Mogamulizumab efficacy is underscored by its associated rash that mimics cutaneous T-cell lymphoma: a retrospective single-centre case series.

BACKGROUND: Mogamulizumab is a humanized antibody against chemokine receptor type 4. It was recently approved by the US Food and Drug Administration for relapsed or refractory mycosis fungoides (MF) and Sézary syndrome (SS). The most commonly reported adverse event in the phase III licensing trial was drug eruption (28%), now termed mogamulizumab-associated rash (MAR). Clinical recommendations about MAR and its treatment differ between the current package insert and postapproval insights reported from two single-centre studies that focused on its characterization, but less so on outcomes and clinicopathological differentiation from cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To describe our experience in the diagnosis of MAR and treatment of patients with CTCL with mogamulizumab. METHODS: This is a single-centre retrospective case series study. RESULTS: We found a higher incidence of MAR in patients with CTCL (17 of 24, 68%) than previously reported. MAR development is associated with complete (11 of 17) or partial (four of 17) responses, with an overall response rate of 88%, compared with 29% (two of seven) in patients without MAR. Diagnosis of MAR may be obscured by its ability to mimic key CTCL features both clinically and histologically, but an absence of T-cell-receptor clonality and relatively decreased CD4 : CD8 ratio compared with baseline lesions strongly favour MAR over recurrent disease. CONCLUSIONS: MAR has the potential to create a significant management problem for patients on mogamulizumab. Misidentification of MAR as recurrent CTCL may detrimentally result in the premature discontinuation of mogamulizumab in patients whose disease is historically hard to treat. Thorough clinicopathological investigation of new lesions during treatment with mogamulizumab is required to inform ideal treatment decisions and achieve better outcomes.

Autologous stem-cell transplantation after second-line brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.

Background: We previously demonstrated that brentuximab vedotin (BV) used as second-line therapy in patients with Hodgkin lymphoma is a tolerable and effective bridge to autologous hematopoietic cell transplantation (AHCT). Here, we report the post-AHCT outcomes of patients treated with second-line standard/fixed-dose BV and an additional cohort of patients where positron-emission tomography adapted dose-escalation of second-line BV was utilized. Patients and methods: Patients on the dose-escalation cohort received 1.8 mg/kg of BV intravenously every 3 weeks for two cycles. Patients in complete remission (CR) after two cycles received two additional cycles of BV at 1.8 mg/kg, while patients with stable disease or partial response were escalated to 2.4 mg/kg for two cycles. All patients, regardless of treatment cohort, proceeded directly to AHCT or received additional pre-AHCT therapy at the discretion of the treating physician based on remission status after second-line BV. Results: Of the 20 patients enrolled to the BV dose-escalation cohort, 8 patients underwent BV dose-escalation. BV escalation was well-tolerated, but no patients who were escalated converted to CR. Of 56 evaluable patients treated across cohorts, the overall response rate (ORR) to second-line BV was 75% with 43% CR. Twenty-eight (50%) patients proceeded directly to AHCT without post-BV chemotherapy, and a total of 50 patients proceeded to AHCT. Thirteen patients received consolidative post-AHCT therapy with either radiation, BV, or a PD-1 inhibitor. After AHCT, the 2-year progression-free survival (PFS) and overall survival were 67% and 93%, respectively. The 2-year PFS among patients in CR at the time of AHCT (n = 37) was 71% compared with 54% in patients not in CR (p = 0.12). The 2-year PFS in patients who proceeded to AHCT directly after receiving BV alone was 77%. Conclusions: Second-line BV is an effective bridge to AHCT that produces responses of sufficient depth to provide durable remission in conjunction with AHCT (clinicaltrials.gov: NCT01393717).

Elevated incidence of fractures in women with invasive breast cancer.

