H. Ludwig

Interferon-α Stimulates the Hypothalamic- Pituitary-Adrenal Axis in vivo and in vitro

The successful therapeutic use of interferon-α (IFN-α) in myeloproliferative disorders offered the possibility to test its acute and long-term effects on the hypothalamic-pituitary-adrenal (HPA) axis

Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: Consensus statement

An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone (Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies. Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the effects of continuous lenalidomide-based therapy in myeloma.

LONG-TERM INTERFERON THERAPY FOR THROMBOCYTOSIS IN MYELOPROLIFERATIVE DISEASES

31 patients with thrombocytosis associated with myeloproliferative disorders were included in a prospective trial of long-term interferon therapy. 6 patients (19%) had side-effects which required withdrawal of interferon within one year. 22 patients (71%) achieved and maintained a complete response (platelet count less than 440 x 10(9)/l) for at least twelve months, with reduction or abolition of symptoms associated with thrombocytosis and a significant fall in bone-marrow megakaryocytes. At twelve months, 25 patients were randomly allocated to maintenance or withdrawal of interferon. Thrombocytosis recurred rapidly when treatment was stopped, but a second remission could be achieved by resumption of interferon therapy.

MAGNETIC RESONANCE IMAGING OF THE SPINE IN MULTIPLE MYELOMA

The lower thoracic and lumbar spine of patients with multiple myeloma was examined by magnetic resonance imaging (MRI), plain radiography, and bone scintigraphy. Three independent investigators evaluated the power of these diagnostic methods to detect bone lesions in 192 vertebrae from 18 patients and in 60 vertebrae from 7 controls. 41 foci with abnormal signal intensity were detected by MRI; X-ray films showed osteolytic lesions in 4 vertebral bodies; and bone scanning was positive in 2 cases. The superiority of MRI in detecting myeloma-associated focal bone lesions was statistically significant, and in one case the lesions were confirmed at necropsy. Deviations in shape and height of vertebral bodies were slightly more easily visible on radiographs. Early detection of imminent medullary compressions in 2 patients led to successful radiotherapy before symptoms appeared.

Deletions of chromosome 13q in monoclonal gammopathy of undetermined significance

Since deletion of chromosome 13q is a clinically relevant feature in multiple myeloma (MM), we analyzed bone marrow plasma cells from 29 patients with monoclonal gammopathy of undetermined significance (MGUS) to investigate the chromosome 13 status in MGUS. Studies were performed by interphase fluorescence in situ hybridization (FISH) with a panel of 13q14-specific probes (RB1, D13S319, D13S25, D13S31). Plasma cells with a deletion of at least one of the 13q14 loci were detected in 13 patients (44.8%) with MGUS. In five patients (17.2%), deletions of all four 13q14-specific probes were observed, and the additional deletion of a 13q telomeric region (D13S327) suggested loss of the entire 13q arm or monosomy 13. Loss of 13q14 was observed to be monoallelic and to occur in 11.0 to 35.0% of plasma cells (cut-off levels for a deletion <10% with all probes). Nine of 17 patients (52.9%) with MM progressing from a pre-existing MGUS had evidence for a deletion of 13q14 as determined by FISH with the RB1 probe. These results suggest that deletion of 13q14 is an early event in the development of monoclonal gammopathies, but its role for the eventual progression to MM remains to be determined prospectively.

Interferon-alfa corrects thrombocytosis in patients with myeloproliferative disorders

