Secondary malignancies in chronic myeloid leukemia patients after imatinib-based treatment: long-term observation in CML Study IV.

Treatment of chronic myeloid leukemia (CML) has been profoundly improved by the introduction of tyrosine kinase inhibitors (TKIs). Long-term survival with imatinib is excellent with a 8-year survival rate of ∼88%. Long-term toxicity of TKI treatment, especially carcinogenicity, has become a concern. We analyzed data of the CML study IV for the development of secondary malignancies. In total, 67 secondary malignancies were found in 64 of 1525 CML patients in chronic phase treated with TKI (n=61) and interferon-α only (n=3). The most common malignancies (n⩾4) were prostate, colorectal and lung cancer, non-Hodgkin's lymphoma (NHL), malignant melanoma, non-melanoma skin tumors and breast cancer. The standardized incidence ratio (SIR) for all malignancies excluding non-melanoma skin tumors was 0.88 (95% confidence interval (0.63-1.20)) for men and 1.06 (95% CI 0.69-1.55) for women. SIRs were between 0.49 (95% CI 0.13-1.34) for colorectal cancer in men and 4.29 (95% CI 1.09-11.66) for NHL in women. The SIR for NHL was significantly increased for men and women. An increase in the incidence of secondary malignancies could not be ascertained. The increased SIR for NHL has to be considered and long-term follow-up of CML patients is warranted, as the rate of secondary malignancies may increase over time.

Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.

Bortezomib improves outcome after SCT in multiple myeloma patients with end-stage renal failure.

Patients with multiple myeloma and dialysis-dependent renal failure have dismal outcomes. In this retrospective analysis of a case series, we evaluated 27 consecutive patients, all of whom required haemodialysis at the time of first-line induction therapy with either bortezomib or a standard regimen followed by high-dose chemotherapy and auto-SCT. The overall response rate was significantly better after bortezomib-based induction before auto-SCT (83% vs 36%, P=0.02) and at day +100 post auto-SCT (100% vs 58%, P=0.01). Bortezomib also prolonged EFS and furthermore, a trend towards a shorter time on haemodialysis was observed in the bortezomib group at a median of 6.1 months (0.2-68.2 months) vs 17.1 months (0.7-94.3 months, P=0.38) in patients who had received vincristine, adriamycin, dexamethasone or vincristine, adriamycin, dexamethasone-like induction regimens. These data demonstrate the superior efficacy of bortezomib-based induction therapy in transplant-eligible patients with end-stage renal failure.

Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma.

Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.

[Cancer of unknown primary. Epidemiology and pathogenesis]. / CUP-Syndrom. Epidemiologie und Pathogenese.

DEFINITION: The term cancer of unknown primary (CUP) describes by definition epithelial malignancies for which no primary tumor can be found after primary diagnostics have been performed. EPIDEMIOLOGY: The CUP syndrome constitutes 2-3% of all fatal cases of malignancies in both men and women. The proportion of women has increased in parallel to the increase of tobacco consumption in women. PATHOGENESIS: The most frequent origin appears to lie in the lungs or upper abdominal organs, while notable differences can be found between older autopsy findings and recent gene expression data with respect to identified primary tumors or tissue assignation. The fact that a primary tumor cannot be identified is probably based on various reasons: a complete regression of a primary tumor in isolated cases seems to be just as plausible as the misclassification of a primary tumor as a metastasis. CONCLUSION: In combination with the fact that a primary tumor cannot be identified by autopsy in more than 20 % of cases, the important conclusion can be drawn that curative approaches seem appropriate for localized CUP cases.

[Structured diagnostics and therapy of the CUP syndrome]. / Strukturierte Diagnostik und internistische Therapie des CUP-Syndroms.

BACKGROUND: In the majority of cases, patients with cancer of unknown primary (CUP) have a poor prognosis with no prospect of being cured. Hence, a reasonable focus of diagnostics on its essential targets seems appropriate. PATIENTS: Particularly important is the identification of all patients who can be assigned to subgroups with a favorable prognosis and who might benefit from a specific therapy. For all other patients, platinum-based combination therapy is the standard cytostatic therapy. THERAPY: In addition to platinum derivatives, taxanes, gemcitabine and irinotecan can also be used. Promising innovative approaches include targeted therapies, in particular bevacizumab and erlotinib, and identification of the tissue origin with micro-RNA or gene expression analyses which can help identify the most suitable organ-specific therapy for individual patients. PERSPECTIVES: It would be desirable if the group of patients treated with unspecific therapy could be reduced by improved diagnostics so that these patients could be treated with organ-specific therapy or with molecularly targeted approaches. Micro-RNA and gene expression analyses appear to be interesting for this purpose. Another complementary approach is to improve the treatment results of patients receiving an unspecific standard combination therapy by additional administration of new targeted substances.

Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.

Prognostic significance of whole-body MRI in patients with monoclonal gammopathy of undetermined significance.