UNLABELLED: This study evaluates the incidence of bone fractures in women with BC.We found that women with invasive breast cancer are at an increased risk for bone fractures, with fractures most commonly occurring at lower extremity and vertebral sites. The risk is further increased in women undergoing cancer therapy. INTRODUCTION: Bone loss and fractures in breast cancer have generally been attributed to aromatase inhibitor use. This study assessed the incidence of fractures after invasive breast cancer diagnosis and evaluated bone density and FRAX risk calculation at time of fracture occurrence. METHODS: Retrospective cohort study of women with invasive breast cancer [June 2003-December 2011] who participated in an academic hospital based genetic biobank. Demographic and clinical characteristics were abstracted from the electronic medical record (EMR). RESULTS: A total of 422 women with invasive breast cancer were assessed; 79 (28 %) sustained fractures during the observation period; fractures occurred at multiple skeletal sites in 27 cases (116 fractures). The incidence of fractures was 40 per 1000 person-years. Women who sustained fractures were mostly white and had a family history of osteoporosis (36.9 %, p = 0.03) or history of a prior fracture (6/79, p = 0.004). Fractures occurred 4.0 years (range 0-12 years) after cancer diagnosis. Fracture cases had femoral neck bone mineral density (BMD) of 0.72 + 0.12 g/cm(2), T-score of -1.2, that is, within the low bone mass range. Fractures most commonly occurred in lower extremities, vertebral, and wrist sites. Hip fractures accounted for 11 % of fractures, occurring at a median age of 61 years. CONCLUSIONS: Fractures occur shortly after commencing cancer therapy. Rapid bone loss associated with cancer therapy may precipitate fractures. Fractures occur at relatively higher BMD in BC. Occurrence of fractures in invasive breast cancer raises the possibility of cancer-induced impairment in bone quality.

Peripheral T-cell lymphomas in a large US multicenter cohort: prognostication in the modern era including impact of frontline therapy.

BACKGROUND: Optimal frontline therapy for peripheral T-cell lymphoma (PTCL) in the modern era remains unclear. PATIENTS AND METHODS: We examined patient characteristics, treatment, and outcomes among 341 newly diagnosed PTCL patients from 2000 to 2011. Outcome was compared with a matched cohort of diffuse large B-cell lymphoma (DLBCL) patients, and prognostic factors were assessed using univariate and multivariate analyses. RESULTS: PTCL subtypes included PTCL, not otherwise specified (PTCL-NOS) (31%), anaplastic large T-cell lymphoma (ALCL) (26%), angioimmunoblastic T-cell lymphoma (23%), NK/T-cell lymphoma (7%), acute T-cell leukemia/lymphoma (6%), and other (7%). Median age was 62 years (range 18-95 years), and 74% had stage III-IV disease. Twenty-three (7%) patients received only palliative care whereas 318 received chemotherapy: CHOP-like regimens (70%), hyperCVAD/MA (6%), or other (18%). Thirty-three patients (10%) underwent stem-cell transplantation (SCT) in first remission. The overall response rate was 73% (61% complete); 24% had primary refractory disease. With 39-month median follow-up, 3-year progression-free survival (PFS) and overall survival (OS) were 32% and 52%. PFS and OS for PTCL patients were significantly inferior to matched patients with DLBCL. On multivariate analysis, stage I-II disease was the only significant pretreatment prognostic factor [PFS: hazard ratio (HR) 0.54, 95% confidence interval (CI) 0.34-0.85, P = 0.007; OS: HR 0.42, 95% CI 0.22-0.78, P = 0.006]. ALK positivity in ALCL was prognostic on univariate analysis, but lost significance on multivariate analysis. The most dominant prognostic factor was response to initial therapy (complete response versus other), including adjustment for stage and SCT [PFS: HR 0.19, 95% CI 0.14-0.28, P < 0.0001; OS: HR 0.26, 95% CI 0.17-0.40, P < 0.0001]. No overall survival difference was observed based on choice of upfront regimen or SCT in first remission. CONCLUSIONS: This analysis identifies early-stage disease and initial treatment response as dominant prognostic factors in PTCL. No clear benefit was observed for patients undergoing consolidative SCT. Novel therapeutic approaches for PTCL are critically needed.

