of CD56dim NK cells by cross-linking CD16 with antibodies resulted in a loss of CD16 and CD62L, which correlated with increased interferon-γ production. A disintegrin and metalloprotease-17 (ADAM17) is shown to be expressed by NK cells, and its selective inhibition abrogated CD16 and CD62L shedding, and led to enhanced interferon-γ production, especially when triggering was delivered through CD16. Fc-induced pro- duction of cytokines by NK cells exposed to rituximab-coated B cell targets was also enhanced by ADAM17 inhibition. This supports an important role for targeting ADAM17 to prevent CD16 shedding and improve the efficacy of therapeutic antibodies. Our findings demonstrate that over-activation of ADAM17 in NK cells may be detrimental to their effector functions by down-regulating surface expression of CD16 and CD62L. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are lymphocytes that play an important role in the immune response to infection and malignancy. Recent studies in mice have shown that stimulation of NK cells with cytokines or in the context of a viral infection results in memory-like properties. We hypothesized that human NK cells exhibit such memorylike properties with an enhanced recall response after cytokine preactivation. In the present study, we show that human NK cells preactivated briefly with cytokine combinations including IL-12,1L-15, and IL-18 followed by a 7- to 21-day rest have enhanced IFN-γ production after restimulation with IL-12 + IL-15, IL-12 + IL-18, or K562 leukemia cells. This memory-like phenotype was retained in proliferating NK cells. In CD56dim NK cells, the memory-like IFN-γ response was cor- related with the expression of CD94, NKG2A, NKG2C, and CD69 and a lack of CD57 and KIR. Therefore, human NK cells have functional memory-like properties after cytokine activation, which provides a novel rationale for integrating preactivation with combinations of IL-12, IL-15, and IL-18 into NK cell immunotherapy strategies. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells have gained attention as a promising adoptive cell therapy platform for their potential to improve cancer treatments. NK cells offer distinct advantages over T-cells, including major histocompatibility complex class I (MHC-I)-independent tumor recognition and low risk of toxicity, even in an allogeneic setting. Despite this tremendous potential, challenges persist, such as limited in vivo persistence, reduced tumor infiltration, and low absolute NK cell numbers. This review outlines several strategies aiming to overcome these challenges. The developed strategies include optimizing NK cell expansion methods and improving NK cell antitumor responses by cytokine stimulation and genetic manipulations. Using K562 cells expressing membrane IL-15 or IL-21 with or without additional activating ligands like 4-1BBL allows "massive" NK cell expansion and makes multiple cell dosing and "off-the-shelf" efforts feasible. Further improvements in NK cell function can be reached by inducing memory-like NK cells, developing chimeric antigen receptor (CAR)-NK cells, or isolating NK-cell-based tumor-infiltrating lymphocytes (TILs). Memory-like NK cells demonstrate higher in vivo persistence and cytotoxicity, with early clinical trials demonstrating safety and promising efficacy. Recent trials using CAR-NK cells have also demonstrated a lack of any major toxicity, including cytokine release syndrome, and, yet, promising clinical activity. Recent data support that the presence of TIL-NK cells is associated with improved overall patient survival in different types of solid tumors such as head and neck, colorectal, breast, and gastric carcinomas, among the most significant. In conclusion, this review presents insights into the diverse strategies available for NK cell expansion, including the roles played by various cytokines, feeder cells, and culture material in influencing the activation phenotype, telomere length, and cytotoxic potential of expanded NK cells. Notably, genetically modified K562 cells have demonstrated significant efficacy in promoting NK cell expansion. Furthermore, culturing NK cells with IL-2 and IL-15 has been shown to improve expansion rates, while the presence of IL-12 and IL-21 has been linked to enhanced cytotoxic function. Overall, this review provides an overview of NK cell expansion methodologies, highlighting the current landscape of clinical trials and the key advancements to enhance NK-cell-based adoptive cell therapy. [ABSTRACT FROM AUTHOR]

A letter in response to the article "Letermovir for cytomegalovirus prophylaxis in hematopoietic-cell transplantation" published in the May 8, 2014 issue is presented.

NK cells, lymphocytes of the innate immune system, are important for defense against infectious pathogens and cancer. Classically, the CD56dim NK cell subset is thought to mediate antitumor responses, whereas the CD56bright subset is involved in immunomodulation. Here, we challenge this paradigm by demonstrating that brief priming with IL-15 markedly enhanced the antitumor response of CD56bright NK cells. Priming improved multiple CD56bright cell functions: degranulation, cytotoxicity, and cytokine production. Primed CD56bright cells from leukemia patients demonstrated enhanced responses to autologous blasts in vitro, and primed CD56bright cells controlled leukemia cells in vivo in a murine xenograft model. Primed CD56bright cells from multiple myeloma (MM) patients displayed superior responses to autologous myeloma targets, and furthermore, CD56bright NK cells from MM patients primed with the IL-15 receptor agonist ALT-803 in vivo displayed enhanced ex vivo functional responses to MM targets. Effector mechanisms contributing to IL-15-based priming included improved cytotoxic protein expression, target cell conjugation, and LFA-1-, CD2-, and NKG2D-dependent activation of NK cells. Finally, IL-15 robustly stimulated the PI3K/Akt/mTOR and MEK/ERK pathways in CD56bright compared with CD56dim NK cells, and blockade of these pathways attenuated antitumor responses. These findings identify CD56bright NK cells as potent antitumor effectors that warrant further investigation as a cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Non- Candida opportunistic yeasts are emerging causes of bloodstream infection ( BSI) in immunocompromised hosts. However, their clinical presentation, management, and outcomes in stem cell transplant ( SCT) recipients are not well described. We report the first case to our knowledge of Pseudozyma BSI in a SCT recipient. He had evidence of cutaneous involvement, which has not been previously described in the literature. He became infected while neutropenic and receiving empiric micafungin, which is notable because Pseudozyma is reported to be resistant to echinocandins. He was successfully treated with the sequential use of liposomal amphotericin B and voriconazole. A review of the literature revealed nine reported instances of Pseudozyma fungemia. We performed a retrospective review of 3557 SCT recipients at our institution from January 2000 to June 2015 and identified four additional cases of non- Candida yeast BSIs. These include two with Cryptococcus, one with Trichosporon, and one with Saccharomyces. Pseudozyma and other non- Candida yeasts are emerging pathogens that can cause severe and disseminated infections in SCT recipients and other immunocompromised hosts. Clinicians should have a high degree of suspicion for echinocandin-resistant yeasts, if patients develop breakthrough yeast BSIs while receiving echinocandin therapy. [ABSTRACT FROM AUTHOR]

