Advanced-stage Cutaneous T-cell Lymphoma Research Articles

Oral bexarotene in a therapy‐resistant Sézary syndrome patient: observations on Sézary cell compartmentalization

A 63-year-old man with therapy-resistant Sézary syndrome was enrolled in a multicenter trial of oral bexarotene for advanced-stage cutaneous T-cell lymphoma (CTCL). Monthly evaluations for efficacy and side-effects were conducted and documented. Gradual improvement in erythema, pruritus, and scale was noted during the initial 16-week trial period and treatment was extended to 40 weeks. From week 20 to week 40, the erythroderma continued to improve and the lymph node burden decreased, but the absolute Sézary cell count inversely increased. By week 40, intractable pruritus and erythroderma abruptly recurred, and bexarotene was discontinued. Bexarotene is well tolerated and can be efficacious in patients with Sézary syndrome. Shifting of Sézary cells between different compartments was noted. Further studies on the interaction between the skin, lymph nodes, and peripheral blood compartments during bexarotene treatment in this subset of patients with CTCL are needed.

Clonal T cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in the skin and blood of patients with parapsoriasis and early-stage mycosis fungoides.

Cutaneous T cell lymphoma (CTCL) and reactive T cell skin diseases represent opposite ends of a spectrum of diseases ranging from overtly malignant to persistently benign. Within this spectrum, the parapsoriasis group is not clearly defined regarding malignant potential. In contrast to consistent findings in advanced-stage CTCL, clonality analysis of parapsoriasis has produced conflicting results in previous studies. As T cell receptor gamma-chain polymerase chain reaction GeneScan analysis (TCR-gamma-PCR-GSA) stands out by its sensitivity, its accuracy in size determination of PCR products, its capacity to identify false positives by repeated analysis and its easy applicability, this approach was used to analyse the clonality status of 41 patients with borderline T cell lymphoproliferative skin diseases, including parapsoriasis (n=27) and early-stage mycosis fungoides (MF) (n=14). A monoclonal T cell infiltrate was demonstrated by repeated TCR-gamma-PCR-GSA in lesional skin specimens in 19.2% of parapsoriasis patients and in 66.6% of early-stage MF cases (p=0.013). In peripheral blood, a monoclonal T cell population was found in a similar percentage of parapsoriasis and of early-stage MF patients (26.7% versus 12.5%; p=0.611). A detailed analysis of parapsoriasis subentities, namely small and large plaque parapsoriasis, and parapsoriasis lichenoides, revealed monoclonality in 2(6)/2(5), 3(14)/2(8) and 0(6)/0/(3) of the skin and peripheral blood specimens, respectively. The high detection rate of false positive cases by repeated analysis (20-37.5%) provides a corrected perspective for the high rates of dominant T cell clones found by others in the peripheral blood of such patients. From the results obtained, three major conclusions can be drawn: firstly, CTCL is clearly associated with detection of monoclonality, even in its early stages; secondly, monoclonality is not a prerequisite for potential CTCL precursor entities; and thirdly, recirculating malignant T cells identical to the skin clone are not readily detected in parapsoriasis or early-stage MF, but may rather indicate disease progression.

Bexarotene Is Effective and Safe for Treatment of Refractory Advanced-Stage Cutaneous T-Cell Lymphoma: Multinational Phase II-III Trial Results

Cutaneous T-cell lymphomas (CTCL) are malignancies of T cells appearing as skin lesions and are responsive to retinoid therapy. Safety and efficacy of a novel RXR-selective retinoid (rexinoid) bexarotene (Targretin, LGD1069; Ligand Pharmaceuticals Inc, San Diego, CA) was evaluated as a single-agent oral therapy administered once daily in an open-label study in patients with refractory advanced-stage CTCL. Ninety-four patients with biopsy-confirmed CTCL in advanced stages (IIB-IVB) were enrolled at 26 centers. Fifty-six patients received an initial dose of 300 mg/m2/d oral bexarotene and 38 started at more than 300 mg/m2/d. Clinical complete and partial responses were reported by Primary End point Classification for the study in 45% (25 of 56) of patients enrolled at 300 mg/m2/d dosing. At more than 300 mg/m2/d, 55% (21 of 38) of patients responded, including 13% (five of 38) clinical complete. For the 300 mg/m2/d initial dose group, the rate of relapse after response was 36% and the projected median duration of response was 299 days. Improvements were also seen in overall body-surface area involvement, median index lesion surface area, adenopathy, cutaneous tumors, pruritus, and CTCL-specific quality of life. The most frequent drug-related adverse events included hypertriglyceridemia (associated rarely with pancreatitis), hypercholesterolemia, hypothyroidism, and headache. Bexarotene is the first in a novel class of pharmacologic agents, the RXR-selective retinoids, or rexinoids. Bexarotene is orally administered, safe, and generally well tolerated with reversible side effects, and is effective for the treatment of advanced, refractory CTCL.

