Outcomes of Human Leukocyte Antigen-Matched Related Donor and Haploidentical Allogeneic Hematopoietic Cell Transplantation Recipients by Immune Profiles of Recipients and Donors.

Haploidentical (Haplo) allogeneic HCTs (alloHCT) have been used more frequently over the last decade as survival is similar to HLA-matched related donor (MRD) alloHCTs. We aimed to identify donor and recipient immune signatures before alloHCT that are associated with clinically meaningful outcomes in MRD vs Haplo alloHCT recipients. This retrospective cohort study of 165 MRD (n = 132) and Haplo (n = 33) alloHCT recipients and their related donors between 2007-2019 with paired peripheral blood samples immunophenotyped for T-cell, B-cell, NK cell and dendritic cell (DC) subsets. Immune cells were quantified before alloHCT in donors and recipients; calculations of immune cell ratios were classified as high, intermediate, and low and analyzed with alloHCT outcomes. Haplo donors were younger than MRD donors (median: 35 vs 51 years), whereas Haplo recipients were older than MRD recipients (median: 68 vs 54 years), were more likely to have a Karnofsky Performance Score ≤ 70 (76% vs 57%), 3+ comorbidities (54% vs 47%), and were in complete remission prior to alloHCT (58% vs 42%). In MRD alloHCT, a lower ratio of CD4+ to CD8+ effector memory cells in the donor was associated with lower 4-yr overall survival (OS; 25% vs 61%; P = .009), lower 4-yr progression free survival (PFS; 25% vs 58%; P = .014) and higher incidence of 1-yr transplant-related mortality (TRM; 39% vs 7%; P = .009) in recipients. A higher ratio of CD8+ effector memory to total NK cells measured in MRD recipients was associated with a higher incidence of grade II-IV aGvHD (63% vs 37%; P = .004) but was not statistically significant for III-IV aGvHD (23% vs 12%). In Haplo alloHCT, a lower ratio of total T-regulatory to CD4+ central memory cells in the donor was associated with lower 4-yr PFS (22% vs 60%; P = .0091). A higher ratio of CD4+ effector memory to CD8+ effector memory cells measured in Haplo recipients pre-alloHCT was associated with lower 4-yr OS (25% vs 88%; P = .0039). In both MRD and Haplo recipients, a higher ratio of CD4+ naïve to CD4+ central memory cells was associated with a higher incidence of grade II-IV aGvHD (64% vs 38%; P = .04). Evaluation of pre-alloHCT immune signatures of the donor and recipient may influence clinically meaningful patient outcomes in both MRD and Haplo transplants.

Identification of Neurotoxicity after Chimeric Antigen Receptor (CAR) T Cell Infusion without Deterioration in the Immune Effector Cell Encephalopathy (ICE) Score.

A consensus grading schema for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) resulting from chimeric antigen receptor (CAR) T cell therapy was published in 2019. Although this consensus grading schema has been imperative in identifying and monitoring CRS and ICANS in our CAR T cell population, we observed patients exhibiting subtle neurotoxicity symptoms prior to a decrease in their immune effector cell (ICE) score, which is one component of ICANS. Because we treat grade 1 ICANS at our institution, identification of early neurotoxicity symptoms is important. Additionally, we found changes in personality, occupational confusion, or inability to answer dichotomous questions were early signs of neurotoxicity. Therefore, we developed a 3-step command tool to supplement the ICE evaluation. We present 2 examples of patients who exhibited early neurotoxicity symptoms and led us to develop this tool and 1 in whom it was effective. We propose that CAR T cell patients are consistently followed by a clinical care provider who is familiar with the patient to recognize early changes in personality, behavior, and cognition. Additionally, we propose that the multistep command tool be used in conjunction with the ICE score to detect early symptoms of ICANS. Early intervention has the potential to prevent irreversible neurotoxicity.

Correction: Immune profiling in diffuse large B-cell lymphoma and mantle cell lymphoma patients treated with autologous hematopoietic cell transplant.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Immune profiling in diffuse large B-cell lymphoma and mantle cell lymphoma patients treated with autologous hematopoietic cell transplant.

This is the first longitudinal study of immune profiles and autologous hematopoietic cell transplant (AHCT) survival in B-cell non-Hodgkin lymphoma (B-NHL) patients and the effect of plerixafor mobilization on immune reconstitution in this population. A comprehensive immunophenotyping panel was performed in 104 consecutive adult B-NHL patients (58% diffuse large B cell and 42% mantle cell) who received AHCT (1/2008-11/2014), at a median of 28 days pre-AHCT (N = 104) and Day +100 (N = 83) post-AHCT. Median follow-up post-AHCT was 61 months (range: 8-120 months). Compared to patients mobilized with filgrastim and plerixafor, patients mobilized with filgrastim alone had a higher proportion of CD4+ naïve (p = 0.006) and CD8+ central memory T-cells (p = 0.006) pre-AHCT. For patients transplanted in complete remission (CR), a higher proportion of CD8+ effector memory T-cells pre-AHCT was associated with worse progression-free survival (PFS; p < 0.01) and overall survival (OS; p < 0.01). A higher ratio of CD8:CD4+ central memory T-cells pre-AHCT was associated with worse PFS (p < 0.0001) and OS (p = 0.0034). This same ratio measured post-AHCT among patients in CR on Day +100 was associated with worse and OS (p = 0.008) but not PFS (p = not significant). These immune subsets are complementary biomarkers which identify patients transplanted in CR who have poor survival prognoses and may warrant further clinical interventions.