Radiological skeletal survey or computed tomography are currently applied to assess bone diseases in patients with monoclonal plasma cell disorders. Whole-body magnetic resonance imaging (whole-body MRI) allows detecting the infiltration of clonal cells in nearly the whole bone marrow compartment even before bone destruction has occurred. Those MRI results (i.e., patterns of bone marrow infiltration) have been demonstrated to be of prognostic significance in patients with symptomatic as well as asymptomatic multiple myeloma. We have therefore analyzed the findings of whole-body MRI in 137 consecutive individuals with monoclonal gammopathy of undetermined significance (MGUS). A focal infiltration pattern was detected in 23.4% of patients. Presence and number of focal lesions as well as value of M-Protein were of independent prognostic significance for progression into a symptomatic disease requiring systemic treatment (P=0.02; P<0.0001 and P=0.0005, respectively). Lower homogeneous signal intensities in T1-weighted images were related to a physiologically higher bone marrow cellularity in younger individuals (P=0.002). We conclude that whole-body MRI identifies patients with focal accumulations of presumably monoclonal cells in bone marrow with prognostic impact concerning the risk of progression into symptomatic disease.

Bisphosphonate treatment and renal function in 201 myeloma patients undergoing stem cell transplantation.

Administration of bisphosphonates (BPs) is an essential supportive treatment for reducing bone-related complications in cancer. Deterioration of renal function is one possible side effect of BPs as well as a clinical feature in multiple myeloma. It has been suggested that the nephrotoxicity of different BPs may differ. We performed a retrospective evaluation of renal function in 201 myeloma patients undergoing myeloablative chemotherapy and treatment with ibandronate (I), pamidronate (P), or zoledronate (Z) for up to 36 months. There was no significant deterioration in mean creatinine clearance (CreaCl) in the entire cohort. The percentage of patients experiencing a decrease in CreaCl ≥ 25 % from baseline was 33.0 % in the I group, 44.4 % in the P group and 21.4 % in the Z group, respectively. CreaCl at baseline (P < 0.0001), relapse/progression (P = 0.0019), proteinuria at baseline (P = 0.039), age (P = 0.0031) were identified as significant independent predictors of decrease in renal function. In both descriptive multivariant analyses, we found no evidence of an advantage of any particular BP with respect to effects on renal function. In line with these data, in a subgroup of 90 patients with a baseline CreaCl <90 ml/min, no significant difference was evident between the cohorts of patients treated with different BPs. Regular treatment with the BPs I, P and Z in myeloma patients undergoing intensive chemotherapy appear to be equally safe for up to 3 years in terms of nephrotoxicity.

Inflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering from multiple myeloma.

Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.

[CUP syndrome: molecular pathogenesis and biology]. / CUP-Syndrom: Molekulare Pathogenese und Biologie.

Carcinoma of unknown primary (CUP) is an intriguing clinical finding defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical workup. CUP is a relatively common clinical entity, accounting for approximately 3-5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. The mechanisms responsible for early metastasis and lack of a detectable primary tumor are largely unknown. Although remarkable tools have been developed for immunohistological classification of CUP on the basis of the likely tissue of origin, data on molecular pathogenesis and biology of this disorder are rare. A wide variety of chromosomal aberrations are seen in CUP, with aberrations of chromosomes 1, 6, 7, and 11 having been most frequently described. 66-75% of CUP express epidermal growth factor receptor while overexpression of Her2/neu seems to be rare. In contrast to most other tumor entities p53 mutations have been found only in a minority of CUP tumors. Recently, several independent studies have demonstrated proof of principle for the use of gene expression microarrays in identifying a primary site for CUP. Therefore, gene expression and also genomic profiling tools represent promising analytical approaches to assist with the management of CUP patients.

Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q.

Deletions of chromosomal arms 1p and 19q are frequent in oligodendroglial tumours and have been associated with sensitivity to radio- and chemotherapy as well as favourable prognosis. By using microarray-based expression profiling, we found that oligodendroglial tumours with 1p and 19q losses showed significantly lower expression of the CBP/p300-interacting transactivator with glutamic acid/aspartic acid-rich carboxyl-terminal domain 4 gene (CITED4) at 1p34.2 as compared to tumours without 1p and 19q losses. Mutational analysis showed no CITED4 mutations in gliomas. However, 1p and 19q losses as well as low expression of CITED4 transcripts were significantly associated with hypermethylation of the CITED4-associated CpG island. In line with the latter finding, treatment of CITED4 hypermethylated glioma cell lines with 5-aza-2'-deoxycytidine and trichostatine A resulted in a marked increase of the CITED4 transcript levels. Furthermore, CITED4 hypermethylation was significantly associated with longer recurrence-free and overall survival of patients with oligodendroglial tumours. Taken together, our results indicate that CITED4 is epigenetically silenced in the vast majority of oligodendroglial tumours with 1p and 19q deletions and suggest CITED4 hypermethylation as a novel prognostic marker in oligodendroglioma patients.

[Dynamic MRI of the bone marrow for monitoring multiple myeloma during treatment with thalidomide as monotherapy or in combination with CED chemotherapy]. / Dynamische MRT des Knochenmarks zum Monitoring des Multiplen Myeloms unter Thalidomid-Monotherapie oder Kombination mit CED-Chemotherapie.

