Amy Kimball

The role of high dose chemotherapy and autologous stem-cell transplantation in peripheral T-cell lymphoma: a review of the literature and new perspectives.

Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkins lymphoma that carries, except for ALK-positive anaplastic large cell lymphoma, a poor prognosis. Only a third of patients live 5years past diagnosis. The incidence of PTCL has been increasing during the last two decades. In recent years, there was a rising interest in PTCL manifested by the abundance of publications dedicated exclusively to this disease. The international T-cell lymphoma project was formed with an aim of unifying efforts towards a better understanding of the diagnosis and management of this disease. Given the poor outcomes of PTCL patients, high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) have been used in the up-front and salvage settings, with different success rates. However, there are no prospective randomized controlled trials addressing the role of HDT/ASCT in a PTCL-restricted population. This article critically reviews the data available from the retrospective and prospective studies addressing this topic. We will emphasize the favorable prognostic factors of HDT/ASCT such as a solid remission at the time of transplantation, a chemotherapy sensitive disease and a low prognostic index score. As novel agents and new therapeutic strategies are introduced, there is a continued need for prospective randomized trials to define the optimal use of HDT/ASCT in managing PTCL.

Optimizing Management of Patients with Adult T Cell Leukemia-Lymphoma

Adult T cell leukemia-lymphoma is a rare disease with a high mortality rate, and is challenging for the clinician. Early allogeneic stem cell transplant can confer durable remission. As novel therapeutic agents become available to treat T cell malignancies, it is increasingly important that medical oncologists, hematologists, and hematopathologists recognize and accurately diagnose adult T cell leukemia-lymphoma. There is no uniform standard of treatment of adult T cell leukemia-lymphoma, and clinical trials remain critical to improving outcomes. Here we present one management approach based on the recent advances in treatment for adult T cell leukemia-lymphoma patients.

Rituximab Maintenance Therapy Until Progression After Rituximab and Chemotherapy Induction in Patients With Follicular Lymphoma

INTRODUCTION The PRIMA (Primary Rituximab and Maintenance) study established 2 years of maintenance rituximab (MR) as a standard of care for follicular lymphoma (FL) patients who achieve an objective response after induction chemotherapy. A 17% improvement in progression-free survival (PFS) compared with those who did not receive MR was observed. However, the decision to stop MR after 2 years was arbitrary, and the PRIMA study reports only short-term follow-up of 3 years. Longer series on FL outcomes describe ubiquitous relapse and death following recurrence. The optimal duration of MR is under investigation. Herein, we report our experience with prolonged MR in FL. PATIENTS AND METHODS In this retrospective analysis, the outcome of 25 consecutive, unselected, previously untreated patients with low-grade high tumor burden FL in need for treatment is described. All patients achieved a partial or complete response to induction immunochemotherapy and received ongoing MR therapy. RESULTS With a median follow-up of 5.0 years and 5.2 years mean duration of MR, there are no relapses. Five deaths have occurred, unrelated to lymphoma or therapy. Prolonged MR treatment has been well-tolerated. Hypogammaglobulinemia is the only observed adverse event, with only one patient requiring monthly intravenous gamma globulin infusions due to recurrent pneumonia. There has been no discontinuation of MR or refusal to remain on MR. CONCLUSION These provocative long-term results suggest that continuous MR beyond 2 years is safe and may be associated with prolonged PFS in patients with FL who achieve an objective response after immunochemotherapy.

Demyelination as a harbinger of lymphoma: a case report and review of primary central nervous system lymphoma preceded by multifocal sentinel demyelination.

BackgroundPrimary central nervous system lymphoma (PCNSL) may rarely be preceded by “sentinel demyelination,” a pathologic entity characterized by histologically confirmed demyelinating inflammatory brain lesions that mimic multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). Interpreting the overlapping radiologic and clinical characteristics associated with each of these conditions—contrast-enhancing demyelination of white matter and relapsing and remitting steroid-responsive symptoms respectively—can be a significant diagnostic challenge.Case presentationWe describe a 57-year-old woman with an unusual clinical course who presented with multi-focal enhancing white matter lesions demonstrated to be inflammatory demyelination by brain biopsy. Despite a good initial response to steroids and rituximab for treatment of presumed tumefactive multiple sclerosis, the patient’s condition rapidly deteriorated, and a repeat brain biopsy six months later was consistent with a diagnosis of diffuse large B-cell lymphoma.ConclusionsEarly clinical suspicion for PCNSL and awareness that biopsied lesions may initially show sentinel demyelination suggestive of alternate diagnoses may be essential for early initiation of appropriate therapies and mitigation of disease progression. Clinical, pathophysiological, and diagnostic aspects of sentinel demyelination and PCNSL are discussed.

Concurrent mutations in ATM and genes associated with common γ chain signaling in peripheral T cell lymphoma

Peripheral T cell lymphoma (PTCL) is a heterogeneous malignancy with poor response to current therapeutic strategies and incompletely characterized genetics. We conducted whole exome sequencing of matched PTCL and non-malignant samples from 12 patients, spanning 8 subtypes, to identify potential oncogenic mutations in PTCL. Analysis of the mutations identified using computational algorithms, CHASM, PolyPhen2, PROVEAN, and MutationAssessor to predict the impact of these mutations on protein function and PTCL tumorigenesis, revealed 104 somatic mutations that were selected as high impact by all four algorithms. Our analysis identified recurrent somatic missense or nonsense mutations in 70 genes, 9 of which contained mutations predicted significant by all 4 algorithms: ATM, RUNX1T1, WDR17, NTRK3, TP53, TRMT12, CACNA2D1, INTS8, and KCNH8. We observed somatic mutations in ATM (ataxia telangiectasia-mutated) in 5 out of the 12 samples and mutations in the common gamma chain (γc) signaling pathway (JAK3, IL2RG, STAT5B) in 3 samples, all of which also harbored mutations in ATM. Our findings contribute insights into the genetics of PTCL and suggest a relationship between γc signaling and ATM in T cell malignancy.

Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional

Invariant natural killer T (iNKT) cells constitute an important subset of T cells that can both directly and indirectly mediate anti-tumor immunity. However, cancer patients have a reduction in both iNKT cell number and function, and these deficits limit the potential clinical application of iNKT cells for cancer therapy. To overcome the problem of limited iNKT cell numbers, we investigated whether iNKT cells can be generated in vitro from bone marrow-derived adult hematopoietic stem-progenitor cells (HSPC). Our data demonstrate that co-culture of HSPC with OP9-DL1 stromal cells, results in a functional CD3(+) T cell population. These T cells can be further differentiated into iNKT cells by secondary culture with CD1d-Ig-based artificial antigen-presenting cells (aAPC). Importantly, these in vitro-generated iNKT cells are functional, as demonstrated by their ability to proliferate and secrete IFN-γ and GM-CSF following stimulation.

Characterization of a case of follicular lymphoma transformed into B-lymphoblastic leukemia

Follicular lymphoma (FL) is a common form of non-Hodgkin lymphoma with an ability to transform into a more aggressive disease, albeit infrequently to B-lymphoblastic leukemia/lymphoma. While t(14;18)(q32;q21) has been associated with approximately 90% cases of FL, that alteration alone is insufficient to cause FL and associated mutations are still being elucidated. The transformation of FL to B-lymphoblastic leukemia generally includes the dysregulation of MYC gene expression, typically through IGH rearrangement. Such cases of “double-hit” leukemia/lymphoma with both BCL2 and MYC translocations warrant further study as they are often not identified early, are associated with a poor prognosis, and are incompletely understood in molecular terms. Here we describe a patient with a diagnosis of FL that transformed to B-lymphoblastic leukemia. Detailed cytogenetic characterization of the transformed specimen using karyotype, fluorescence in situ hybridization, microarray and gene rearrangement analyses revealed a complex karyotype comprised principally of whole chromosome or whole arm copy number gains or losses. Smaller, single-gene copy number alterations identified by microarray were limited in number, but included amplification of a truncated EP300 gene and alterations in NEIL1 and GPHN. Analyses defined the presence of an IGH/BCL2 fusion due to a translocation as well as a MYC/IGH fusion due to an insertion, with both rearrangements involving the same IGH allele. The data illustrate the value in characterizing double-hit lymphoma cases with both traditional and novel technologies in the detailed cytogenetic workup.

Death-associated Protein Kinase-1 Expression and Autophagy in Chronic Lymphocytic Leukemia Are Dependent on Activating Transcription Factor-6 and CCAAT/Enhancer-binding Protein-β.

Expression of DAPK1, a critical regulator of autophagy and apoptosis, is lost in a wide variety of tumors, although the mechanisms are unclear. A transcription factor complex consisting of ATF6 (an endoplasmic reticulum-resident factor) and C/EBP-β is required for the IFN-γ-induced expression of DAPK1. IFN-γ-induced proteolytic processing of ATF6 and phosphorylation of C/EBP-β are obligatory for the formation of this transcriptional complex. We report that defects in this pathway fail to control growth of chronic lymphocytic leukemia (CLL). Consistent with these observations, IFN-γ and chemotherapeutics failed to activate autophagy in CLL patient samples lacking ATF6 and/or C/EBP-β. Together, these results identify a molecular basis for the loss of DAPK1 expression in CLL.

Giant Cell Tumor of the Tendon Sheath With Discordant Metabolism as a False Positive on Staging of Mantle Cell Lymphoma.

A baseline F-FDG PET/CT scan in a patient with mantle cell lymphoma showed diffuse minimally FDG-avid lymphadenopathy and splenomegaly. There was also a focus of uptake in the left subscapularis muscle without a CT correlate. A post-chemotherapy scan showed interval decrease in size, and resolution of FDG uptake, of the lymph nodes and spleen. Persistent activity was seen in the subscapularis muscle. Posttreatment biopsy of the FDG-avid lesion showed a benign giant cell tumor of tendon sheath. This case illustrates that a lesion with a markedly discordant SUV should raise suspicion for a second process.

Effects of Toll-like receptor signals in T-cell neoplasms

T-cell neoplasms have poor prognosis and few effective therapeutic options. Therefore, identification of factors in T-cell leukemia/lymphoma that are associated with cancer progression may represent novel therapeutic targets. Recent studies have highlighted a previously unappreciated role for the expression of Toll-like receptors (TLRs) on T cells and their effects on cell survival and proliferation. TLRs can bind exogenous molecules derived from pathogens as well as endogenous self-ligands released from damaged cells. Recent reports demonstrate that TLR engagement on primary mouse or human T cells enhances proliferation and/or cell survival. The mechanisms by which TLR stimulation on T cells influences these parameters and the different T-cell subsets that are affected by TLR stimulation are currently under investigation. Furthermore, neither the biological importance of stimulating TLRs on neoplastic T cells nor the prevalence of TLR expression in T-cell malignancies have yet to be characterized. Based on published reports and compelling preliminary data, we propose that the activation of the TLR-MyD88 signaling pathway in neoplastic T cells contributes to disease progression by reducing cell death and enhancing cell division. In this article, we present both theoretical arguments and experimental data in support of this hypothesis.