Background The use of T-cell replete haploidentical hematopoietic cell transplant (haplo- HCT) has increased substantially since the introduction of post-transplant cyclophosphamide ( PTCy) regimens. Limited data exist concerning infectious complications of haplo- HCT utilizing mobilized peripheral blood ( PB) hematopoietic cells. Methods This retrospective cohort study included all adult patients at our institution undergoing PB haplo- HCT with PTCy between June 2009 and June 2015. Infections were microbiologically confirmed. Invasive fungal infections ( IFI) classified as 'proven' or 'probable' by standard definitions were included. Results In total, 104 patients were identified. Median follow-up was 218 days (range: 6-1576). A total of 322 episodes of infection were recorded. Eighty-nine percent of patients experienced at least one infection. Median time to first infection was 22 days. Patients experiencing at least one bacterial, viral, and IFI were 62%, 72%, and 6%, respectively. The majority (69%) of bacterial infections were caused by enteric organisms. Seven cases of Staphylococcus aureus infection were recorded, with one bacteremia case. Cytomegalovirus ( CMV) viremia occurred in 54/71 (76%) at-risk patients at a median time of 24 days. Sixteen (15%) patients developed CMV disease. Nineteen percent (20/104) of patients developed BK polyomavirus-associated cystitis. Six (6%) patients experienced a total of seven IFI. Infection was the primary cause of death for 12% (6/51) of patients and was a secondary cause for 41%. Conclusion In PB haplo- HCT patients, a high incidence of CMV viremia and disease was observed. Infections with enteric bacteria were common. Fungal and staphylococcal infections were uncommon. Further studies are needed to compare infectious complications in haplo- HCT with other transplant modalities. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) remains a therapeutic challenge, and a paucity of tumor-specific targets has significantly hampered the development of effective immunebased therapies. Recent paradigm-changing studies have shown that natural killer (NK) cells exhibit innate memory upon brief activation with IL-12 and IL-18, leading to cytokine-induced memory-like (CIML) NK cell differentiation. CIML NK cells have enhanced antitumor activity and have shown promising results in early phase clinical trials in patients with relapsed/refractory AML. Here, we show that arming CIML NK cells with a neoepitope-specific chimeric antigen receptor (CAR) significantly enhances their antitumor responses to nucleophosphmin-1 (NPM1)-mutated AML while avoiding off-target toxicity. CIML NK cells differentiated from peripheral blood NK cells were efficiently transduced to express a TCR-like CAR that specifically recognizes a neoepitope derived from the cytosolic oncogenic NPM1-mutated protein presented by HLA-A2. These CAR CIML NK cells displayed enhanced activity against NPM1-mutated AML cell lines and patient-derived leukemic blast cells. CAR CIML NK cells persisted in vivo and significantly improved AML outcomes in xenograft models. Single-cell RNA sequencing and mass cytometry analyses identified up-regulation of cell proliferation, protein folding, immune responses, and major metabolic pathways in CAR-transduced CIML NK cells, resulting in tumor-specific, CAR-dependent activation and function in response to AML target cells. Thus, efficient arming of CIML NK cells with an NPM1-mutation-specific TCR-like CAR substantially improves their innate antitumor responses against an otherwise intracellular mutant protein. These preclinical findings justify evaluating this approach in clinical trials in HLA-A2+ AML patients with NPM1c mutations. [ABSTRACT FROM AUTHOR]

Abstract: Natural killer (NK) cells are effector lymphocytes that are under clinical investigation for the adoptive immunotherapy of hematologic malignancies, especially acute myeloid leukemia. Recent work in mice has identified innate memory-like properties of NK cells. Human NK cells also exhibit memory-like properties, and cytokine-induced memory-like (CIML) NK cells are generated via brief preactivation with IL-12, IL-15, and IL-18, which later exhibit enhanced functionality upon restimulation. However, the optimal cytokine receptors and signals for maintenance of enhanced function and homeostasis after preactivation remain unclear. Here, we show that IL-12, IL-15, and IL-18 preactivation induces a rapid and prolonged expression of CD25, resulting in a functional high-affinity IL-2 receptor (IL-2Rαβγ) that confers responsiveness to picomolar concentrations of IL-2. The expression of CD25 correlated with STAT5 phosphorylation in response to picomolar concentrations of IL-2, indicating the presence of a signal-competent IL-2Rαβγ. Furthermore, picomolar concentrations of IL-2 acted synergistically with IL-12 to costimulate IFN-γ production by preactivated NK cells, an effect that was CD25 dependent. Picomolar concentrations of IL-2 also enhanced NK cell proliferation and cytotoxicity via the IL-2Rαβγ. Further, after adoptive transfer into immunodeficient NOD-SCID-γc −/− mice, human cytokine–preactivated NK cells expand preferentially in response to exogenous IL-2. Collectively, these data demonstrate that human CIML NK cells respond to IL-2 via IL-2Rαβγ with enhanced survival and functionality, and they provide additional rationale for immunotherapeutic strategies that include brief cytokine preactivation before adoptive NK cell transfer, followed by low-dose IL-2 therapy. [Copyright &y& Elsevier]

Summary: Ruxolitinib for steroid‐refractory acute graft‐versus‐host disease (SR‐aGVHD) results in resistance or intolerance in 1/5 of patients. Outcomes of such patients are undefined. We identified these patients in a multicentre review and reported outcomes. Ruxolitinib‐resistant aGVHD was identified in 48/307 patients. Among patients receiving additional therapy, the overall response rate to next therapy was 36%. Median survival was 21 days. Ruxolitinib intolerance led to treatment discontinuation in 16/307 patients. Ten intolerant patients received additional therapy with 50% experiencing continued improvement of aGVHD. Median survival was 50 days in these patients. These data serve as a baseline for future SR‐aGVHD studies. [ABSTRACT FROM AUTHOR]

Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design. Subjects received G-CSF 10 mcg/kg D1–D8, plerixafor D4–D8, and azacitidine 75 mg/m2 D4–D8, but the trial was amended to reduce G-CSF dose to 5 mcg/kg for 5 days after 2 patients had significant leukocytosis. Plerixafor was dose escalated to 560 mcg/kg/day without dose limiting toxicity. Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients, and ORR of 53% in patients receiving the triplet. Evidence of mobilization correlated with a higher ORR, 60% vs. 17%. Plerixafor, G-CSF and azacitidine appears tolerable when given over 5 days and has encouraging response rates. Plerixafor and G-CSF can be safely combined with azacitidine for 5 days in patients with MDS. The overall response rate of 53% for evaluable patients with this regimen is higher than expected and more responses were seen in patients with blast mobilization. [ABSTRACT FROM AUTHOR]

• The use of HLA-haploidentical and umbilical cord blood transplants expands the access to transplantation is regardless of patient race or ethnicity. • The risk of grade II-IV and III-IV acute graft-versus-host disease is increased after umbilical cord blood transplantation. • The risk of transplantation-related mortality is increased with umbilical cord blood transplantation. Although hematopoietic cell transplantation from an HLA-matched unrelated donor is potentially curative for hematologic malignancies, survival is lower for African Americans compared with Caucasians. Because only approximately 20% of African Americans will have an HLA-matched unrelated donor, many of these patients undergo HLA-haploidentical relative or umbilical cord blood transplantation. In this study, we analyzed outcomes after HLA-haploidentical related donor (n = 249) and umbilical cord blood (n = 118) transplantations in African American patients with hematologic malignancy between 2008 and 2016. The predominant disease was acute myelogenous leukemia for recipients of both types of donor grafts. The incidences of grade II-IV and III-IV acute graft-versus-host disease were higher after umbilical cord blood transplantation compared with HLA-haploidentical relative transplantation (56% and 29%, respectively, versus 33% and 11%, respectively; P <.0001). The 2-year incidence of transplantation-related mortality adjusted for age and conditioning regimen intensity was higher after umbilical cord blood transplantation compared with HLA-haploidentical related donor transplantation (31% versus 18%; P =.008); however, there were no between-group differences in the 2-year adjusted incidence of relapse (30% versus 34%; P =.51), overall survival (54% versus 57%; P =.66), or disease-free survival (43% versus 47%; P =.46). Our findings show that the use of HLA-haploidentical and umbilical cord blood transplants expands the access to transplantation with comparable leukemia-free and overall survival for African Americans with hematologic malignancies. [ABSTRACT FROM AUTHOR]