PURPOSE: To quantify changes of bone marrow microcirculation in multiple myeloma (MM) using contrast enhanced dynamic MRI (dMRI) during thalidomide as antiangiogenic monotherapy or in combination with chemotherapy (cyclophosphamide, etoposide, dexamethasone). MATERIALS AND METHODS: The study includes 63 patients with refractory or relapsed MM, who underwent dMRI with high temporal resolution (T1w-turboFLASH) of the lumbar spine before and following treatment. The contrast uptake was quantified using a two compartment model with the output parameters amplitude and k (ep) (exchange rate constant). The evaluation considered the initial dMRI finding (pathological or non-pathological) and the clinical therapeutic response (response or no response). RESULTS: During monotherapy with thalidomide (n = 38), no significant changes of the dMRI parameters were found, even when considering the initial dMRI finding (positive n = 22) and the therapeutic response (responder n = 14). The combination with chemotherapy (n = 25) had a significant reduction of k (ep) (p = 0.01) in 18 patients with positive initial dMRI finding and therapeutic response. Reduction of the amplitude was seen in most cases, but in the end without any significance (p = 0.09). CONCLUSION: dMRI can quantify significant changes of bone marrow microcirculation solely during treatment with thalidomide combined with chemotherapy, not with thalidomide alone.

Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin's lymphoma.

Recently, centrosome aberrations have been described as a possible cause of aneuploidy in many solid tumors. To investigate whether centrosome aberrations occur in non-Hodgkin's lymphoma (NHL) and correlate with histologic subtype, karyotype, and other biological disease features, we examined 24 follicular lymphomas (FL), 18 diffuse large-B-cell lymphomas (DLCL), 33 mantle cell lymphomas (MCL), and 17 extranodal marginal zone B-cell lymphomas (MZBCL), using antibodies to centrosomal proteins. All 92 NHL displayed numerical and structural centrosome aberrations as compared to nonmalignant lymphoid tissue. Centrosome abnormalities were detectable in 32.3% of the cells in NHL, but in only 5.5% of lymphoid cells from 30 control individuals (P<0.0001). Indolent FL and MZBCL contained only 25.8 and 28.8% cells with abnormal centrosomes. In contrast, aggressive DLCL and MCL harbored centrosome aberrations in 41.8 and 35.0% of the cells, respectively (P<0.0001). Centrosomal aberrations correlated to lymphoma grade, mitotic, and proliferation indices, but not to the p53 labeling index. Importantly, diploid MCL contained 31.2% cells with abnormal centrosomes, while tetraploid samples harbored centrosome aberrations in 55.6% of the cells (P<0.0001). These results indicate that centrosome defects are common in NHL and suggest that they may contribute to the acquisition of chromosomal instability typically seen in NHL.

Centrosome replication, genomic instability and cancer.

Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. In addition, a growing body of evidence indicates that centrosomes might be important for initiating S phase and completing cytokinesis. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations in G(1)/S phase regulating proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16(INK4A) and p15(INK4B), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation, but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on the role of centrosomes in cell cycle progression, as well as causes and consequences of aberrant centrosome replication in human neoplasias.

Response to thalidomide in progressive multiple myeloma is not mediated by inhibition of angiogenic cytokine secretion.

Thalidomide (Thal) is a drug with anti-angiogenic properties. To explore whether the effect of Thal on angiogenesis is associated with a reduction of angiogenic cytokine levels in progressive multiple myeloma (MM), plasma levels of basic fibroblast growth factor, vascular endothelial growth factor, interleukin 6, tumour necrosis factor-alpha and hepatocyte growth factor (HGF) were measured in 51 patients at 0, 3 and 6 months of Thal therapy. After 6 months of treatment, 26 patients were considered to be responsive to Thal therapy, including 17 minimal responses, eight partial responses and one complete response. Only HGF (decreasing, P = 0.02) in the group of responsive patients showed a statistically significant change over a period of 6 months. Because HGF levels are known to correlate to MM tumour burden, we conclude that the mechanism of action of Thal in MM is not caused by a specific inhibition of angiogenic cytokine secretion.

Salvage therapy for multiple myeloma with thalidomide and CED chemotherapy.

The feasibility and efficacy of a combination of thalidomide, cyclophosphamide, etoposide, and dexamethasone were studied in 56 patients with poor-prognosis multiple myeloma. Of 50 patients evaluable for response, 4% achieved complete response (CR), 64% partial response (PR), 18% minimal response (MR), 6% stable disease (SD), and 8% progressive disease (PD), resulting in an objective response rate (> or = MR) of 86.0% (76.7% overall objective response rate in intent-to-treat analysis; n = 56). Subsequent to successful remission induction, 18 patients received autologous or allogeneic stem cell transplantation. The median progression-free survival in all patients was 16 months. The median overall survival time could not be calculated, since the last observed death occurred after 16 months of follow-up (median follow-up of 14 months) with a corresponding estimated survival probability of 55%. Severe adverse effects (World Health Organization III/IV) included infectious complications (35.7%) and cardiovascular events (7.1%). The data suggest that Thal improves antitumor activity of salvage chemotherapy regimens in poor-prognosis multiple myeloma.