Cutaneous T-cell lymphoma: a paradigm for biological therapies.

Mycosis Fungoides and Sézary Syndrome are the most common types of cutaneous T-cell lymphomas. There is no current standard of care for Mycosis Fungoides/Sézary Syndrome, with a general tendency to rely on topical interventions for early disease delaying systemic, more toxic therapy until the development of extensive symptoms. Knowledge of the biological characteristics of this disease has allowed for the development of rational interventions and a significant advance in its treatment. Retinoids are active in Mycosis Fungoides/Sézary Syndrome with the newer rexinoids being available in topical and systemic forms. Interferon alpha remains one of the most active therapeutic agents for Mycosis Fungoides/Sézary Syndrome, especially in combination with other agents such as PUVA. The monoclonal antibody alemtuzumab leads to responses in at least half of patients with advanced disease with its side effect profile consisting mainly of immunosupression and infusion reactions. The recombinant IL2-diphteria toxin denileukin diftitox (Ontak) is active in this disease and appears to have a beneficial effect in symptoms relief and quality of life. Extracorporeal photochemotherapy as an immunostimulating intervention seems to be very effective in a subset of patients, but its availability is limited to less than a hundred centers worldwide. Experimental and less studied interventions include autologous and allogeneic peripheral stem cell transplantation, Interleukin-12, the histone-deacetylator depsipeptide and the synthetic deoxynucleotide CpG7909. Cutaneous T-cell lymphoma has served as a paradigm for the development of biological agents. Further knowledge of the signaling pathways in Mycosis Fungoides/Sézary Syndrome will allow for the development of more effective treatment strategies.

A role for protein kinase C delta in the differential sensitivity of MCF-7 and MDA-MB 231 human breast cancer cells to phorbol ester-induced growth arrest and p21(WAFI/CIP1) induction.

The goal of this study was to investigate the differential sensitivity of estrogen receptor (ER) positive MCF-7 and ER negative MDA-MB 231 breast cancer cells to phorbol myristate acetate (PMA)-dependent growth arrest. MCF-7 cells were growth arrested by 80% while MDA-MB 231 cells were arrested by 20% in response to seven days of treatment with 10 nM PMA. Coincident with the increased sensitivity of MCF-7 cells to be growth arrested by the protein kinase C (PKC) activator PMA, PMA induced 9-fold higher levels of the cyclin dependent kinase (Cdk) inhibitor p21(WAF1/GIP1) in MCF-7 compared to MDA-MB 231 cells. A comparison of the PKC isoforms expressed in MCF-7 versus MDA-MB 231 cells showed that only the PMA-sensitive PKC delta and eta isoforms were expressed at markedly (> or =10-fold) elevated levels in MCF7 versus MDA-MB 231 cells. These results suggested that the differential sensitivity to growth arrest and induction of p2l(WAFl/CIPl) could reflect, at least in part, increased expression of PMA-dependent PKC isoforms delta and/or eta. Direct evidence to support this hypothesis was provided by the ability of transient transfections into MCF-7 cells of constitutively active PKC delta but not of PKC's eta or alpha or epsilon to enhance p21(WAFl/CIP1) promoter activity. These results suggest that PKC delta plays a fundamental role in the regulation of growth in estrogen receptor positive breast cancer cells.

8-chloro-cAMP and 8-chloro-adenosine act by the same mechanism in multiple myeloma cells.