SummaryDuring previous therapeutic trials with interferon, decreased levels of peripheral platelet counts have been observed. Taking advantage of this effect, we investigated the efficacy of recombinant interferon (rec-IFN) in the treatment of thrombocytosis in myeloproliferative diseases. A total of 15 patients with polycythemia vera, essential thrombocytosis, or chronic myeloid leukemia received rec-IFN-alfa at initial doses of 25–70×106 units/week; maintenance therapy following week 8 of treatment consisted of 20–35×106 units/week rec-IFN. Observation periods ranged from 24 to 48 weeks. Significant reductions in the number of platelets were noted in all cases; 12/15 patients achieved platelet counts below 440×109/1 and maintained those normal values for at least 4 weeks. The number of bone marrow megakaryocytes, which had been increased prior to treatment, diminished during rec-IFN therapy, while the previously shortened platelet half-life further decreased with rec-IFN treatment. During rec-IFN-induced remission, the plasma levels of platelet factors, the activity of natural killer cells, and platelet aggregation showed changes between slight improvement and normal values. Severe side effects were only observed with the highest rec-IFN doses; dosage adjustments were effective in improving or eliminating all treatment-related symptoms. Rec-IFN may prove to be a valuable therapeutic alternative to cytostatic treatment of thrombocytosis in myeloproliferative disorders.

Recombinant interferon alfa-2C versus polychemotherapy (VMCP) for treatment of multiple myeloma: a prospective randomized trial.

Forty-two previously untreated patients with multiple myeloma were entered in a prospective, randomised trial comparing recombinant interferon alfa-2C monotherapy with VMCP (vincristin, melphalan, cyclophosphamide and prednisolone). Both treatment arms were comparable for the stratification variables such as paraprotein type, stage of disease, and renal function. Rec. interferon effected 14% responses and 29% minor responses, while 57 and 32% of VMCP-treated patients achieved a pathologically documented remission (P less than 0.001). The time on initial treatment was significantly shorter in the IFN group (3.2 months) than in the VMCP group (7.6 months). In four patients in the IFN arm, primary treatment had to be changed according to progressive or severe stationary disease. Since all four patients responded to second line therapy (VMCP) no significant difference has been observed between the two groups in survival (median follow-up greater than 12 months). Despite this clear superiority of the conventional four-drug polychemotherapy, there was some suggestion that IFN might be particularly active in cases with low tumor-burden (stage I, II), and light-chain or IgA paraprotein type.

Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma – a report on two cases

Abstract. B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, del14(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.

Expression of MUM1/IRF4 mRNA as a prognostic marker in patients with multiple myeloma

other AML subtypes is higher than that found in northern European and US studies (among non-Hispanics), and is similar to that reported by Central and South American, Spanish and Iranian studies. If confirmed, the peculiar geographical pattern of APL distribution could reflect the spread of susceptible genotypes during ancient migrations from the Middle East and Caspian areas toward the Mediterranean. We believe that our data, together with data from geographically and ethnically heterogeneous cancer registries, are helpful to clarify the role of genetic predisposition in the observed ethnic differences of APL incidence rates.

Chromosomal aberrations are shared by malignant plasma cells and a small fraction of circulating CD19+ cells in patients with myeloma and monoclonal gammopathy of undetermined significance

Summary.u2002 In the present study, we aimed to identify distinct structural and numerical chromosomal aberrations in peripheral blood B cells of patients with myeloma and monoclonal gammopathy of undetermined significance (MGUS), which reflect changes thought to occur at different stages of the disease process. Peripheral blood from 12 patients with multiple myeloma and three patients with MGUS was investigated for the occurrence of retinoblastoma‐1 gene deletions, p53 gene deletions and numerical aberrations demonstrated previously to be present in the patients bone marrow CD138+ cells. By combining immunocytochemical staining for light chains and interphase fluorescence in situ hybridization (FISH), aberrant light‐chain +ve cells were detected in the circulating CD19+ cell fraction. Each kind of chromosomal change present in the myeloma tumour cells was found to be shared by a small fraction of CD19+ cells (0·1–1·8%; median 0·36%, nu2003=u20036). In one MGUS patient, aberrant cells could be identified with a frequency of 0·34% within the CD19‐sorted cell fraction. Clonotypic cells were detected with a frequency of 0·01–0·07% of peripheral blood nucleated cells by m‐RNA in situ hybridization with patient‐specific probes in three investigated patients. These results provide evidence that the circulating clonotypic B cells are closely related to the malignant plasma cells in myeloma and MGUS.