Bexarotene.

Bexarotene is a selective retinoid X receptor (RXR) agonist. It binds to, and activates RXRs which function as ligand-activated transcription factors that control gene expression. This leads to modulation of cell growth, apoptosis, and differentiation. In patients with refractory or persistent early stage cutaneous T cell lymphoma (CTCL), the overall response rate was 54% after oral bexarotene 300 mg/m2/day. The overall response rate in patients with refractory or persistent advanced stage CTCL was 45% at the same dosage. An overall response rate of 63% was reported after topical bexarotene 0.1 to 1% twice daily in patients with early stage CTCL. Another trial reported an overall response rate of 44% after topical bexarotene 1% once daily escalated up to 4 times daily. Plaque elevation was significantly reduced, and the severity of moderate to severe psoriasis was substantially improved in patients receiving oral bexarotene 0.5 to 2 mg/kg/day. At clinically relevant oral dosages, bexarotene significantly decreases levels of serum thyrotropin and free thyroxine. The most common adverse events associated with oral bexarotene are hypertriglyceridemia, hypercholesterolemia, central hypothyroidism and headache. Reversible acute pancreatitis has occurred during oral bexarotene therapy. Adverse events associated with the topical formulation are limited to rash, pruritus, and pain.

P-Glycoprotein Expression and Multidrug Resistance in Cutaneous T-cell Lymphoma

Advanced-stage cutaneous T-cell lymphoma (CTCL) is generally resistant to standard chemotherapy. Because P-glycoproteiri (P-gp) has beeti detected in other types of resistant solid tumors, leukemias, and lymphomas, we analyzed P-gp expression in CTCL. Twenty-seven patients with CTCL and circulating Sezary cells in the peripheral blood as observed on a peripheral smear treated at the Yale Photopheresis Center between 1987 and 1993 were identified. Twenty-five of these patients had skin biopsies evaluated for expression of P-gp using JSB-I (Accurate Chemical), MRK-16 (gift of T. Tsuruo), and UIC-2 (gift of E. Metchner). P-gp expression was considered present if immunoreactivity was noted with two of the three antibodies. Eighteen of 25 patients (72%) evaluated exhibited expression. The patients were treated with vairiaus combinations of drugs consisting of topical and systemic steroids, electron beam therapy. psoralens in combination with UV light A (PUVA), systemic chemotherapy, and photophersis before testing the tissue for P-gp expression. Treatment with systemic chemotherapy in P-gp-positive patients produced responses in 3 and no responses in II patints (4 were lost to follow-up). Seven patients did not express P-gp: One patiem responded to treatment. five did not respond, and one patient was lost to follow -up. These results demonstrate that P-gp is frequently expressed in CTCL. P-gp expression in our study was not a useful predictor of drug resistance.

Clonal T-cell receptor gamma-chain gene rearrangement by PCR-based GeneScan analysis in advanced cutaneous T-cell lymphoma: a critical evaluation.