Previous work with 8-chloro-cAMP (8-Cl-cAMP) has raised questions as to whether it works as a cAMP analogue or as a nucleoside analogue after its conversion to 8-chloro-adenosine (8-Cl-Ado). Although degradation of 8-Cl-cAMP to 8-Cl-Ado in culture medium or plasma has been shown, cellular pharmacology data are missing. The purpose of the present study was to identify the cellular metabolism of these drugs and their actions in a human multiple myeloma cell line. The cells were incubated with either 8-Cl-Ado or 8-Cl-cAMP to follow the cellular metabolism of these agents. Both 8-Cl-cAMP and 8-Cl-Ado incubation resulted in the accumulation of 8-Cl-Ado mono-, di-, and tri-phosphate (8-Cl-ATP), however, the triphosphate was the major cytotoxic metabolite. Accumulation of 8-Cl-ATP was dependent on both the exogenous concentration of 8-Cl-Ado and incubation time. At the 10 microM level of 8-Cl-Ado, >400 microM 8-Cl-ATP accumulated in multiple myeloma cells after continuous incubation for 12 h. Similar incubation with 8-Cl-cAMP also resulted in accumulation of 8-Cl-ATP in the cells, albeit at a lower level. The formation of 8-Cl-ATP from 8-Cl-cAMP was inhibited by >80% in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine in the medium, suggesting extracellular conversion of 8-Cl-cAMP to 8-Cl-Ado. Cells lacking Ado kinase did not accumulate 8-Cl-ATP, either from 8-Cl-Ado or 8-Cl-cAMP, and were resistant to these agents. There was also a decline in the endogenous level of the cellular ATP pool parallel to the accumulation of 8-C1-ATP. The elimination of 8-Cl-ATP was biphasic and slow from the cells. The accumulation of 8-Cl-ATP and a decline in the ATP pool inhibited RNA synthesis but did not affect DNA synthesis for up to 12 h of incubation. Taken together, these data demonstrate that the cytotoxic metabolite of 8-Cl-Ado and 8-Cl-cAMP is 8-Cl-ATP. Hence, 8-Cl-cAMP serves as a prodrug and is converted to 8-Cl-Ado in medium with subsequent phosphorylation to accumulate as 8-Cl-ATP in cells. At the cellular level, 8-Cl-ATP is associated with a decrease in the endogenous ATP pool; at the nuclear level, it inhibits RNA synthesis.

Primary cutaneous B-cell lymphoma: review and current concepts.

PURPOSE: Primary cutaneous B-cell lymphoma (PCBCL) has only recently been recognized as a distinct clinical entity. With the advent of improved immunophenotyping and immunogenotyping, increasing numbers of PCBCL cases are being diagnosed. However, there is much confusion regarding the classification, treatment, and prognosis of these patients. The purpose of this article is to review and analyze the available data to provide the clinician with a concise summary of the diagnosis, prognosis, and treatment of PCBCL. DESIGN: We conducted a thorough review of the medical literature on PCBCL, with a focus on classification, prognosis, and treatment trials. RESULTS AND CONCLUSION: PCBCL is defined as a B-cell lymphoma originating in the skin. There is no evidence of extracutaneous disease at presentation and for 6 months after diagnosis, as assessed by adequate staging procedures. Currently, the European Organization for Research and Treatment of Cancer classification is the most concise disease classification scheme, dividing the subtypes of PCBCL by clinical behavior and histopathologic findings. Based on this classification, the most common subtype of PCBCL is follicular center cell lymphoma. PCBCL is generally an indolent form of lymphoma with a good prognosis. Although local cutaneous recurrences are observed in 25% to 68% of patients, dissemination to internal organs is rare. Five-year survival rates typically range from 89% to 96%. A specific subtype, large B-cell lymphoma of the leg, is noted to have a poorer prognosis, with a 5-year survival rate of 58%. Overly aggressive treatment of PCBCL has not been shown to improve survival or prevent relapse. The treatment of choice usually varies depending on the type of PCBCL, the body surface area, and the location of the involvement, as well as the age and general health condition of the patient. The majority of studies indicate that PCBCL is highly responsive to radiation therapy. Polychemotherapy should be reserved for involvement of noncontiguous anatomic sites or those with extracutaneous spread.

Regulation of protein kinase C delta by estrogen in the MCF-7 human breast cancer cell line.