Summary: We retrospectively analyzed outcomes in patients with acute myeloid leukemia (AML) receiving reduced‐intensity conditioning (RIC) hematopoietic stem cell transplants (HCT) from a peripheral blood (PB) source. We identified 46 haploidentical HCT (haplo), 59 matched unrelated donor HCT (MUD), and 40 matched related donor HCT (SIB) patients at a single institution. Haplo had improved overall survival (OS) when compared to MUD, HR 2.03 (P = 0.01) but not SIB, HR 1.17 (P = 0.61). There were no differences in relapse rates or treatment‐related mortality (TRM). Haplo had higher rates of acute graft‐versus‐host disease (GVHD) grade II–IV at day 180 than MUD (44% vs. 25%, P = 0.03) and SIB (44% vs. 13% P < 0.01). Rates of acute GVHD III–IV and chronic GVHD were similar among the groups. Haplo had slower engraftment rates compared to MUD with neutrophil engraftment at 87% vs. 93%, (P < 0.01) and platelet engraftment at 59% vs. 86%, (P < 0.01) at 28 days. Although patients receiving haplo had higher acute GVHD II–IV and slower engraftment, they did not have increased TRM. These data may suggest that patients receiving haplo have improved OS compared to MUD for AML patients receiving RIC transplants. This should be confirmed using a larger cohort. [ABSTRACT FROM AUTHOR]

• An adaptive mathematical model has been developed to quantify killer immunoglobulin-like receptor (KIR)-KIR ligand (KIRL) interactions. • The magnitude of inhibitory and missing KIR-KIRL interactions predicts overall survival and relapse risk following HLA-matched unrelated donor (URD) hematopoietic cell transplantation (HCT). • Cumulative known KIR-KIRL interactions predict clinical outcomes after URD HCT. • High inhibitory KIR-KIRL interaction scores correlates with robust natural killer cell recovery after URD HCT. Killer immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) interactions play an important role in natural killer (NK) cell-mediated graft-versus-leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Here we present a novel adaptive mathematical model designed to quantify these interactions to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA- matched unrelated donor (URD) HCT recipients were studied retrospectively. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction, and the directionality of interactions was denoted by either a positive (activating) or negative (inhibition) symbol; these interactions were then summed. The absolute values of both the missing KIRL and inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted score (w-KIR score) and subsequently a simplified, nonweighted KIR-KIRL interaction score (IM-KIR score). Increased w-KIR score and IM-KIR score were predictive of all-cause mortality and relapse (w-KIR score: hazard ratio [HR],.37 P =.001] and.44 P =.044], respectively; IM-KIR score: HR,.5 P =.049] and.44 P =.002], respectively). IM-KIR score was also associated with NK cell reconstitution post-HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA-matched URD HCT with hematologic malignancies. Image, graphical abstract [ABSTRACT FROM AUTHOR]

• Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is rare after reduced-intensity conditioning (RIC) transplantation with a cumulative incidence of 1.6% in our large modern cohort. • VOD/SOS continues to be associated with a high nonrelapse mortality (NRM); in our cohort, day 100 NRM was 23% in patients with VOD/SOS compared with 6.4% in patients without VOD/SOS. • VOD/SOS in RIC patients often does not meet classical Baltimore/Seattle criteria and has a later onset, a lower peak bilirubin, and better survival than VOD/SOS in patients with myeloablative conditioning. • VOD/SOS after RIC is strongly associated with higher-dose busulfan (6.4 versus 3.2 mg/kg) in the RIC regimen and use of sirolimus in the graft-versus-host disease prophylaxis regimen. fludarabine with intravenous busulfan at doses of 3.2 mg/kg (Flu/Bu1) or 6.4 mg/kg (Flu/Bu2). Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced-intensity conditioning (RIC) HCT is low compared with myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007 and 2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range, 5 to 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval [CI], 1.1% to 2.4%). Day 100 nonrelapse mortality rate was 23% in the VOD/SOS cohort compared with 6.4% in patients without VOD/SOS (P =.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2 ± ATG (fludarabine with two doses of busulfan, total dose 6.4 mg/kg, with or without anti-thymocyte globulin), compared with 0.15% after Flu/Bu1 ± ATG (fludarabine with single busulfan dose 3.2 mg/kg, with or without anti-thymocyte globulin) (P =.0002); the incidence rate was 2.1% after RIC HCT with sirolimus-containing graft-versus-host disease prophylaxis, compared with 0.8% for RIC without sirolimus (P =.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio [HR], 5.1; 95% CI, 1.8 to 14.2; P =.002) and RIC regimen with Flu/Bu2 ± ATG (HR, 34; 95% CI, 4.5 to 252; P <.001) or other (HR, 32; 95% CI, 3.9 to 257; P =.001) compared with Flu/Bu1 ± ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared with a previously published cohort of 76 patients with VOD/SOS who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT. [ABSTRACT FROM AUTHOR]

• PIRCHE scores offer a method of quantifying indirect T cell alloreactivity. • PIRCHE scores offer a broad range of measurement of HLA disparity. • Graft-versus-host PIRCHE scores correlate with acute graft-versus-host disease. • PIRCHE scores may improve donor selection in haploidentical transplantation. The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score quantifies the number of PIRCHEs in patient-donor pairs and represents an in silico measure of indirect alloreactivity. This biologic process is defined as T cell recognition of epitopes derived from mismatched, allogeneic HLA peptides that are subsequently presented by shared HLA molecules. Its association with clinical outcome has not been examined in haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplantation cyclophosphamide (PTCy). We hypothesized that the PIRCHE score (PS) would correlate with indirect alloreactivity and predict graft-versus-host disease (GVHD) risk and the incidence of relapse after haplo-HCT with PTCy. We retrospectively analyzed 148 patients who underwent peripheral blood stem cell T cell-replete haplo-HCT with PTCy at a single center between 2009 and 2016. For each patient-donor pair, the PS was calculated using the PIRCHE online matching tool. PSs were categorized by class and vector. The median class I graft-versus-host (GVH) PS was 11 (range, 0 to 56), and the median class I host-versus-graft (HVG) PS was 10 (range, 0 to 51). Class I GVH PS was associated with increased risk of grade II-IV acute GVHD (adjusted hazard ratio, 1.03 per PS unit increase; 95% confidence interval, 1.01 to 1.05; P =.008) but not of chronic GVHD or relapse. Our data show that use of the PS is a novel strategy for predicting clinical outcome in haplo-HCT; further studies using registry data and prospective cohorts are warranted to validate these findings. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 55-year-old man presented in a hospital with a rapidly growing tongue lesion over one week. The patient's intraoral examination revealed a necrotic mass infiltrated and surrounded by green areas and that histology shows diffuse infiltration by large cells. The article discusses a case of virescent tounque.

Highlights • MAC regimens for haplo-HCT with PTCy were associated with reduced relapse but increased NRM. • There were no differences in OS or DFS between RIC and MAC haplo-HCT patients. • Rates of acute and chronic GVHD were not different between our RIC and MAC patients. Abstract T cell replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) of 148 patients that underwent haplo-HCT with either MAC (n = 61) or RIC (n = 87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (hazard ratio [HR],.47; 95% confidence interval [CI],.31 to.70), but was associated with higher NRM (HR, 1.74; 95% CI, 1.13 to 2.67). OS and DFS were not significantly different between groups (HRs for MAC versus RIC were.87 [95% CI,.64 to 1.18] and.90 [95% CI,.68 to 1.18] for OS and DFS, respectively). Rates of acute and chronic GVHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo-HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study. [ABSTRACT FROM AUTHOR]

Decitabine has been explored as a reduced-intensity therapy for older or unfit patients with acute myeloid leukemia (AML). To better understand the risk of infections during decitabine treatment, we retrospectively examined the culture results from each infection-related serious adverse event that occurred among 85 AML and myelodysplastic syndromes ( MDS) patients treated in a prospective clinical study using 10-day cycles of decitabine at Washington University School of Medicine. Culture results were available for 163 infection-related complications that occurred in 70 patients: 90 (55.2%) events were culture-negative, 32 (19.6%) were gram-positive bacteria, 20 (12.3%) were gram-negative bacteria, 12 (7.4%) were mixed, 6 (3.7%) were viral, 2 (1.2%) were fungal, and 1 (0.6%) was mycobacterial. Infection-related mortality occurred in 3/24 (13%) of gram-negative events, and 0/51 gram-positive events. On average, nearly one third of patients experienced an infection-related complication with each cycle, and the incidence did not decrease during later cycles. In summary, in patients receiving 10-day decitabine, infectious complications are common and may occur during any cycle of therapy. Although febrile events are commonly culture-negative, gram-positive infections are the most frequent source of culture-positive infections, but gram-negative infections represent a significant risk of mortality in AML and MDS patients treated with decitabine. [ABSTRACT FROM AUTHOR]

