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Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer

PURPOSE To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study. PATIENTS AND METHODS Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life. RESULTS The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms. CONCLUSION Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.

Malignant lymphoma-associated autoimmune diseases – a descriptive epidemiological study

Abstract. Lymphoproliferative disorders and autoimmune diseases have some common aspects in their clinical appearance. We reviewed 940 patient charts with malignant lymphomas to assess the rate of associated autoimmune diseases. Of 421 non-Hodgkins lymphoma (NHL) patients (230 males, 191 females), 32 (7.6%) had an autoimmune disease (26 females, six males, mean age 48.3 years). The most common diagnosis was Sjögrens syndrome. The other cases were autoimmune skin diseases (5), thyroiditis (3), polymyositis (2), scleroderma (2), other musculoskeletal disorders (2), rheumatoid arthritis (1), vasculitis (1), undifferentiated collagenosis (1), colitis ulcerosa (1), autoimmune hepatitis (1), Addisons disease (1), and autoimmune hemolytic anemia (1). Of 519 Hodgkins lymphoma patients (308 males, 211 females), an associated autoimmune disease occurred in 45 (8.6%) (25 females, 20 males, mean age 39.2 years). In 31 cases, we found autoimmune thyroid disorders, then came glomerulonephritis (3), immune thrombocytopenia (3), insulin-dependent diabetes mellitus (2), autoimmune hemolytic anemia (1), seronegative spondylarthritis (1), systemic lupus erythematosus (1), mixed connective tissue disease (1), scleroderma (1), and vasculitis (1). We also analyzed histology, choice of treatment, and sequence of appearance of the disease types. We found a difference between NHL and Hodgkins lymphoma patients, since in NHL autoimmunity – mostly from Sjögrens syndrome – preceded the lymphoma diagnosis (70%), but in Hodgkins the autoimmunity developed mainly after the treatment of malignancy. The relatively high prevalence of autoimmune diseases in malignant lymphomas has several explanations. Clinicians have to consider autoimmunity when treating lymphoproliferative disorders.

Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia: interim results from a phase 3, randomised, double-blind, placebo-controlled trial

Summary Background Bendamustine and rituximab (BR) has been a standard of care for the management of patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). We evaluated the efficacy and safety of adding idelalisib, a first-in-class targeted PI3Kδ inhibitor, to BR in patients with R/R CLL Methods This trial was a global, multicenter, double-blind, placebo -controlled trial in adult patients (≥18 years) with R/R CLL requiring treatment for their disease. Patients had to have measurable lymphadenopathy (≥1 nodal lesion ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter) by computer tomography or magnetic resonance imaging, disease progression within <36 months since last prior therapy, a Karnofsky Performance Status score ≥60 and adequate bone marrow, liver and kidney function. Key exclusion criteria included histological transformation to an aggressive lymphoma (eg, Richter transformation) or disease refractory to bendamustine. Patients were randomised 1:1 using a central interactive web response system that assigned a unique treatment code for each patient, to receive intravenous BR infusions for a maximum of 6 cycles in addition to blinded study drug matching the assigned treatment of either twice-daily oral idelalisib 150 mg or placebo administered continuously until disease progression or intolerable study drug-related toxicity. Randomisation was stratified based on high-risk features (IGHV, del(17p)/TP53 mutation) and refractory vs relapsed disease. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee in the intent-to-treat population. Overall survival was a key secondary endpoint. Crossover was not permitted to the idelalisib arm at progression. The trial is ongoing (ClinicalTrials.gov # NCT01569295). Findings Between 26 June 2012 and 21 August 2014, 416 patients with R/R CLL were enrolled; 207 patients were randomised to the idelalisib and 209 to the placebo arm. After the prespecified interim analysis, the Independent Data Monitoring Committee (IDMC) recommended discontinuation and unblinding of the trial due to efficacy. Updated data are presented in this manuscript with a cutoff date of 07 October 2015. Median (95% CI) PFS was 20·8 (16·6, 26·4) and 11·1 (8·9, 11·1) months in the idelalisib and placebo arms, respectively (hazard ratio [HR], 0·33; 95% CI, 0·25, 0·44; P<0·0001) at a median (Q1, Q3) follow-up of 14 (7, 18) months. The most frequent grade 3 or greater AEs were neutropenia (124/207 [60%]) and febrile neutropenia (48/207 [23%]) in the idelalisib arm and neutropenia (99/209 [47%]) and thrombocytopenia (27/209 [13%]) in the placebo arm. Serious AEs included febrile neutropenia, pneumonia and pyrexia and were common in both treatment arms. An increased risk of infection was observed in the idelalisib vs placebo arm. Interpretation Idelalisib plus BR is superior to BR alone, improving PFS and OS. This regimen represents an important new treatment option for patients with R/R CLL.

Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma

BACKGROUND Brentuximab vedotin is an anti‐CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkins lymphoma. METHODS We conducted an open‐label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkins lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression‐free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. RESULTS At a median follow‐up of 24.9 months, 2‐year modified progression‐free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.7 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.03). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.72 [95% CI, 0.44 to 1.17]; P=0.19). All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony‐stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow‐up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary‐related toxicity. CONCLUSIONS A+AVD had superior efficacy to ABVD in the treatment of patients with advanced‐stage Hodgkins lymphoma, with a 4.9 percentage‐point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON‐1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011‐005450‐60.)