Immune signatures associated with improved progression-free and overall survival for myeloma patients treated with AHSCT.

Multiple therapeutic options exist for multiple myeloma (MM), including autologous hematopoietic stem cell transplantation (AHSCT). Measurement of minimal residual disease (MRD) and immune reconstitution is rapidly becoming an integral part of the care of MM patients. We investigated comprehensive immune profiling (IP) associated with progression-free survival (PFS) and overall survival (OS). From August 2007 to January 2014, 101 consecutive MM patients underwent peripheral blood IP and marrow MRD testing before and approximately 100 days after AHSCT. Higher pre-AHSCT CD19+ B-cell counts correlated with improved 2-year PFS (83% [highest quartile] vs 53% [lowest quartile]; P = .01) and OS (93% [highest quartile] vs 63% [lowest quartile]; P = .0003). This effect was seen primarily in patients with MRD-positive marrow tests. Higher γδ T-cell counts post-AHSCT correlated with improved 2-year PFS (65% [highest quartile] vs 45% [lowest quartile]; P = .02) and OS (89% [highest quartile] vs 65% [lowest quartile]; P = .01). Higher CD4+ central memory (CM) cell counts post-AHSCT were associated with improved 2-year OS (95% [upper quartile] vs 47% [lowest quartile]; P = .0003) but not PFS. The higher γδ T-cell and CD4+ CM-cell count associations were primarily observed in MRD-negative patients post-AHSCT and in patients not receiving maintenance therapy. This proof-of-concept study demonstrates that IP before and after AHSCT can be of complementary prognostic value for depth of response. Maintenance therapy seems to overcome negative IP. IP and MRD should be measured in clinical trials of maintenance therapy with novel agents post-AHSCT for MM to confirm their utility for prognosis and management.

Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome.

In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival.

Unusual Manifestations of Monoclonal Gammopathy: I. Ocular Disease.

Essential monoclonal gammopathy is usually an asymptomatic condition, the characteristics of which have been defined over approximately 70 years of study. It has a known population-attributable risk of undergoing clonal evolution to a progressive, symptomatic B-cell neoplasm. In a very small fraction of patients, the monoclonal immunoglobulin has biophysical characteristics that can lead to tissue deposition syndrome (e.g. Fanconi renal syndrome) or, by chance, have characteristics of an autoantibody that may inactivate critical proteins (e.g. acquired von Willebrand disease). In this report, we describe the very uncommon forms of ocular injury that may accompany essential monoclonal gammopathy, which include crystalline keratopathy, crystal-storing histiocytosis, hypercupremic keratopathy, and maculopathy. The first three syndromes result from uncommon physicochemical alterations of the monoclonal immunoglobulin that favor crystallization or exaggerated copper binding. The last-mentioned syndrome is of uncertain pathogenesis. These syndromes may result in decreased visual acuity. These ocular findings may lead, also, to the diagnosis of monoclonal gammopathy.

Unusual Manifestations of Essential Monoclonal Gammopathy. II. Simulation of the Insulin Autoimmune Syndrome.

In rare cases, the monoclonal immunoglobulin that characterizes essential monoclonal gammopathy interacts with a self-antigen with functional consequences and a resulting clinical syndrome. This event is presumably random and results from the clone of B lymphocytes making a monoclonal immunoglobulin that simulates an autoimmune antibody. Thus, by chance, the monoclonal immunoglobulin has sufficient affinity for an epitope on a normal protein that functional consequences ensue. One such rare event is the synthesis and secretion of a monoclonal immunoglobulin that binds to human insulin. Inactivation of insulin by antibody results in (1) an early postprandial hyperglycemia, (2) followed by either or both (i) a reactive overshot in insulin secretion, as a result of hypertrophied or hyperplastic islet beta cells, later falling glucose levels, and (ii) an unpredictable dissociation of insulin from the complex, and, several hours later, (3) a resultant increase in free insulin levels and severe hypoglycemia with clinical consequences, ranging from sweating, dizziness, headache, and tremors to confusion, seizures, and unconsciousness. These attacks are invariably responsive to glucose administration. This very uncommon manifestation of a monoclonal gammopathy can occur in patients with essential monoclonal gammopathy or myeloma. The monoclonal anti-insulin immunoglobulin in monoclonal gammopathy has a low affinity for insulin, but has a high capacity for insulin-binding, resulting in the syndrome of episodic hypoglycemic attacks. This phenomenon of an insulin-binding monoclonal immunoglobulin simulates the acquired insulin autoimmune syndrome, although the latter is mediated by a polyclonal antibody response in the majority of cases studied, and has linkage to HLA class II alleles.

Biology of BM failure syndromes: role of microenvironment and niches.

The BM microenvironment and its components regulate hematopoietic stem and progenitor cell (HSC) fate. An abnormality in the BM microenvironment and specific dysfunction of the HSC niche could play a critical role in initiation, disease progression, and response to therapy of BM failure syndromes. Therefore, the identification of changes in the HSC niche in BM failure syndromes should lead to further knowledge of the signals that disrupt the normal microenvironment. In turn, niche disruption may contribute to disease morbidity, resulting in pancytopenia and clonal evolution, and its understanding could suggest new therapeutic targets for these conditions. In this chapter, we briefly review the evidence for the importance of the BM microenvironment as a regulator of normal hematopoiesis, summarize current knowledge regarding the role of dysfunctions in the BM microenvironment in BM failure syndromes, and propose a strategy through which niche stimulation can complement current treatment for myelodysplastic syndrome.