Many hematologic malignancies are diseases of aging, and the use of hematopoietic cell transplant (HCT) is growing rapidly among older adults. Modern post-transplant cyclophosphamide (PTCy) protocols with haploidentical (haplo) donors have dramatically expanded the donor pool for patients requiring HCT. Initial studies were performed with bone marrow grafts, which require the donor to undergo anesthesia during harvest. However, the use of mobilized peripheral blood stem cells (PBSCs) may be desirable, especially with older donors. However, data on PBSC haplo-HCT in older adults are lacking. To characterize the impact of age on outcomes in haplo-HCT, we identified all adult patients undergoing haplo-HCT with PTCy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at our institution from January 2009 to June 2016. Patients were grouped into 3 cohorts: Age 1 (≤55), Age 2 (55 to 65), and Age 3 (≥65). To characterize the impact of donor type on outcomes in older patients, we identified age- and disease risk index (DRI)-matched patient age ≥ 65 undergoing HLA-matched unrelated donor (MUD) HCT for AML or MDS during the same time frame. Patients were scored for disease risk and underlying comorbidities using the DRI and HCT-specific comorbidity index. Overall survival (OS) was analyzed using 3 different Cox proportional hazards models. We identified 112 haplo-HCT patients, 95 with AML and 17 with MDS. There were 61 patients in Age 1, 29 patients in Age 2, and 22 in Age 3. Median OS was 448, 397, and 147 days in Age 1, Age 2, and Age 3 patients (log-rank, P  = .04). After adjusting for other risk factors, age ≥ 65 was associated with significantly worse OS after haplo-HCT (aHR, 2.16; 95% CI, 1.15 to 4.07). There was a trend toward increased relapse among older patients at 2 years (56%; 95% CI, 32% to 79%) versus Age 1 (41%; 95% CI, 28% to 54%) and Age 2 (31%; 95% CI, 12% to 50%) ( P  = .08). Among patients age ≥ 65, donor type (MUD versus haplo) did not impact OS (aHR, 1.03; 95% CI, .56 to 1.88) after adjusting for other risk factors. Prior allo-HCT (aHR, 4.95; 95% CI, 1.82 to 13.49) and myeloablative conditioning (aHR, 1.97; 95% CI, 1.04 to 3.73) were associated with inferior survival. Although age ≥ 65 was associated with inferior OS in our haplo-HCT cohort, no difference was seen in survival between MUD and haplo-HCT. Therefore, the use of haploidentical donors in older patients is a reasonable treatment option, especially if there is concern for clinical deterioration. A careful pretransplant evaluation and analysis of risks and benefits is warranted when offering this transplant modality to older adults, especially in patients with previous transplant or poor performance status. Strategies to reduce the risk of relapse and decrease nonrelapse mortality in older adults are areas of ongoing research, and prospective studies are needed. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) is recommended for patients with T cell acute lymphoblastic leukemia (T-ALL) in second or later complete remission (CR) and high-risk patients in first CR. Given its relative rarity, data on outcomes of HCT for T-ALL are limited. We conducted a multicenter retrospective cohort study using data from 208 adult patients who underwent HCT between 2000 and 2014 to describe outcomes of allogeneic HCT for T-ALL in the contemporary era. The median age at HCT was 37 years, and the majority of patients underwent HCT in CR, using total body irradiation (TBI)-based myeloablative conditioning regimens. One-quarter of the patients underwent alternative donor HCT using a mismatched, umbilical cord blood, or haploidentical donor. With a median follow up of 38 months, overall survival at 5 years was 34%. The corresponding cumulative incidence of non-relapse mortality and relapse was 26% and 41%, respectively. In multivariable analysis, factors significantly associated with overall survival were the use of TBI (HR, 0.57; P  = .021), age >35 years (HR, 1.55; P  = .025), and disease status at HCT (HR, 1.98; P  = .005 for relapsed/refractory disease compared with CR). Relapse was the most common cause of death (58% of patients). Allogeneic HCT remains a potentially curative option in selected patients with adult T-ALL, although relapse is a major cause of treatment failure. [ABSTRACT FROM AUTHOR]

Background: The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT.Methods: A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model.Results: Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy.Conclusions: The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. [ABSTRACT FROM AUTHOR]

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL. [ABSTRACT FROM AUTHOR]

Use of high-dose post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis has expanded the use of unmanipulated haploidentical hematopoietic cell transplantation. The immediate post-transplantation course in T cell–replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling cytokine-release syndrome (CRS), previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received granulocyte colony–stimulating factor–mobilized T cell–replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T cell therapies, we found 65 of 75 (87%) met criteria for CRS, although most cases were only mild (grades 1 or 2). However, 9 patients (12%) experienced severe (grades 3 or 4) CRS. Median survival was 2.6 months (95% confidence interval [CI], .43 to 5.8) in patients with severe CRS, compared with 13.1 months (95% CI, 8.1 to not reached) in patients with mild CRS. Transplantation-related mortality was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI, 1.43 to 14.67) compared with that in the mild CRS cohort. Severe CRS patients had a significant delay in median time for neutrophil engraftment . Serum IL-6 levels were measured in 10 haplo-HCT patients and were elevated in the early post-transplantation setting. Seven patients with CRS were treated with tocilizumab, resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT and is associated with worse outcomes. Anti–IL-6 receptor therapy is associated with rapid resolution of the CRS symptoms. [ABSTRACT FROM AUTHOR]

Recent studies comparing allogeneic hematopoietic cell transplantation (HCT) using HLA-matched unrelated donors (MUD) versus HLA-haploidentical donors in patients with acute myeloid leukemia (AML) have suggested equivalent outcomes. The graft source used in most studies of haploidentical transplants has been bone marrow. Similar comparisons between MUD and haplo-HCT using peripheral blood as a graft source have not been adequately performed. We reviewed the records of all 52 AML patients who underwent haplo-HCT (using peripheral blood and post-transplantation high-dose cyclophosphamide) between January 2010 and August 2015 at our institution and compared their outcomes with 88 patients who had a MUD transplant in the same time frame and were frequency matched (preanalysis) to the haploidentical group for conditioning intensity. Multivariate analysis found no difference in outcomes between the 2 groups with the exception of slower count recovery after haploidentical allografts (HR, .48; 95% CI, .32 to .74 for platelets, and HR, .47; 95% CI, .32 to .71 for neutrophils; P < .001 for both comparisons). Our retrospective analysis, although limited by the small sample size, suggests largely similar outcomes with peripheral blood haploidentical versus MUD transplants for AML. [ABSTRACT FROM AUTHOR]

Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 ± .5 versus .8 ± .4 g/dL, respectively; P < .001). In multivariate analysis DeltaAlb remained a significant predictor of severe aGVHD (odds ratio, 5.68; 95% CI, 1.65 to 19.64; P = .006; area under the ROC curve, .74; 95% CI, .63 to .86; P < .001). The best cutoff for DeltaAlb to predict severe aGVHD was .9, with a sensitivity, specificity, and overall classification accuracy of 77%, 66%, and 69%, respectively. The model was validated using the bootstrap technique, with no significant change in its performance. These results were not generalizable to a cohort of 30 patients who received less mucotoxic myeloablative or reduced-intensity conditioning. In conclusion, with mucotoxic myeloablative HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for ultimately allowing for individualized GVHD prophylaxis and potential intervention according to the predicted risk. [ABSTRACT FROM AUTHOR]