We have previously shown that estrogen up-regulates expression of protein kinase C (PKC) delta in the rat and rabbit corpus luteum as well as in luteinized rat granulosa primary cell cultures. To determine whether a similar regulation of the PKC delta isoform by estrogen occurred in another estrogen responsive system, we investigated the estrogen receptor positive MCF-7 human breast cancer cells. In a characterization of PKC isoforms in MCF-7 cells we determined that PKC delta was the predominant PKC isoform. However in contrast to the effect of estrogen on PKC delta expression in ovarian cells, estrogen treatment of MCF-7 cells resulted in a significant decrease in PKC delta protein and mRNA expression in a time and dose dependent manner. Treatment of MCF-7 cells with 10(-10)-10(-8) M estrogen for 7 days down-regulated specifically PKC delta mRNA and protein while expression of other PKC isoforms was unchanged. The opposite regulation of PKC delta expression in ovarian and breast cancer cells prompted us to evaluate the type of estrogen receptor present in both cell types. Results showed that luteinized rat granulosa cells expressed predominantly estrogen receptor beta while the MCF-7 cells expressed predominantly estrogen receptor alpha and barely detectable levels of estrogen receptor beta. These results suggest that the differential ability of estrogen to regulate PKC beta expression could potentially be a result of differential signaling through the two estrogen receptor subtypes.

8Cl-cAMP cytotoxicity in both steroid sensitive and insensitive multiple myeloma cell lines is mediated by 8Cl-adenosine.

We have examined the cytotoxic effects of cyclic adenosine-3', 5'-monophosphate (cAMP) derivatives on multiple myeloma cells lines and determined that the 8-Chloro substituted derivative (8Cl-cAMP) is one of the most potent. We report here that 8Cl-cAMP is cytotoxic to both steroid sensitive and insensitive myeloma cells with a half maximal concentration of approximately 3 micromol/L. 8Cl-cAMP toxicity in myeloma cells is dependent on phosphodiesterase activity in the serum of cell culture medium. A metabolite of 8Cl-cAMP, 8-Chloro-adenosine (8Cl-AD), kills myeloma cells as effectively as 8Cl-cAMP. Adenosine deaminase (ADA) converts 8Cl-AD into 8Cl-inosine and abrogates the cytotoxic effects of 8Cl-cAMP, 8Cl-AMP, and 8Cl-AD, as does 5-(p-Nitrobenzyl)-6-Thio-Inosine (NBTI), an inhibitor of nucleoside uptake. These data suggest that 8Cl-cAMP must be converted to 8Cl-AD and that 8Cl-AD is the compound that enters the cell. Contrary to glucocorticoid-mediated cell death in myeloma cells, the pathway of 8Cl-AD-mediated cell death appears to be independent of interleukin-6 (IL-6) actions. Although the exact mode of action for this agent is currently unknown, its ability to kill steroid sensitive and insensitive multiple myeloma cells in an IL-6 independent fashion may offer exciting new therapeutic options.

Association of PKC delta and active Src in PMA-treated MCF-7 human breast cancer cells.

Phorbol ester treatment of MCF-7 cells led to the tyrosine phosphorylation and activation of PKC delta. However, through Western blot analysis and in vitro immunecomplex kinase assays, we detected a differential localization of tyrosine-phosphorylated PKC delta and catalytically active PKC delta. Catalytically active PKC delta was concentrated in Triton X-100 solubilized-membrane fractions while tyrosine-phosphorylated PKC delta was localized to the cytosol fraction. Phorbol ester treatment of MCF-7 cells stimulated both the time-dependent in vivo association of Src with PKC delta, evidenced in Src immunoprecipitates by the co-immunoprecipitation of PKC delta, and activation of Src, evidenced in Src immunoprecipitates as an increase in reactivity with a Src antibody (clone 28) reactive only with active Src (dephosphorylated on residue 530) and in Src and PKC delta immunoprecipitates by an increase in Src kinase activity. While our data are consistent with reports in the literature showing the activator/stimulus-dependent tyrosine phosphorylation of PKC delta, our data show that the tyrosine phosphorylation of PKC delta is not essential for kinase activity. These results are the first to demonstrate an in vivo association between PKC delta and active Src in the absence of over-expression of either PKC delta or Src, and support the association of Src and PKC delta towards a physiological function.