Detection of clonal T-cell receptor gamma (TCRgamma)-chain gene rearrangement is a promising approach to distinguish between cutaneous T-cell lymphomas (CTCLs) and reactive T-cell infiltrates. Despite the improved sensitivity by using the polymerase chain reaction (PCR) rather than Southern blot analysis, monoclonality could be demonstrated in only 53-90 per cent of CTCL biopsies in recent studies. In the present study, formalin-fixed, paraffin-embedded specimens of 21 selected patients with clear-cut advanced-stage CTCL were analysed using a semi-nested TCRgamma PCR with newly developed consensus primer pairs. Detection of PCR products was done by GeneScan analysis (GSA); this technique is advantageous due to its sensitivity and accuracy in the detection and size determination of PCR products and it is easier to interpret than direct read-outs from TGGE or DGGE gels. In serial dilution experiments, TCRgamma-PCR-GSA allowed the detection of clonal, rearranged T-cells with a high in vitro sensitivity against a polyclonal background (1-6 per cent). Despite the selection of clear-cut, advanced-stage CTCL cases, however, dominant clonal TCRgamma-chain gene rearrangement was found in only 16 of the 21 patients analysed, indicating an overall clinical sensitivity of 76 per cent. Specificity was evaluated using biopsy specimens from 21 control patients suffering from long-standing psoriasis (n=13) and eczema (n=8). Surprisingly, GeneScan profiles showing apparently single dominant peaks were detected in 14 per cent of these skin lesions, but these profiles turned out to be pseudo-monoclonal by repeated determinations. In conclusion, TCRgamma-PCR-GSA does not suffice reliably to exclude malignancy, due to its limited clinical sensitivity, but with precautions taken to detect pseudo-monoclonality and to secure specificity, TCRgamma-PCR-GSA is a valuable instrument in the diagnosis of CTCL.

Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have achieved a complete response to total skin electron beam therapy

To evaluate the impact of systemic adjuvant therapies on relapse-free (RFS) and overall survival (OS) of cutaneous T-cell lymphoma (CTCL) patients treated with total skin electron beam therapy (TSEBT). Between 1974 and 1990, TSEBT (36 Gy at 1 Gy/day; 9 weeks; 6 MeV electrons) was administered with curative intent to a total of 163 CTCL (mycosis fungoides) patients using six fields supplemented by orthovoltage boosts (120 kvp, 1 Gy x 20) to the perineum, soles of feet, and apical scalp (120 kvp, 2 Gy x 3). In this group, all patients who achieved a clinical complete response or a good partial response were offered one of two competing regimens of either adjuvant doxorubicin/cyclophosphamide or adjuvant extracorporeal photochemotherapy (ECP). When the results for the group who achieved a complete response (CR) to TSEBT were analyzed, OS for T1 and T2 patients was excellent (85-90% at 5-10 years) and not improved by either adjuvant regimen. However, T3 and T4 patients who received either adjuvant doxorubicin/cyclophosphamide (75% at 3 years) or adjuvant ECP (100% at 3 years) had better overall survival than those who received neither adjuvant regimen (approximately 50% at 5 years). The difference between the OS curves for those who received ECP vs. those who received no adjuvant therapy approached statistical significance (p < 0.06), while a significant survival benefit from the addition of chemotherapy for TSEBT complete responders was not observed. Neither adjuvant therapy provided benefit with respect to relapse free survival after TSEBT. These results suggest that an adjuvant nontoxic regimen of extracorporeal photochemotherapy may prolong survival in advanced stage CTCL patients who have achieved a complete remission after TSEBT. The combination of doxorubicin/cyclophosphamide had no significant impact on overall survival in those patients who achieved CR to TSEBT, and neither adjuvant therapy had an impact on relapse free survival for all T-stages. Such results are the basis for the current development of a prospective, randomized trial studying the impact of ECP after TSEBT in patients with advanced stage CTCL.

Genotypic Analysis of Cutaneous T-Cell Lymphomas

The gene encoding the beta-chain of the T-cell antigen receptor (TCR) has been analyzed for evidence of rearrangement in skin, blood, and lymph node specimens from 23 cases of known or suspected cutaneous T-cell lymphoma (CTCL). Two cutaneous large cell lymphomas, 4 cases of Sézary syndrome, and 5 cases of advanced (tumor) stages of mycosis fungoides showed clonal rearrangement of the TCR beta-chain gene in all samples, including lymph nodes in which histologic examination revealed only dermatopathic lymphadenitis. These results indicate that DNA analysis provides a valuable means for improving the diagnosis of extracutaneous disease in advanced stages of CTCL. In contrast, the gene was in a germline configuration in all samples from 12 patients with plaque stages of mycosis fungoides or suspected early CTCL, suggesting that in these 2 conditions the T-cell proliferation is either polyclonal or contains very few monoclonal (i.e., neoplastic) cells.