The impact of Janus kinase (JAK) 1/2 inhibitor therapy before allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into 5 groups: (1) clinical improvement (n = 23), (2) stable disease (n = 31), (3) new cytopenia/increasing blasts/intolerance (n = 15), (4) progressive disease: splenomegaly (n = 18), and (5) progressive disease: leukemic transformation (LT) (n = 13). Overall survival (OS) at 2 years was 61% (95% confidence interval [CI], 49% to 71%). OS was 91% (95% CI, 69% to 98%) for those who experienced clinical improvement and 32% (95% CI, 8% to 59%) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors ( P = .03), dynamic international prognostic scoring system score ( P = .003), and donor type ( P = .006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, 2 patients developed serious adverse events necessitating delay of HCT and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days before conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplantation outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy before HCT were particularly encouraging, and need further prospective validation. [ABSTRACT FROM AUTHOR]

Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT. [ABSTRACT FROM AUTHOR]

Abstract: Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell–replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant. [Copyright &y& Elsevier]

NK cells are innate lymphocytes important for host defense against viral infections and malignancy. However, the molecular programs orchestrating NK cell activation are incompletely understood. MicroRNA-155 (miR-155) is markedly upregulated following cytokine activation of human and mouse NK cells. Surprisingly, mature human and mouse NK cells transduced to overexpress miR-155, NK cells from mice with NK cell-specific miR-155 overexpression, and miR-155-/- NK cells all secreted more IFN-g compared with controls. Investigating further, we found that activated NK cells with miR-155 overexpression had increased per-cell IFN-γ with normal IFN-γ+ percentages, whereas greater percentages of miR-155-/- NK cells were IFN-γ+. In vivo murine CMV-induced IFN-γ expression by NK cells in these miR-155 models recapitulated the in vitro phenotypes. We performed unbiased RNA-induced silencing complex sequencing on wild-type and miR-155-/- NK cells and found that mRNAs targeted by miR-155 were enriched in NK cell activation signaling pathways. Using specific inhibitors, we confirmed these pathways were mechanistically involved in regulating IFN-g production by miR-155-/- NK cells. These data indicate that miR-155 regulation of NK cell activation is complex and that miR-155 functions as a dynamic tuner for NK cell activation via both setting the activation threshold as well as controlling the extent of activation in mature NK cells. In summary, miR-155-/- NK cells are more easily activated, through increased expression of proteins in the PI3K, NF-kB, and calcineurin pathways, and miR-155-/- and 155-overexpressing NK cells exhibit increased IFN-γ production through distinct cellular mechanisms. [ABSTRACT FROM AUTHOR]

• Combining DSTAT with azacitidine appears feasible with no increased toxicity seen. • A 20 % response rate was observed in this patient population with HMA refractory MDS. • Mobilization of myeloblasts was not observed during the first cycle of DSTAT and azacitidine. Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119–302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study. [ABSTRACT FROM AUTHOR]

Single-center studies have reported increased risk of CMV infection in patients undergoing allogeneic transplant using haploidentical graft with post-transplant cyclophosphamide (HaploCy), however limited data exists regarding the impact of this transplant platform on the incidence of non-CMV herpes viruses (NCHV) infection (viremia/disease). Furthermore, it is unclear if the donor type or altered immune reconstitution resulting from the use of PTCy contributes to this infection risk. To study this, patients reported to the CIBMTR with AML/ALL/MDS transplanted between 2012 and 2017 receiving HaploCy (n = 757), matched-sibling donors receiving PTCy (SibCy, n=403), or matched sibling with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) with either marrow or peripheral blood grafts were examined (Table 1). Too few matched unrelated donors (MUD) receiving PTCY reported to CIBMTR resulted in exclusion of MUD transplants. The cumulative incidence of NCHV in the HaploCy, SibCy and SibCNI were 6.9% (99% CI, 4.7-9.4), 3.2% (1.3-5.9), and 1.7% (1-2.6) respectively by day 30 [p<0.001] and increased to 13.9% (10.8 – 17.3), 10.7 % (7.1 – 15), and 5.7% (4.3 – 7.3) by 6 months after transplant [p<0.001] [Figure 1]. Notably, this is driven by a higher frequency of HHV-6 viremia [HaploCy = 9.3%; SibCy = 5.7%; SibCNI = 1.9%]. Figure 2 shows the multivariable models of survival, relapse, transplant related mortality, and chronic GVHD with a reference group of SibCNI without NCHV infection for the main effect variable of donor and infection. The model examines through the first 2 years after transplant and there was a center effect. Our results suggest that HaploCY is associated with an increased incidence of NCHV infection and HHV-6 viremia predominates. The SibCy cohort experienced an increased incidence of NCHV infections as well. However, only in the HaploCy group is this independently associated with increased TRM and decreased survival. Improved surveillance and preemptive treatment may mitigate the mortality associated with NCHV infections in HaploCy recipients. [ABSTRACT FROM AUTHOR]

There are reports of high rates of viral infections after haploidentical transplant, particularly in the setting of PTCy (HaploCy) but detailed data on incidence are lacking. We describe here the comparative incidence of community respiratory virus (CRV) infections occurring by day 180 post-transplant by donor source and their impact on outcomes including survival, relapse, chronic GVHD, and transplant related mortality (TRM) using CIBMTR registry data. The analysis included 2765 patients, all > 2 years of age, who underwent first allogeneic HCT for AML, ALL or MDS from 100 centers between 2012 and 2017 receiving either HaploCy (n=757), Matched related donor (MRD) transplant with PTCy (SibCy n= 403), and MRD transplant with calcineurin inhibitor and either MTX or MMF (SibCNI n= 1605). The cumulative incidences of CRV in the HaploCy, SibCy and SibCNI were: 3% (99% CI, 1.6-4.8), 3% (1.3-5.5) and 2.4 %(1.5-3.5) respectively at day 30 (P =0.649, NS), but notably higher at 15.5% (12.3-19), 16.2% (11.7-21.2) and 9.4 %(7.6-11.4) at 6 months (P<.001) post-transplant [Figure 1]. Identified CRV included primarily Rhinovirus, Parainfluenza, and RSV accounting for approximately 70% of all CRV reported [Table 1]. Figure 2 shows the multivariable models through 2 years post-transplant for survival, relapse, TRM, and chronic GVHD with a reference group of SibCNI without CRV infection for the main effect variable of donor type and infection. Patients in the HaploCy cohort who developed a CRV by day 180 had a higher risk of TRM [p=0.002] and inferior survival [p = 0.001] compared to the reference group. Older age, more advanced disease, and higher HCT-CI were all associated with increased mortality. The incidence of CRVs is higher for patients receiving PTCy, regardless of donor. This finding justifies further studies to understand long-term antiviral immune recovery in different donor sources and GVHD prophylaxis regimens. The higher overall mortality for HaploCy patients developing CRV infection warrants consideration for patient education and heightened awareness for clinicians, as well as long term follow up studies of such patients. [ABSTRACT FROM AUTHOR]

Haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide (PTCy) as graft versus host disease (GVHD) prophylaxis is frequently used for patients who do not have HLA-identical donors. However, the effect of PTCy on immune reconstitution (IR) has not been studied extensively in large prospective cohorts, despite a high incidence of early viral infections. We quantified IR in 60 patients after haplo-HCT with PTCy, mycophenolate mofetil and tacrolimus (TAC) and compared results to 34 patients with 8/8 HLA matched related or unrelated donors (MD) receiving TAC and methotrexate for GVHD prophylaxis. Both groups received reduced intensity conditioning for hematologic malignancies. Samples were prospectively collected at 1, 2, 3, 6, 9, 12, 18, 24 and 30 months after HCT and analyzed using multi-color flow cytometry to characterize distinct lymphocyte populations. Peripheral blood NK cells 1 month after PTCy were characterized using CyTOF and a panel of 35 metal-labeled monoclonal antibodies and compared to age-matched healthy donor NK cells. Recovery of all T cell subsets (CD4Tcon, CD4Treg, CD8) was significantly reduced in the PTCy cohort compared to MD early after HCT (Figure 1A, B, C). Despite delayed CD4Treg recovery, the Treg:Tcon ratio was significantly higher early after HCT in the PTCY cohort due to relatively deeper depression in CD4Tcon (0.18 vs 0.06, p<0.0001 at 1 month, 0.12 vs 0.06, p=0.0004 at 3 months, Figure 1D). Absolute NK cells were lower at 1 month after PTCy (Figure 1E), entirely due to reduced numbers of CD56dimCD16+ NK cells (Figure 1G). Subsequently, CD56dim NK cells remained significantly lower in the PTCy group until 3 months after HCT. In contrast, recovery of CD56brightCD16− NK cells was significantly increased in the PTCy cohort at 2, 3 and 6 months after HCT (p<0.01. Figure 1F). The distribution of NK subsets 1 month post-HCT was also significantly different between two cohorts due to a higher frequency of immature NK cells in the PTCY cohort (Figure 1H). CyTOF analysis performed 1 month after haplo-HCT showed that NK cells expressed higher level of activating receptor NKp46, CD95, granzyme-B and inhibitory receptor NKG2A and lower expression of CD57 compared to HD (Figure 2). Functional assays showed that PTCy NK cells displayed reduced degranulation and release of IFNγ after activation compared to HD. These functions were rescued after priming with low dose IL-15 in vitro. In summary, the effect of PTCy on IR was most pronounced at 1 month with significantly delayed recovery of CD3, CD4Tcon, CD4Treg, CD8 and CD56dim NK cells. After PTCy, NK cells display an immature phenotype and functional impairment that is at least partly corrected by priming with low dose IL-15. Impairment of NK and T cell recovery early after PTCy-based HCT underscores the need to adopt novel strategies to overcome immune defects induced by this platform. [ABSTRACT FROM AUTHOR]

Single-institution studies suggest increased incidence of CMV infection (DNAemia/organ disease) in recipients of haploidentical grafts with PTCy (HaploCy). It is unclear what factors confer the increased risk. Given increased use of PTCy in matched-sibling donor transplant (SibCy), we examined the impact of donor type and PTCy on transplant outcomes by donor(D)/recipient(R) CMV serostatus and reported CMV DNAemia by day 180. Patients reported to the CIBMTR with AML/ALL/MDS receiving HaploCy (n = 757), SibCy (n=403), or Sib with calcineurin inhibitor and methotrexate/mycophenolate mofetil (SibCNI, n=1605) between 2012 and 2017 were examined (Table 1). Too few MUD with PTCy were reported to include MUD cohorts. Cumulative incidences of CMV DNAemia by d180 were 42% (99% CI, 37-46), 37% (31 - 43), and 23% (20 - 26) for HaploCy, SibCy, and SibCNI respectively [p<0.001]. CMV organ disease was similar [HaploCy, 4% (2-6); SibCy, 4% (2-7); SibCNI, 2% (1-3); p=0.115]. Median onset (days) of CMV infection differed [HaploCy: 38 (range, 2 – 176); SibCy, 32 (5 – 136); SibCNI: 42 (4 – 176), p<0.001]. Figures 1 and 2 show the multivariable analyses for survival, relapse, transplant related mortality, and chronic GVHD examining the effect of D/R CMV serostatus and by CMV DNAemia by day 180. Reference groups were D-/R- SibCNI and SibCNI without CMV DNAemia, respectively. The risk of CMV infection was greatest for CMV Seropositive recipients (R+) with the greatest risk in PTCy recipients regardless of donor [HaploCy: RR 50.3 (14.4 – 175.2); SibCy: RR 47.7 (13.3 – 171.4); SibCNI: RR 24.4 (7.2 – 83.1); p<0.001]. The D+/R- groups also have increased risk for CMV infection [HaploCy: RR 16.3 (4 – 70.5); SibCy: RR 10.1 (2.3 – 43.9); SibCNI: 8.4 (2.4 – 29.2)]. Our study shows that PTCy is associated with higher incidence of CMV infection among both Haplo and Sib transplants. Among seropositive and CMV-infected patients, HaploCy had worse OS and TRM, whereas differences between SibCy and SibCNI were not significant. Neither CMV infection nor serostatus affect relapse. This study supports use of more aggressive prevention strategies in patients receiving PTCy and at risk for CMV infection. [ABSTRACT FROM AUTHOR]

T cell-replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by cytokine release syndrome (CRS). The deleterious impact of severe CRS has been reported in single institution analyses. To determine the effect of CRS on outcomes after haplo-HCT using a large international multi-center cohort. This retrospective analysis includes all patients who underwent haplo-HCT at four academic centers (two in the US, one in Italy, one in Colombia) between 2009 and 2018. CRS was graded based on criteria by Lee (Blood 2014). Outcomes were assessed using no CRS as the comparison group. We compared overall survival and cumulative incident functions across three CRS grade groups using log-rank and Fine-Gray tests. We performed the multivariable analysis using proportional hazards models to control for confounders (including age, gender, dri, HCT-CI, active disease, conditioning intensity, stem cell source). A total of 451 patients were included (Table 1). The incidence of CRS was high (89%), and 17% of patients had severe (grade 3-5) CRS. The incidence of severe CRS was higher in patients receiving peripheral blood grafts (19.5% vs. 4.9%, p=0.0026). Overall survival was better in mild CRS (HR 0.621, p=0.0319) and worse in severe CRS (HR 2.125, P=0.0022). Relapse was lower in both mild CRS (HR 0.429, p=0.0002) and severe CRS (HR 0.324, p=0.0004). Transplant related mortality was not significantly different in mild CRS, but much higher in severe CRS (HR 5.332, p=0.0002). Neutrophil and platelet engraftment were not significantly different in mild CRS, but worse in severe CRS (HR 0.476, p = 0.0008 and HR = 0.590, p = 0.0296). All grade chronic GVHD was significantly reduced in patients with severe CRS (HR 0.256, p=0.0273). There were no other statistical differences in rates of all grade or severe acute or chronic GVHD. Multivariable models adjusting for potential confounders confirmed these effects. These effects did not differ by stem cell source. This international, multi-center analysis in consistent with published single center experiences showing that CRS is a common complication after haplo-HCT and that severe (grade ≥3) CRS is associated with increased TRM and worse overall survival. Importantly, these data are the first to show that mild (grade 1-2) CRS is associated with lower rate of relapse without affecting TRM, thereby improving OS. [ABSTRACT FROM AUTHOR]