Adoptive immunotherapy for leukemia: donor lymphocytes transduced with the herpes simplex thymidine kinase gene for remission induction. HGTRI 0103.

This study will evaluate the safety and efficacy of allogenic donor lymphocyte infusions in patients who have relapsed hematologic malignancies after allogeneic bone marrow transplantation (BMT). Donor lymphocyte transfusions have resulted in the cure of some patients with relapsed leukemia or lymphoproliferative disorder after allogeneic BMT, but has been complicated by the development of graft versus host disease (GvHD). We hypothesize that a retroviral vector containing the Herpes simplex thymidine kinase (HStk) gene will allow for retention of the anti-leukemia response of transfused donor lymphocytes while allowing for the adverse effects of GVHD to be mitigated. Patients with relapsed hematologic malignancies after allogeneic BMT will be infused with ex vivo gene modified donor lymphocytes. The Herpes Simplex thymidine kinase (HStk) gene will be transduced into the cells ex vivo using LTKOSN. 1 vector supernate. Insertion of the HStk gene into lymphocytes confers a sensitivity to the anti-herpes drug ganciclovir (GCV). This selective destruction of donor lymphocytes in situ will be used to abrogate the effect of graft versus host disease, if it develops.

Interferon-alpha resistance in a cutaneous T-cell lymphoma cell line is associated with lack of STAT1 expression.

Interferon-alpha (IFN alpha) mediates its biological effects through activation of the JAK-STAT signaling pathway and it has been shown to be one of most effective therapeutic agents for a number of hematological malignancies, including cutaneous T-cell lymphoma (CTCL). Nevertheless, its efficacy is limited by the development of clinical resistance but the reasons for resistance in CTCL are unknown. Here, we report the development of an IFN alpha-resistant CTCL cell line (HUT78R), characterized by its ability to proliferate in high concentration of recombinant IFN alpha, which can be used as a model system to study IFN resistance. The levels of IFN receptor expression and binding affinity were found to be comparable between the parental sensitive (HUT78S) and resistant (HUT78R) cells. However, IFN alpha stimulation failed to induce interferon-stimulated gene factor 3 (ISGF3) complex formation in HUT78R cells. In addition, the expression of the IFN-inducible 2-5 OAS gene was significantly reduced in HUT78R cells, suggesting the presence of a defect in the Jak-STAT signaling pathway. Our results showed that the IFN alpha-activated form of a latent transcriptional factor STAT1 was not found in HUT78R cells, whereas activated STAT2 and STAT3 were clearly detectable. By Western blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses, we found that HUT78R cells do not express any STAT1 protein or mRNA, suggesting the possibility of a null mutation in the STAT1 gene. Resistance to the growth inhibitory effect of IFN alpha in CTCL cells may result from lack of STAT1 expression.

2-Chlorodeoxyadenosine in cutaneous T-cell lymphoproliferative disorders.

The efficacy and toxicity of 2-chlorodeoxyadenosine (2-CdA) in cutaneous T-cell lymphoproliferative disorders was examined. Between February 1991 and April 1996, 25 patients with relapsed or refractory cutaneous T-cell lymphoproliferative disorders (24 mycosis fungoides or Sezary syndrome, one Ki-1+ anaplastic large cell lymphoma) were treated with 2-CdA initially administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days (13 patients). The infusion duration was subsequently reduced to 5 days (9 patients) because of prohibitive hematologic toxicity. Three patients were treated at the same daily dose by bolus injection over two hours for 5 days. Cycles were administered at 28 day intervals. Seventeen patients received more than one cycle. An overall response rate of 24% was achieved. Three patients (12%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (12%) had a partial response with a median duration of 2 months (range, 2 to 4). Nineteen patients (76%) had no response. The most significant toxicities encountered were myelosuppression (64%) and infectious complications (64%). 2-CdA has activity as a single agent in patients with previously treated relapsed T-cell lymphoproliferative disorders.

