Alemtuzumab in relapsed immune severe aplastic anemia: Long-term results of a phase II study.

Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia.

Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

Clonality in immune aplastic anemia: Mechanisms of immune escape or malignant transformation.

Aplastic anemia (AA) is the prototypic bone marrow failure syndrome and can be classified as either acquired or inherited. Inherited forms are due to the effects of germline mutations, while acquired AA is suspected to result from cytotoxic T-cell mediated immune attack on hematopoietic stem and progenitor cells. Once thought to be a purely "benign" condition, clonality in the form of chromosomal abnormalities and single nucleotide variants is now well recognized in AA. Mechanisms underpinning this clonality likely relate to selection of clones that allow immune evasion or increased cell survival the marrow environment under immune attack. Widespread use and availability of next generation and other genetic sequencing techniques has enabled us to better understand the genomic landscape of aplastic anemia. This review focuses on the current concepts associated with clonality, in particular somatic mutations and their impact on diagnosis and clinical outcomes in immune aplastic anemia.

Influence of Killer Immunoglobulin-Like Receptors and Somatic Mutations on Transplant Outcomes in Acute Myeloid Leukemia.

Natural killer (NK) cells are regulated by killer immunoglobulin-like receptor (KIR) interactions with human leukocyte antigen class I ligands. Various models of NK cell alloreactivity have been associated with outcomes after allogeneic hematopoietic cell transplant (alloHCT), but results have varied widely. We hypothesized that somatic mutations in acute myeloid leukemia (AML) in the context of KIR profiles may further refine their association with transplant outcomes. In this single-center, retrospective, observational study, 81 AML patients who underwent matched-related donor alloHCT were included. Post-HCT outcomes were assessed based on mutational status and KIR profiles with the Kaplan-Meier method and log-rank test. On multivariable analysis those with any somatic mutations and C1/C2 heterozygosity had less acute graft-versus-host disease (GvHD) (hazard ratio [HR], 0.32; 95% confidence interval [CI], 0.14-0.75; P = .009), more relapse (HR, 3.02; 95% CI, 1.30-7.01; P = .010), inferior relapse-free survival (RFS; HR, 2.22; 95% CI, 1.17-4.20; P = .014), and overall survival (OS; HR, 2.21; 95% CI, 1.17-4.20; P = .015), whereas those with a missing KIR ligand had superior RFS (HR, 0.53; 95% CI, 0.30-0.94; P = .031). The presence of a somatic mutation and donor haplotype A was also associated with less acute GvHD (HR, 0.38; 95% CI, 0.16-0.92; P = .032), more relapse (HR, 2.72; 95% CI, 1.13-6.52; P = .025), inferior RFS (HR, 2.11; 95% CI, 1.07-4.14; P = .030), and OS (HR, 2.20; 95% CI, 1.11-4.38; P = .024). Enhanced NK cell alloreactivity from more KIR activating signals (donor B haplotype) and fewer inhibitory signals (recipient missing KIR ligand or C1 or C2 homozygosity) may help mitigate the adverse prognosis associated with some AML somatic mutations. These results may have implications for improving patient risk stratification prior to transplant and optimizing donor selection.

Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia.

Although genomic alterations drive the pathogenesis of acute myeloid leukemia (AML), traditional classifications are largely based on morphology, and prototypic genetic founder lesions define only a small proportion of AML patients. The historical subdivision of primary/de novo AML and secondary AML has shown to variably correlate with genetic patterns. The combinatorial complexity and heterogeneity of AML genomic architecture may have thus far precluded genomic-based subclassification to identify distinct molecularly defined subtypes more reflective of shared pathogenesis. We integrated cytogenetic and gene sequencing data from a multicenter cohort of 6788 AML patients that were analyzed using standard and machine learning methods to generate a novel AML molecular subclassification with biologic correlates corresponding to underlying pathogenesis. Standard supervised analyses resulted in modest cross-validation accuracy when attempting to use molecular patterns to predict traditional pathomorphologic AML classifications. We performed unsupervised analysis by applying the Bayesian latent class method that identified 4 unique genomic clusters of distinct prognoses. Invariant genomic features driving each cluster were extracted and resulted in 97% cross-validation accuracy when used for genomic subclassification. Subclasses of AML defined by molecular signatures overlapped current pathomorphologic and clinically defined AML subtypes. We internally and externally validated our results and share an open-access molecular classification scheme for AML patients. Although the heterogeneity inherent in the genomic changes across nearly 7000 AML patients was too vast for traditional prediction methods, machine learning methods allowed for the definition of novel genomic AML subclasses, indicating that traditional pathomorphologic definitions may be less reflective of overlapping pathogenesis.

Large granular lymphocytic leukaemia after solid organ and haematopoietic stem cell transplantation.

T-cell large granular lymphocytic leukaemia (T-LGLL) is a chronic clonal lymphoproliferative disorder of cytotoxic T lymphocytes which commonly occurs in older patients and is often associated with autoimmune diseases. Among 246 patients with T-LGLL seen at our institution over the last 10 years, we encountered 15 cases following solid organ or haematopoietic stem cell transplantation. Here, we studied the clinical characterization of these cases and compared them to de novo T-LGLL. This experience represented a clear picture of the intricate nature of the disease manifestation and the complexities of several immune mechanisms triggering the clonal expansion.