In the setting of haploidentical hematopoietic cell transplantation (haplo-HCT), post-transplant cyclophosphamide (PTCy) selectively eliminates alloreactive T cells in-vivo , resulting in favorable graft versus host disease (GVHD), non-relapse mortality (NRM) and relapse outcomes. However, few studies have examined the impact of PTCy on immune reconstitution (IR). We quantified IR in 63 patients after haplo-HCT with PTCy, mofetil mycophenolate and tacrolimus (TAC) and compared results to 93 patients with 8/8 HLA matched related or unrelated donors (MD) receiving TAC, methotrexate and sirolimus for GVHD prophylaxis. Both groups received reduced intensity conditioning for hematologic malignancies. The median age of the Haplo-PTCy and MD cohorts was 55 and 57 years. Patient samples were analyzed using multi-color flow cytometry panels to characterize distinct lymphocyte populations. All IR values are expressed as median absolute cell count per μL. One month after HCT, recovery of all T cell subsets (CD3, CD4Tcon, Treg, CD8) was significantly reduced in the PTCy cohort compared to MD (Figure A, B, C). Recovery of CD4Tcon was also reduced at 2 and 3 months after PTCy (p<=0.01) but recovery of Treg was significantly suppressed for one year after HCT (Figure B). By 2 months post-HCT, CD8 T cell recovery was similar in both cohorts. Despite delayed Treg recovery, the Treg:Tcon ratio was significantly higher after PTCy at 1 and 3 months after HCT (0.18 vs 0.09, p<0.0001, 0.12 vs 0.08, p=0.0006). As CD4Tcon recovery improved, the Treg:Tcon ratio became significantly lower in the Haplo-PTCy cohort at 9 (0.09 vs 0.12, p=0.03) and 12 months (0.07 vs 0.1, p=0.01) post HCT. NK cells were lower 1 month after PTCy (52.7 vs 91.1, p=0.08), but were significantly higher at 2, 3 and 6 months (153.4 vs 94.8, p=0.001, 153.7 vs 87.5, p=0.008, 180 vs 102, p=0.01, respectively, Figure D) compared to the MD cohort. Delayed NK cell recovery at 1 month after PTCy was due entirely to reduced numbers of CD56dim NK cells (Figure E). Subsequently recovery of CD56dim NK cells was similar in both cohorts. Recovery of CD56bright NK cells was significantly increased in the PTCy cohort (p<0.0001. Figure F). Consistent with prior reports, 1 year cumulative incidence of extensive cGvHD was lower in the PTCy cohort compared to the MD cohort, 13% (5-26%, 95% CI) and 40% (30-50%, 95% CI) respectively, p=0.003, without increased NRM (p=0.28) or relapse (p=0.17). In summary, the effect of PTCy on IR was most pronounced 1 month after transplant with significantly delayed recovery of CD3, CD4Tcon, Treg, CD8 and CD56dim NK cells. Slow recovery of CD4Tcon persisted for 3 months and delayed recovery of Treg persisted for 1 year. Beginning 2 months after HCT, recovery of both CD56dim and CD56bright NK cells was more rapid in the PTCy cohort. Further studies will examine the effects of these differences in IR on clinical outcomes such as relapse, infections and GVHD. [ABSTRACT FROM AUTHOR]

Killer immunoglobulin-like receptor (KIR) and KIR-ligand (KIRL) interactions play an important role in natural killer (NK) cell mediated graft versus leukemia (GVL) effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Herein, a novel mathematical method, designed to quantify these interactions, is presented to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA matched unrelated donor (URD)-recipient pairs undergoing HCT for hematologic malignancy were studied retrospectively. Patients and their donors were matched at 8/8 loci, including HLA-A, -B, -C, -DRB1. KIR genotyping was determined by intermediate resolution, quantitative PCR. KIR-KIRL interaction unit values were ascribed (fig. 1). Each URD recipient pair's KIR-KIRL interaction scores were calculated by summing interaction values using a system of matrix equations (fig.2). Ninety-eight donor-recipient pairs with known KIR genotyping were studied (median follow=583 days). The study cohort was heterogeneous with 86 patients received ATG for in vivo T cell depletion. Both the iKIR-KIRL interaction score and the missing KIRL score were significantly associated with protection from all-cause mortality, with a HR of 2.7 (95% CI: 1.5, 4.6; p = 0.0006) and 3.2 (1.7, 6.0; p = 0.0004), respectively. Both iKIR-KIRL interaction score and the missing KIRL score were also significantly associated with relapse protection HR of 2.6 (1.3, 5.4; p = 0.01) and HR of 3.5 (1.5, 8.3; p = 0.005) respectively. Activating KIR component score alone did not have a protective effect against all-cause mortality or relapse. Score components were used to develop a combined inhibitory and missing KIR-KIRL interaction scores (IM-KIR Score). Increased IM-KIR score was predictive of all-cause mortality (HR = 0.44; 0.26, 0.73; P=0.002) and decrease in risk of relapse (HR = 0.5; 0.25, 1.0; P=0.049). IM-KIR score was also associated with increased NK cell reconstitution post HCT. For every 1 unit increase in IM-KIR, recipient NK cell count/mL increased by fifty (SE= 25.2, P= 0.046) at day 30 post-HCT. This study develops a logic-based quantitative method to understand the variation in, and the cumulative effect of, KIR and KIRL interactions on clinical outcomes following HLA-matched unrelated HCT. KIR-KIRL interactions as reflected by the IM-KIR score, significantly influence relapse risk and survival in recipients of HLA matched URD HCT with hematological malignancies. If verified in a larger cohort of patients these findings have the potential to alter the current practice of donor selection in the HLA matched setting. [ABSTRACT FROM AUTHOR]

When selecting a human leukocyte antigen (HLA) matched unrelated donor (URD) for hematopoietic cell transplantation (HCT) it is generally accepted that donor age, sex, ABO blood group and viral serologic status should be considered. However, the inter-relationship among these variables is not well established and a consensus on how strongly to consider each variable has not been reached. Selection of the optimal donor gets more complicated as new donor recipient pair (DRP) selection parameters, including killer immunoglobulin-like receptors (KIR) haplotypes are included. In this study we seek to develop a logic-based method to reduce the inconsistencies in donor selection in the HLA matched HCT. Retrospective review of eligible adults with known KIR genotyping receiving HLA-A, B, C & DRB1 allelically matched URD HCT for hematologic malignancy. Donor recipient pairs were selected based on donor age, sex match, CMV sero-status match, and ABO compatibility when possible; KIR genotype was not considered in DRP selection. KIR-KIR ligand interactions were calculated for each DR pair and interaction unit values were ascribed as previously described and each DRP IM KIR score (eq. 1) was calculated. IM KIR Score = |iKIR| + |mKIRL|.......... [1] Weights of each donor risk variable (age, sex, CMV & ABO match) contribution were ascribed using Cox regression methods and summed up to determine donor risk parameter. Donor risk parameters and reciprocal-IM-KIR were finally combined into a donor risk index. Ninety-eight DRP with known HLA & KIR genotyping were studied. A higher IM-KIR score describes a DRP with increased iKIR-KIR ligand interactions and missing KIR ligand interactions; which was associated with a favorable survival after HCT, HR of 0.44 (95%CI: 0.26 to 0.73; P=0.002). Univariate analysis of overall survival for donor age, sex match, ABO compatibility and CMV status were all statistically insignificant (p>0.05). Donor risk parameter was predictive of mortality with a hazard ratio (HR) of 2.76 (95% CI: 1.22-6.18, p=0.014). Combining the two into a donor risk index was predictive of survival with a HR of 2.38 (1.44-3.92, p=0.001). ROC-AUC comparison of survival for IM-KIR score and donor risk parameter showed AUCs of 0.63 and 0.67 respectively. Further, the combined donor risk index shows improved sensitivity and specificity over the donor risk parameter with AUCs of 0.72 and 0.67 respectively. A novel IM-KIR score independently predicts survival in HLA matched DRP, as does a formalized donor risk parameter which includes non-HLA donor characteristics. Moreover, their addition enhanced the specificity and sensitivity of predicting survival in these patients. If validated in a larger exploration and validation cohort this method of donor selection may improve the donor selection process, decreasing variability in clinical outcomes and improve overall survival. [ABSTRACT FROM AUTHOR]