Recurring structural chromosome abnormalities in peripheral blood lymphocytes of patients with mycosis fungoides/Sézary syndrome.

Cytogenetic analysis was performed on peripheral blood lymphocyte cultures from 19 patients with mycosis fungoides (MF)/Sézary syndrome (SS) stimulated with either phytohemagglutinin, a conventional mitogen, or a combination of interleukin-2 (IL-2) plus IL-7. The use of both PHA-stimulated and IL-2 plus IL-7-stimulated cultures enhanced the ability to identify clonal abnormalities. Clonal abnormalities were observed in 11 patients (53%) including one with monosomy for the sex chromosome as the sole abnormality. Five of the 11 patients with clonal abnormalities had normal peripheral white blood cell counts, indicating detectability of clones in the absence of frankly leukemic disease. The presence of clonal abnormalities correlated with advanced stage disease and a significantly reduced survival duration from the time of cytogenetic studies. Clonal abnormalities involving chromosomes 1 and 8 were observed in six cases. In five cases with aberrations of chromosome 1, loss of material involved the region between 1p22 and 1p36. In an additional case, a reciprocal translocation involving 1p33 was observed. Clonal abnormalities involving chromosomes 10 and 17 were observed in 5 cases, clonal abnormalities involving chromosome 2 in 4 cases, and clonal abnormalities involving chromosomes 4, 5, 6, 9, 13, 15, 19, and 20 in 3 cases. In 2 cases a der(8)t(8;17)(p11;q11) was observed. Regions of the genome that encode T-cell receptors were not involved in abnormalities. The region between 1p22 and 1p36 is identified as a region of the genome that requires detailed analysis toward the identification of potential gene(s) involved in the process of malignant transformation and/or progression in MF/SS.

Cyclic adenosine-3',5'-monophosphate-mediated cytotoxicity in steroid sensitive and resistant myeloma.

Multiple myeloma is a neoplastic proliferation of plasma cells. Glucocorticoids are among the most effective agents against multiple myeloma, acting through the glucocorticoid receptor to induce programmed cell death. However, some patients do not respond to glucocorticoids, and those that do respond eventually develop resistance to this therapy. Alternative strategies using drugs that mediate cytotoxicity through complementary pathways have theoretical appeal. Cyclic adenosine-3',5'-monophosphate (cAMP) derivatives are cytotoxic to a number of cell lines of lymphocytic origin. cAMP analogues activate protein kinase A, affecting cell growth and differentiation. The cascade of events initiated by cAMP derivatives and glucocorticoid, although distinct, may share some distal molecular targets. We have found that pharmacological concentrations of 8-chloro-cAMP, dibutyryl-cAMP, and 8-bromo-cAMP are cytotoxic to multiple myeloma cells, enhance glucocorticoid effects, and can kill glucocorticoid-resistant clones. cAMP analogues induce apoptosis as demonstrated by the fragmentation of myeloma DNA chromatin in a distinctive ladder pattern. In contrast to glucocorticoids, cAMP growth inhibition cannot be reversed by exogenous interleukin 6. cAMP derivatives have activity against multiple myeloma and are appropriate candidates for clinical trials.

Phase I/II trial of combined 131I anti-CEA monoclonal antibody and hyperthermia in patients with advanced colorectal adenocarcinoma.