Uro-Vaxom® and the management of recurrent urinary tract infection in adults : a randomized multicenter double-blind trial

A total of 112 patients with recurrent lower urinary tract infection (UTI) completed the 6-month period of the trial. Patients were treated for 3 months, under double-blind conditions, with one capsule daily of either Uro-Vaxom (UV) or placebo, together with an antibiotic or chemotherapeutic agent when necessary, and observed for a further 3 months. During the 6 months of the trial a significant decrease in the number of recurrences (p < 0.0005) was noted in the UV group as compared to the placebo group. A total of 67.2% of the patients had no recurrences (p < 0.0005). The incidence of bacteriuria (germs > or = 10(5)/ml), dysuria and leukocyturia was significantly reduced. UV was well tolerated, no side effects were recorded during the trial. The drug is a useful adjuvant for the management of UTIs and for the prevention of recurrences.

Paraneoplastic rheumatic syndromes

Paraneoplastic symptoms caused by a malignancy but not directly related to tumour invasion are the result of a wide variety of tumour-derived biologic mediators, such as hormones, peptides, antibodies, cytotoxic lymphocytes, autocrine and paracrine mediators. Recognition of paraneoplastic syndromes is important, as it may lead to an early diagnosis of cancer. On the other hand, the clinical severity of the symptoms can be used as a guide to the extent of response to underlying tumour therapy. The quality of life of the patient is affected, therefore the palliative treatment of paraneoplasia is very important.

Hypothyroidism and thyroiditis after therapy for Hodgkin's disease

During the follow-up of thyroid function of 151 patients with Hodgkin’s disease in complete remission for at least 1 year, 26 cases of subclinical, 12 cases of manifest clinical hypothyroidism and 2 cases of hyperthyroidism (Graves-Basedow disease) were confirmed. Thyroid dysfunction was more frequent in patients who had undergone mantle or neck radiotherapy. Hypothyroidism was most often revealed from the 6th year on following radiotherapy. Thyroid autoantibody positivity was found to be more frequent in patients with thyroid dysfunction, and conversely, thyroid dysfunction was more frequent among the 28 patients with autoantibody positivity. Ultrasound examination and fine needle aspiration cytology of the thyroid confirmed thyroiditis in 96% of the patients with antibody positivity. No relationship was found between thyroiditis and the form of treatment for Hodgkin’s disease. We have found that both neck irradiation and thyroiditis may play a role in the increased number of thyroid dysfunction in patients treated for Hodgkin’s disease. Thyroiditis is not caused by neck radiotherapy but may be the result of immune regulation disorders in Hodgkin’s disease. For substitution or isohormone therapy, levothyroxine is suggested for use. We suggest that examination of the thyroid should be performed at least once a year during the follow-up of Hodgkin’s disease patients.

Immunoregulatory T cells in the peripheral blood of patients with Hodgkin's lymphoma

We aimed at investigating the distribution of various types of immunoregulatory T cells in the peripheral blood of patients with Hodgkin’s lymphoma (HL) (n = 94) being in the state of long-lasting complete remission using flow cytometry. Healthy patients (n = 41) as ‘negative’ and patients in complete remission with breast cancer (n = 47) as ‘positive’ controls were investigated in the study. We found significant elevations in the number of CD4+CD25high naturally occurring regulatory T cells, CD4+/intracellular IL-10+ (Tr1) and CD8+/intracellular IL-10+ T cells in HL compared to the healthy controls. In carcinoma patients, however, the number of Tr1 and CD8+/IL-10+ T cells was higher than that in the other two groups. The increase in the number of CD4+CD25high T cells seems to be characteristic of HL compared to the two other types of regulatory T cells. This change exists for a long time and it seems to be a characteristic of HL and independent of the types of therapy and the duration of time since therapy.

Successful Treatment of B Cell Chronic Lymphocytic Leukemia-Associated Severe Paraneoplastic Pemphigus with Cyclosporin A

Since the first description of paraneoplastic pemphigus, several cases have been described in the literature. However, curative therapy is usually a challenge to the physicians treating this disease. Several publications are available discussing the efficacy of steroids, cyclophosphamide and cyclosporin A. Recently, a report of the successful use of rituximab was also published. However, the use of cyclosporin A is controversial in the case of B cell malignancies, as there are reports showing the cytotoxic effect of this drug on B cells. However, other authors report no effect, or even unwanted effects resulting in B cell proliferation. We report the case of a 50-year-old Caucasian male. He developed a B cell lymphoma consisting of CD5/CD20-double-positive cells, and 2 months later, it was followed by a very severe paraneoplastic pemphigus affecting the mucosa and the skin. The lymphoma was well managed with CHOP and CVP polychemotherapy, followed by oral chlorambucil; however, the bullous eruptions did not disappear. Oral steroids, cyclophosphamide, plasmapheresis and IVIG therapy were only partially successful, so we decided to use oral cyclosporin A. Starting with 7 mg/kg and maintaining a steady plasma level of no less then 110 ng/l, the bullae completely disappeared within 6 weeks, and the patient has been in remission for 17 months now, taking the oral cyclosporin A continuously. The underlying B cell disorder did not relapse during the therapy.

Aspects of B-Cell Non-Hodgkin's Lymphoma Development: A Transition from Immune-Reactivity to Malignancy

The development of B‐cell lymphomas is an intricate interplay among various pathogenic factors, leading to a multi‐step process, encompassing various stages of B‐cell maturation. Besides genetic abnormalities, a variety of environmental and microbial factors, as well as disproportional immune‐regulatory processes lead to the malignant transformation. Yet, little is known about the exact chain of events, which lead from the physiological polyclonal B‐cell activation as a response to exogenous antigens through oligoclonality to a monoclonal, uncontrolled, malignant B‐cell proliferation. The aim of the present review was to summarize the potential harmful steps in the development of B‐cell lymphomas, according to conventional and novel theories, and to depict therapeutic regimens presently in use as well as to envision future drug developments, beneficial in the battle against this lymphoid malignancy.