Karin Hohloch

Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group

PURPOSE The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome. PATIENTS AND METHODS One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter. RESULTS The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased beta2-microglobulin (beta2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, beta2-MG, and TK were independent prognostic factors for OS. CONCLUSION Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.

Population pharmacokinetics of melphalan and glutathione S-transferase polymorphisms in relation to side effects.

Melphalan is associated with severe side effects such as mucositis, diarrhea, and myelosuppression. We investigated how much the individual severity of these side effects is predicted by pharmacokinetics. In addition, we studied glutathione S‐transferase GSTM1, GSTT1, and GSTP1 polymorphisms in relation to adverse events. A high interindividual pharmacokinetic variability was observed in 84 patients. There was a linear correlation between creatinine and melphalan clearance (P=0.0004). Patients treated with a dose ⩾70 mg/m2 had a 23‐fold increased risk to develop mucositis (P<0.001) and a 12‐fold increased risk to develop diarrhea (P<0.001) compared with lower doses. The GSTP1 codon 105 polymorphism may be relevant for development of mucositis and the GSTT1 deletion may predict diarrhea, but these findings require confirmation. Melphalan‐induced side effects were significantly dependent only on dose. Therapeutic drug monitoring or genotyping for GST does not appear to be very helpful in optimizing therapy with melphalan.

Genetic polymorphisms in the amino acid transporters LAT1 and LAT2 in relation to the pharmacokinetics and side effects of melphalan.

Objectives Melphalan is widely used in the treatment of multiple myeloma. Pharmacokinetics of this alkylating drug shows high inter-individual variability. As melphalan is a phenylalanine derivative, the pharmacokinetic variability may be determined by genetic polymorphisms in the L-type amino acid transporters LAT1 (SLC7A5) and LAT2 (SLC7A8). Methods Pharmacokinetics were analysed in 64 patients after first administration of intravenous melphalan. Severity of side effects was documented according to WHO criteria. Genomic DNA was analysed for polymorphisms in LAT1 and LAT2 by sequencing of the entire coding region, intron-exon boundaries and 2 kb upstream promoter region. Selected polymorphisms in the common heavy chain of both transporters, the protein 4F2hc (SLC3A2), were analysed by single nucleotide primer extension. Results Melphalan pharmacokinetics was highly variable with up to 6.2-fold differences in total clearance. A total of 44 polymorphisms were identified in LAT1 and 21 polymorphisms in LAT2. From all variants, only five were in the coding region and only one heterozygous non-synonymous polymorphism (Ala94Thr) was found in LAT2. Numerous polymorphisms were found in the LAT1 and LAT2 5′-flanking regions but did not correlate with expression of the respective genes. No significant correlations could be observed between the polymorphisms in 4F2hc, LAT1, and LAT2 with melphalan pharmacokinetics or with melphalan side effects. Conclusions The study confirmed that these transporter genes are highly conserved, particularly in the coding sequences. Genetic variation in 4F2hc, LAT1, and LAT2 does not appear to be a major cause of inter-individual variability in pharmacokinetics and of adverse reactions to melphalan.

Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms

AIM We investigated whether genetic polymorphisms may contribute to the interpatient variability of cisplatin-induced nephrotoxicity. PATIENTS & METHODS Polymorphisms in the candidate genes GSTM1, GSTT1, OCT1, OCT2, LARP2, ERCC1, XRCC1 and EPO were analyzed for associations with nephrotoxicity in 79 cancer patients receiving cisplatin-containing chemotherapy. RESULTS Higher cisplatin dose was associated with strongly decreased estimated glomerular filtration rates (eGFR) (r(2) = 0.205). Two highly genetically linked polymorphisms in the ERCC1 gene, 8092C>A and Asn118Asn, were significantly associated with change in eGFR, accounting for an additional 13% of interindividual variability. Homozygous carriers of the 8092A allele in ERCC1 showed no reduction in eGFR, compared with the 11.5% mean eGFR decrease in C allele carriers (p = 0.004). Homozygous carriers of the C allele of Asn118Asn showed no reduction in eGFR, compared with the 12.8% mean eGFR decrease seen in T allele carriers (p = 0.047). Polymorphisms in the other candidate genes were not associated with cisplatin-induced nephrotoxicity. CONCLUSION Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.

Radioimmunotherapy Confers Long-Term Survival to Lymphoma Patients with Acceptable Toxicity: Registry Analysis by the International Radioimmunotherapy Network

The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients’ conditions, lymphoma subtypes, and hematologic side effects of radioimmunotherapy treatment. Methods: RIT-N is located at the University of Göttingen, Germany, and collected data from 14 countries. Data were entered by investigators into a Web-based central database managed by an independent clinical research organization. Results: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lymphomas. The mean overall survival was 28 mo for follicular lymphoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organization grade III) for platelets and leukocytes, with a median nadir of 7,000/μL and 2.2/μL, respectively. Conclusion: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option.

Massive intrafollicular and arterial hyalinosis of the spleen following rituximab and methylprednisolone therapy in a patient with splenic marginal zone lymphoma.

Cecilia Y S Ho Alex W H Ng Janet F Y Lee Anthony W I Lo Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, and Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

Radioimmunotherapy for consolidation and relapse therapy for aggressive B-cell non-Hodgkin lymphoma: Retrospective analysis of the International RIT-Network.

8105 Background: Radioimmunotherapy (RIT) for lymphoma has shown high response rates and durable remissions especially in indolent lymphomas. In aggressive lymphoma, data are sparse, studies with RIT are ongoing. Data of pts with DLBCL in the international RIT-Network (RIT-NT) were analyzed with regard to indication, line of therapy and outcome. Methods: The RIT-NT, started in December 2006, is a web-based registry that collects observational data from RIT-treated patients with malignant lymphoma from across the world. As of January 1, 2010, data of 1,111 pts have been entered into the database. In the following analysis data from patients with DLBCL (n=198) are evaluated. Results: 198 pts with DLBCL are registered. Histologic subtypes: 180 diffuse large B-cell, primary mediastinal, 6 large cell anaplastic, 2 intravascular. Median age 61 years (range 17-88), 27% of pts > 70 years old. Stage at diagnosis: stage I 16 pts, II 52 pts, III 57 pts, IV 70 pts. 171 pts had 1-3 previous chemotherapies (Ctx), 19 pt...

Pharmacokinetics of melphalan and genotypes of glutathione S-transferases GSTM1 and GSTT1 and correlation to adverse effects

6614 Background: Melphalan is associated with side effects such as mucositis, diarrhea and myelosuppression. We investigated, whether the known interindividual differences in severity of these side effects might be explained by individual pharmacokinetics or by individual genotypes of glutathione S-tranferases GSTM1 and GSTT1, enzymes that might be involved in the detoxification of Melphalan. Methods: An eight point pharmacokinetic sampling was performed in 84 patients after first administration of intravenous melphalan. From these 61 suffered from multiple myeloma, 15 from non-Hodgkin lymphoma and 8 from various other malignancies. Forty-one patients were treated with 10–20 mg/m2, 12 patients with 50–70 mg/m2, 18 patients with 100 mg/m2 and 13 patients with 140 mg/m2. Occurrence and intensity of non-hematological and hematological toxicities were documented. Melphalan was measured with a newly developed sensitive HPLC method (limit of quantification 0.01 μg/ml). The entire gene deletion polymorphisms of ...