BACKGROUND: This pilot project was undertaken to evaluate the toxicity of and tumor response to combined 131I anti-carcinoembryonic antigen monoclonal antibody (131I anti-CEA RMoAb) and hyperthermia in patients with metastatic colorectal adenocarcinoma. METHODS: Nine patients who had colorectal carcinoma with liver metastases were enrolled in this study. Intact 131I anti-CEA RMoAb was used (the specific antibody was IMMU-4, provided by Immunomedics, Inc., Morris Plains, NJ). During the diagnostic phase, dosimetry revealed that the tumor site received a higher radiation dose than the surrounding normal tissues in only six patients. These six, who were treated with radioimmunotherapy and hyperthermia, were the basis of this study. The first three patients were treated with 30 mCi/m2 of 131I anti-CEA RMoAb, and the next three received 60 mCi/m2. Pharmacokinetic clearance data were reported for all nine patients. RESULTS: Thermometry data revealed an average T90 of 40.3 (+/- 1.4 degrees C) and T50 of 41.1 (+/- 1.2 degrees C). The average thermal dose equivalent at 42.5 degrees C was 34.5 (+/- 21.5) minutes. The average Tmin, Tmax, and Tmeam were 40 (+/- 1.2 degrees C), 42.4 (+/- 0.7 degrees C), and 41.1 (+/- 1.1 degrees C), respectively. The pharmacokinetic clearance data of antibody showed monoexponential plasma clearances in all patients except one, in whom a biexponential plasma clearance was observed. In general, similar plasma and whole-body clearances as well as similar urinary excretions were observed when diagnostic and therapeutic phases for each patient were compared. Two of the six patients showed a marked improvement in their symptoms; five patients showed a drop in carcinoembryonic antigen levels. A follow-up computed tomography scan one month after treatment showed no change in tumor volume in five patients; one patient showed a partial response. Three patients developed toxicity, two developed moderate thrombocytopenia (39,000 and 58,000), and the other patient developed hematoma resulting from the insertion of a catheter for thermometry. CONCLUSIONS: It is feasible to combine hyperthermia and radiolabeled monoclonal antibodies, and the combination was well tolerated by these patients. The interaction between hyperthermia and low dose rate radioimmunotherapy is complex. Further studies are necessary to explore the use of this combined modality in the management of maligancies.

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma.

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.

Chemotherapy for mycosis fungoides and the Sézary syndrome.

Although conventional cytotoxic chemotherapy agents used alone or in combination have demonstrated activity in MF/SS, there are no studies that clearly demonstrate improvement in survival of treated patients. Newer compounds worthy of further clinical investigation in these patients include temazolamide, an alkylating agent with activity in brain neoplasms, the taxanes, and topoisomerase inhibitors, including topotecan and CPT-11. In addition, the combination of cytotoxic chemotherapies with biologic modalities, such as targeted toxins and immunomodulatory agents, has yet to be explored.

Treatment of mycosis fungoides with photochemotherapy (PUVA): long-term follow-up.

BACKGROUND: Mycosis fungoides (MF) is a non-Hodgkin's T-cell lymphoma of the skin that often begins as limited patches and plaques with slow progression to systemic involvement. No studies have been published comparing photochemotherapy (PUVA) with other topical therapies in the treatment of early-stage disease. OBJECTIVE: The purpose of the study was to examine our long-term experience using PUVA to treat early-stage MF and to compare its effectiveness and side-effect profile with other previously reported topical therapies. METHODS: Eighty-two patients with MF (83% stage IA or IB) were treated with PUVA. Clinical and histologic features were observed for a period from 2 months to 15 years (median, 43 months). RESULTS: A response was noted in 78 patients (95%) with complete clinical and histologic clearing in 53 patients (65%) for all stages. The mean duration of total complete response to PUVA for all stages was 43 months (3.6 years). The mean survival of our study group for all stages was 8.5 years. Signs of chronic actinic skin damage were found in 10% of patients, including three patients with basal cell carcinomas and three patients with squamous cell carcinomas. In a nonrandomized comparison with previously reported data for other topical therapies, the efficacy and side-effect profile of PUVA compared favorably. CONCLUSION: PUVA is an effective and safe therapy for MF with prolonged disease-free remissions being achieved. Patients with stage I and II MF respond best to PUVA. Palliative therapy with PUVA is useful in more advanced cases of MF.