Introduction HLH has historically been considered a pediatric disease. There are limited prospective data for adults with HLH, particularly on management during and outcomes after allogeneic HSCT. Following the CTN1204 study of HSCT in pediatric HLH, this retrospective analysis sets a benchmark for adult-onset HLH. Subjects We identified 20 patients, median 45yo (21-72), who underwent RIC HSCT for HLH since 2010. 5 (25%) had a malignancy, 3 (15%) a rheumatologic diagnosis, and 3 (15%) a viral precipitant. Of 17 patients tested, 65% had ≥1 variant in HLH-associated or immunologically-relevant genes. (Table) Initial therapy was largely etoposide/dexamethasone (n=16) or malignancy-directed chemotherapy (n=5), with multiple agents, including alemtuzumab, as salvage/bridging therapy. (Figure 1) 17 patients received alemtuzumab as "pre-conditioning" for HSCT, intentionally stopped median 25 days (19-32) prior to cell infusion. Conditioning was fludarabine/busulfan (n=17) in 7 related and 11 unrelated HSCTs or fludarabine/cyclophosphamide/TBI in 2 haploidentical HSCTs. 50% received PBSCs. HSCT occurred median 8 mos after HLH diagnosis (3-13). Results All patients engrafted neutrophils (median 15.5 days) and platelets (median 19.5 days). Donor leukocyte and T-cell chimerisms were variable (30day 43-100%, 5-100%; 1 yr 67-100%, 40-100%). 2 patients received CD34-selected infusions for cytopenias with full donor chimerism; 2 had DLIs for T-cell chimerism ≤20% to augment sustained remission. There was no correlation between alemtuzumab timing and chimerism. With follow-up of 22 months (3-61), 6mo Grade II-IV acute GvHD was 17%, and 12mo cGvHD was 35%. 2 patients relapsed with DLBCL at 3-4 mos; 1 with concurrent HLH. There were no isolated HLH relapses. Before HSCT, patients experienced 7 viral, 8 bacterial, and 5 fungal infections, plus 3 surgeries. In the year following HSCT, 3 patients had CMV, 1 adenoviral, 1 fungal, and 7 bacterial infections. 3 patients required steroids for hyperinflammatory pulmonary syndromes. 18mo OS was 83% (95% CI, 56-94) which compares favorably with 80% OS on CTN1204 and 57-60% on prior CIBMTR query of HSCT in adults with histiocytic diseases. (Figure 2) (Nikiforow. Tandem Mtg 2014). Conclusions Variants in genes associated with familial HLH and other syndromes of immune dysregulation (e.g., Chediak Higashi, Familial Mediterranean Fever) reflect a significant and under-appreciated predisposition to adult-onset HLH. Infectious complications and need for 2nd cell therapies occur, but overall, RIC HSCT preceded by alemtuzumab therapy is a highly feasible approach in adults. [ABSTRACT FROM AUTHOR]

Introduction Patients who receive HLA matched allogeneic hematopoietic cell transplant (HCT) from donors with killer immunoglobulin-like receptor (KIR) haplotype B have improved survival, decreased acute GVHD, and less CMV reactivation when compared with those transplanted with KIR haplotype A donors. However, the effect of NK cell (CD56+) reconstitution kinetics on clinical outcomes in patients with different KIR haplotypes is not well studied. Objectives Compare CD 56+ cell reconstitution kinetics in HCT patients with donor KIR Haplotypes A and B and its effect on clinical outcomes. Methods We assessed absolute NK and T cell counts at days +30, +60 and +100 in 10/10 allele level HLA matched unrelated HCT recipients with known donor KIR typing. KIR haplotype B was assigned when KIR2DL5, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS5 or KIR3DS1 were present in the donor, and haplotype A in their absence. We also evaluated potential impact of NK cell and T cell count recovery on key post transplant outcomes in these patients. Results The study population consisted of 60 adult HCT patients with a median age of 52 years; 55% had lymphoid and 45% had myeloid disease; 57% received a reduced intensity conditioning regimen; 82% underwent T cell depletion with ATG; 88% received GCSF mobilized PBSCT. Recipients of donor haplotype A had a median absolute CD56+ cell count of 210mL−1 (±156) on day (d) +30; 189 (±225) on d+60, and 160 (±120) on d+100; recipients of haplotype B had median absolute CD56 cell counts of 286 (±276) on d+30, 196 (±194) on d+60, and 165 (±124) on d+100 (P=N.S. for haplotype B vs. A). As a whole, median CD56+ cell counts peaked at d+30 post HCT, a phenomenon more pronounced in haplotype B (fig. 1), and then declined at d+60 and d+100. There was no correlation between CD56 and CD3 at d+60. Survival was superior in patients who had CD56+ cell count > median for the entire cohort (227 µL−1) on d+60 (p=.039) (fig. 2); ROC-AUC analysis confirmed the deleterious effect of low NK cell counts, with a higher mortality rate observed in those with CD56+ cell count of <50µL−1 (p = 0.039). These patients developed frequent viral reactivation. In this small heterogeneous cohort of patients GVHD, relapse and viral reactivation were not significantly different between the 2 KIR haplotypes. CMV reactivation was not significantly different between the KIR haplotype A and B. Conclusions The magnitude of NK cells reconstitution at d+60 may override the effect of KIR Haplotype on survival in patients with myeloid and lymphoid malignancies, as well as play an important role in controlling viral reactivation. Our data demonstrates that poor NK cell recovery does not necessarily imply delayed T cell reconstitution; suggesting that the adverse survival effect may be NK cell mediated. Ongoing work is examining relationship between NK- and T-cell reconstitution as well as KIR-KIR ligand interactions, and clinical outcomes. [ABSTRACT FROM AUTHOR]

Introduction High dose post-transplant cyclophosphamide has improved the outcomes and expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). The impact of HLA disparity in this setting, however, is unclear and is traditionally measured at the antigen or allele level. The Predicted Indirectly Recognizable HLA Epitopes (PIRCHES) model provides a novel tool to calculate the number of mismatched HLA peptides between donor and host that can be processed and presented by shared HLA antigens for T cell recognition. No data exist on the relationship between PIRCHES mismatch and clinical outcome in haplo-HCT with post-transplant cyclophosphamide. Methods 148 patients who received a peripheral blood, T-cell replete haplo-HCT with post-transplant cyclophosphamide at a single center between 2009 and 2016 were retrospectively analyzed. The PIRCHES mismatch load was calculated using the PIRCHES matching tool online and was categorized by class and vector. The primary outcome was incidence of relapse. The association between PIRCHES mismatch and outcome was analyzed using the Cox proportional hazard model or Gray's sub-distribution method for competing risk as appropriate. This study was approved by the Institutional Review Board. Results The median follow-up for survivors was 34.0 months (range, 14.5-78.3 months). One-hundred (67.6%) patients were deceased and 61 (41.2%) patients relapsed during follow-up. Class I graft-versus-host (GvH) PIRCHES mismatch had a median of 11 with a range of 0 to 56. Class II GvH PIRCHES mismatch had a median of 29 with a range of 0 to 122. Class I GvH PIRCHES mismatch was associated with worse acute graft-versus-host disease (aGvHD) (grades II-IV) (HR 1.021 per unit PIRCHES mismatch increase; 95% CI 1.001-1.040; p=0.036). Class I GvH PIRCHES mismatch was not associated with treatment-related mortality (TRM), but was associated with a trend towards worsened overall survival (OS) (HR 1.015 per unit PIRCHES mismatch increase; 95% CI 0.999-1.033; p=0.073). Class I host-versus-graft (HvG) PIRCHES mismatch was associated with worse relapse-free survival (RFS) (HR 1.018; 95% CI 1.001-1.035; p=0.036) and worse OS (HR 1.018; 95% CI 1.001-1.035; p=0.036) but not relapse. Class II PIRCHES mismatch was not associated with relapse, OS, RFS, TRM, or aGvHD. Both class I and II PIRCHES mismatch were not associated with chronic GvHD or engraftment. Discussion Class I GvH PIRCHES mismatch was associated with greater aGvHD and a trend towards worsened OS, while class I HvG PIRCHES mismatch was associated with worsened RFS and OS. Class II PIRCHES mismatch was not associated with outcomes and appears to be tolerated by this patient cohort. PIRCHES mismatch represents a novel strategy to predict clinical outcome in haplo-HCT. Further studies using registry data and prospective studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]