Extended experience with a non-cytotoxic DNMT1-targeting regimen of decitabine to treat myeloid malignancies.

The nucleoside analogue decitabine can deplete the epigenetic regulator DNA methyltransferase 1 (DNMT1), an effect that occurs, and is saturated at, low concentrations/doses. A reason to pursue this molecular-targeted effect instead of the DNA damage/cytotoxicity produced with high concentrations/doses, is that non-cytotoxic DNMT1-depletion can cytoreduce even p53-null myeloid malignancies while sparing normal haematopoiesis. We thus identified minimum doses of decitabine (0·1-0·2 mg/kg) that deplete DNMT1 without off-target anti-metabolite effects/cytotoxicity, and then administered these well-tolerated doses frequently 1-2X/week to increase S-phase dependent DNMT1-depletion, and used a Myeloid Malignancy Registry to evaluate long-term outcomes in 69 patients treated this way. Consistent with the scientific rationale, treatment was well-tolerated and durable responses were produced (~40%) in genetically heterogeneous disease and the very elderly.

Idiopathic aplastic anemia vs hypocellular myelodysplastic syndrome.

Proper diagnostic distinction of bone marrow failure syndromes can often be challenging. In particular, for older patients with idiopathic aplastic anemia (AA), differential diagnosis includes myelodysplastic syndrome (MDS), which can atypically present in a hypocellular form. In addition to blasts and overt dysplasia, the presence of chromosomal abnormalities and a spectrum of somatic mutations may be revealing. Both clonal cytogenetic aberrations and somatic mutations most typically correspond to a clonal myelodysplasia, but clonal somatic mutations have also recently been found in AA. True driver myeloid mutations are uncommon in AA. Marrow hypocellularity in AA and occasionally in MDS patients points toward a similar immune mechanism responsible for deficient blood cell production and indicates that cytopenias in early hypocellular MDS might be treated with immunosuppressive modalities. Primary hypocellular MDS has to be distinguished from post-AA secondary MDS, most commonly associated with del7/7q. Post-AA MDS evolves at the rate of about 10% in 10 years, but recent observations suggest that widespread use of eltrombopag may influence the risk of progression to MDS. This complication likely represents a clonal escape, with founder hits occurring early on in the course of AA. A similar mechanism operates in the evolution of paroxysmal nocturnal hemoglobinuria (PNH) in AA patients, but PNH clones are rarely encountered in primary MDS.

To be or not to be a case of heparin resistance.

Heparin resistance can be defined as high doses of unfractionated heparin (UFH), greater than 35,000 IU/day, required to raise the activated partial thromboplastin time (aPTT) and activated coagulation time (ACT) to within therapeutically desired ranges or the impossibility of doing so. The most common pathology responsible is the deficiency of anti-thrombin III (ATIII) deficiency. Other clinically relevant conditions that can present with heparin resistance are congenital deficiencies; use of high doses of heparin during extracorporeal circulation, use of asparaginase therapy and disseminated intravascular coagulation (DIC). Most of these conditions effect the ATIII levels. Patients are typically identified in an acute phase, when determination of the cause of resistance is challenging. We present a case where a patient presented with suspected heparin resistance in an acute phase of sickness, where timely intervention was able to prevent a potentially fatal situation. Abbreviations: Neuroendocrine tumors (NETs), World health Organization (WHO), Radiation therapy (RT).

A case of madness resulting in a fortunate outcome; case report of a psychotic break as a result of cortisol secreting thymic neuroendocrine thymic tumor.

Representing a mere 2-5% of the total thymic malignancies and 0.4% of total carcinoid tumors, primary thymic neuroendocrine tumors (NETs) are the zebras of the thymic neoplasms. They were initially characterized as 'epithelial thymomas'; later, the term carcinoid tumors was coined by Rosai and Higa. These tumors are highly unpredictable in their presentation and prognosis. Coupled with variable clinical presentation, rare pathologic diagnosis and absence of diagnostic and prognostic parameters, it is a challenge for both patients and clinicians. Treatment entails local definitive therapy, symptom control and systemic chemoradiation given either pre or post operatively based on staging and resectability. We hereby report a peculiar case of psychosis that likely resulted from one such rare tumor.

Case series of multiple primary cancers in single individuals: diagnostic and therapeutic dilemmas.

Background and Objectives: Cancer recurrence represents treatment failure; the development of new primary tumors is suggestive of persistent exposure to etiological risk factors or genetic predisposition due to mutations in multiple cell lines. Case presentation/Design/Methods: The first case is a 65-years-old Caucasian male who presented with esophageal and lung cancer diagnosed synchronously. Smoking was the common risk factor for both cancers, underscoring field cancerization. The diagnosis and management was a challenge and different from either cancer presenting alone. Multidisciplinary approach was used and led to good outcomes. The second case is a 72-years-old Caucasian male presenting a rare dilemma of genetic mutation leading to multiple primary gastrointestinal cancers in a single individual. The gene explaining this group of cancers has not been diagnosed yet and the field needs to be explored further. Conclusion: Multiple primary cancers can be secondary to a common environmental risk factor or genetic mutations.