Kenneth B. Hymes

Improved long term survival after intracavitary interleukin‐2 and lymphokine‐activated killer cells for adults with recurrent malignant glioma

Background. The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin‐2(IL‐2) plus lymphokine‐activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity.

Bexarotene: a clinical review.

Bexarotene (Targretin®, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor®, Pfizer) or fenofibrate (TriCor™, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak®, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.

Large-cell variants of mantle cell lymphoma: cytologic characteristics and p53 anomalies may predict poor outcome.

Large‐cell variants are uncommon in mantle cell lymphoma (MCL). Here we describe the pathologic and clinical findings in five patients with large‐cell lymphoma related to MCL (L‐MCL), and compare them to a group of classic small‐cell MCL (s‐MCL) cases.

A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma

Belinostat is a pan‐histone deacetylase inhibitor with antitumour and anti‐angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T‐cell lymphoma (PTCL) or cutaneous T‐cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m2 intravenously ×5 d of a 21‐d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1–9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin‐directed therapy (range 0–4) and four prior systemic therapies (range 1–9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment‐related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment‐related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.

Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition

Abstract The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

The role of histone deacetylase inhibitors in the treatment of patients with cutaneous T-cell lymphoma.

The term epigenetics refers to modifications in gene activity that occur without directly affecting the DNA sequence, and irregularities in cellular epigenetics have been implicated in the development of a number of malignancies. As such, there is considerable interest in the anticancer effects of agents that can modify cellular epigenetics. Histone deacetylase (HDAC) inhibitors represent a class of anticancer agents that have shown promise in the treatment of both solid and hematologic malignancies. Although there are a number of HDAC inhibitors in advanced stages of clinical development, vorinostat, and more recently, romidepsin, are currently the only HDAC inhibitors approved for use. Vorinostat was approved in the United States in 2006 for the treatment of cutaneous manifestations of T-cell lymphoma in patients with progressive, persistent, or recurrent disease on or following 2 systemic therapies. Romidepsin was approved in the United States in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received >/= 1 prior systemic therapy. This review aims to assess the clinical progress that vorinostat and other HDAC inhibitors have made in symptom relief and treatment of patients with CTCL and to provide practical advice for the management of associated toxicities.

CD20 positive mycosis fungoides: a case report

CD20 positive T‐cell lymphoma is extremely rare. Most reported cases are nodal peripheral T‐cell lymphomas (PTCLs) or rarely lymphoma involving extranodal sites. Only two cases of CD20 positive T‐cell lymphomas involving the skin have been previously reported and were classified as PTCL – not otherwise specified. We present a case report of a 53‐year‐old man with CD20 positive mycosis fungoides (MF) involving the skin and an inguinal lymph node. The patient presented with erythematous patches and plaques of the right lower extremity and was found to have an enlarged inguinal lymph node 2 years later. Flow cytometric immunophenotyping of the lymph node aspirate showed a CD2+/CD3+/CD4+/CD5+/CD7−/CD8− T‐cell population with CD20 co‐expression. Molecular studies by polymerase chain reaction demonstrated clonal T‐cell receptor γ chain gene rearrangement. Immunoglobulin heavy and light chain gene rearrangements were not identified. To our knowledge, this is the first case of CD20 positive MF involving a lymph node to be reported in the literature.

Mycosis fungoides metastasizing to the brain parenchyma: case report.

OBJECTIVE AND IMPORTANCE Mycosis fungoides is a rare T-cell lymphoma of the skin that can, in one-half to three-quarters of patients suffering from this disease, involve the viscera in late stages of the disease. Although autopsy series performed more than 2 decades ago showed that the incidence of metastatic mycosis fungoides to the central nervous system is approximately one of seven, a total of only several dozen cases have been reported to date. As compared to meningeal involvement, intraparenchymal metastases are even rarer. We describe a biopsy-proven case of intraparenchymal central nervous system mycosis fungoides in a patient with nonprogressive skin involvement and no detectable visceral involvement, and we present a review of the relevant literature. CLINICAL PRESENTATION A 68-year-old man, 3 years after the diagnosis of his skin disease, developed fatigue, confusion, and frontal lobe signs without the presence of cerebriform cells in the peripheral blood or any other clinical evidence of visceral involvement. Magnetic resonance imaging revealed a diffuse area of increased T2-weighted signal involving the white matter of both cerebral hemispheres as well as a focal area of T2 abnormality along the body of the corpus callosum. The radiological differential diagnosis was either leukodystrophy caused by chemotherapy, progressive multifocal leukoencephalopathy, or glioma with associated white matter changes. INTERVENTION A stereotactic serial brain biopsy revealed diffuse perivascular infiltrates of atypical lymphocytes, as well as several large cells with cerebriform nuclei consistent with mycosis fungoides. The cells were immunoreactive for LCA, MT1, UCHL1, and CD3. CONCLUSION We stress the importance of including mycosis fungoides as part of the differential diagnosis for a brain lesion in patients with cutaneous T-cell lymphoma, because treatments do exist, and we conclude that a serial stereotactic biopsy may be necessary to provide a definitive diagnosis.

Denileukin diftitox for the treatment of cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma/mycosis fungoides (CTCL/MF) is a rare lymphoproliferative disorder which can present as an indolent or as an aggressive process involving skin, lymph nodes, and blood. In stages IA, IB and IIA, it is usually managed with topical medications and phototherapy. If there is progression despite application of these treatments, or if the patient presents with a higher stage of disease, systemic chemotherapy or retinoids, rexinoids, biologic response modifiers are often necessary. Consequently, patients are often treated with a sequence of modalities and drugs. Denileukin diftitox (DD, Ontak®) is a targeted immunotoxin which has biological activity against malignancies expressing the IL-2 receptor. In addition to its unique mechanism of action, DD has a toxicity profile which does not overlap with most commonly used chemotherapeutic agents. CTCL/MF has been found be particularly susceptible to treatment with this agent. This review will describe the development DD, its proposed mechanism of action, the clinical trials which identified its utility in the treatment of CTCL/MF, the common toxicities encountered with this agent, and the management of these toxicities. In addition the incorporation of DD in the sequential treatment of CTCL/MF and data suggesting potential combination therapies employing this novel agent will be discussed.

In vitro suppressor T lymphocyte dysfunction in autoimmune thrombocytopenic purpura associated with a complement-fixing antibody.

Ig secretion of peripheral blood mononuclear cells (PBMC) was measured in Epstein Barr virus (EBV) seropositive autoimmune thrombocytopenic purpura (ATP) patients and controls following in vitro infection with EBV. EBV infected PBMC from patients with ATP secreted Ig for a longer period of time than EBV infected control cells and had higher peak Ig production. Removal of T cells or CD8 cells from control PBMC increased the duration and level of Ig production to that achieved by ATP PBMC. Total T or CDS cell depletion of ATP PBMC had no effect on the enhanced level or duration of Ig secretion. Depletion of control CD4 lymphocytes decreased Ig production.