Effects of platelet concentrate storage time reduction in patients after blood stem cell transplantation.

OBJECTIVE: To evaluate the clinical effect of platelet concentrate (PC) transfusions after PC storage time reduction to 4 days. PATIENTS AND METHODS: This was a single-centre cohort study comparing two 3-month periods of time, before and after the reduction of PC storage time from 5 to 4 days. Seventy-seven consecutive patients with PC transfusions were enrolled after blood stem cell transplantation. Corrected platelet count increment (CCI) on the morning after transfusion, time to next platelet transfusion, need for red blood cell (RBC) transfusion and clinical bleeding symptoms were compared. RESULTS: Platelet concentrate storage time was reduced between period 1 (storage for up to 5 days, median storage time 78 h, range 11-136 h) and period 2 (storage for up to 4 days, median storage time 53 h, range 11-112 h). Patients were comparable for age, weight, body surface area, underlying disorder, type of transplantation and transfused platelet dose. The CCI increased from a median of 4 (range 0-20) to 8 (0-68) × 10(9) /l per 10(11) platelets/m(2) (P < 0·0001). Time to next PC transfusion increased from 1·1 to 2·0 days (P < 0·0001). Any bleeding symptom was noted in 20 of 36 patients (56%) vs. 9/41 patients (22%, P < 0·01). Nose bleeds, haematuria and bleeding at more than one site were significantly reduced. Frequency of RBC transfusion within 5 days after PC transfusion was reduced from 74 to 58% (P < 0·0001). CONCLUSION: Platelet concentrate storage time shortening was associated with highly significant CCI increase, reduced RC needs and lower patient numbers with bleeding events.

[Therapy of multiple myeloma. What is confirmed?]. / Therapie des multiplen Myeloms. Was ist gesichert?

Multiple myeloma (MM) is a malignant plasma cell disorder with clonal development. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) are precursor stages of MM and both have to be differentiated from MM which is characterized by organ complications. High-dose chemotherapy combined with autologous stem cell support is the therapy of choice for most patients in order to achieve long-lasting complete remission with few symptoms, prevention of new organ complications and survival prolongation. Patients who cannot be intensively treated due to advanced age and comorbidities should be treated with low-dose chemotherapy, normally alkylating agents, for improved quality of life and also survival prolongation. Including thalidomide, lenalidomide, pomalidomide, bortezomib or carfilzomib in both high-dose and low-dose chemotherapy concepts results in a significantly higher remission rate and longer survival. Allogeneic stem cell transplantation is associated with a relatively high mortality during the first year after transplantation which will be refined with the aim of healing in various trials and is an alternative treatment approach for selected patients. A treatment concept for MM patients has to be individually complemented by local irradiation, administration of bisphosphonates and supportive infusions of immunoglobulins.

Autoimmunity resulting from cytokine treatment predicts long-term survival in patients with metastatic renal cell cancer.

PURPOSE: In patients undergoing cytokine therapy, systemically applied interleukin-2 (IL-2) and/or interferon-alpha (IFN-alpha) have been reported to induce thyroid dysfunction as well as thyroid autoantibodies. We analyzed the correlation of thyroid autoimmunity with HLA phenotype, various other autoimmune parameters, and patient survival. PATIENTS AND METHODS: For this purpose, antithyroglobulin autoantibodies, antimicrosomal thyroid autoantibodies, thyroglobulin receptor autoantibodies, thyroid dysfunction, and multiple clinical parameters were determined in 329 unselected patients with metastatic renal cell cancer before and after systemic IL-2 and IFN-alpha2 therapy. For statistical analysis, we used both univariate and multivariate Cox proportional hazards models and the two-tailed Fisher's exact test. RESULTS: Antithyroglobulin autoantibodies and antimicrosomal thyroid autoantibodies were detected in 60 patients (18%); positive autoantibody titers of various other autoimmune parameters were statistically unrelated. The presence of thyroid autoantibodies was correlated with prolonged survival (P<.0001). There was a statistically significant difference in frequencies of HLA-Cw7 expression between thyroid autoantibody-positive and -negative patients (P< or =.05), and the Cw7 expression was associated with prolonged overall survival (P = .009). CONCLUSION: The evaluation of thyroid autoantibodies during cytokine therapy could be a useful prognostic marker for patients with renal cell carcinoma who benefit from cytokine treatment. IL-2- and IFN-alpha2-induced tumor control and prolonged survival may require breaking of immunologic tolerance against self-antigens.

Prognostic value of clinical, laboratory, and histological characteristics in multiple myeloma: improved definition of risk groups.

Follow-up data of 320 multiple myeloma (MM) patients entering the German Myeloma Treatment Group (GMTG) trial MM01 were analysed for factors predicting overall (OAS) and tumour related survival (TRS). Response to primary induction chemotherapy was relevant for prognosis if a limit of 25% tumour cell mass (TCM) reduction was used to separate responders from non-responders. Furthermore, TCM, histological grading of myeloma cells, degree of bone marrow infiltration, haemoglobin, platelet counts, calcium, creatinine, albumin, beta 2M, and Bence Jones proteinuria correlated to both OAS and TRS. Age was relevant for OAS only. The multivariate analysis revealed histological grading, TCM and platelets as the most reliable prognostic factors. Based on these data the Durie/Salmon classification could be improved by defining poor prognosis patients (50% TRS: 16 months) characterised by pretreatment platelets of < or = 150,000 and/or poorly differentiated myeloma cell morphology. Patients lacking both risk factors displayed 50% survival times of 46 months in stage III and 88 months in stage II.

A comparison of polychemotherapy and melphalan/prednisone for primary remission induction, and interferon-alpha for maintenance treatment, in multiple myeloma. A prospective trial of the German Myeloma Treatment Group.

406 untreated multiple myeloma patients of stage I (n = 54), II (n = 148) and III (n = 204) were enrolled in the trial. 51/54 stage I and 60/148 stage II patients were asymptomatic and followed without treatment until disease progression (progression free survival: 60% after 4 years for stage I versus 50% after 1 year for stage II). Symptomatic patients of stage I (n = 3/54) and II (n = 88/148) presenting with tumour progression, received melphalan 15 mg/m2 intravenously (i.v.) and prednisone 60 mg/m2 oral days 1-4 (MP). Stage II disease remission rate was 59%, and 50% tumour related survival (TRS) was 59 months. Stage III patients were randomised to receive MP or VBAMDex (vincristine/BCNU/doxorubicin/melphalan/dexamethasone) treatment. 43% of MP treated patients responded compared with 64% of the VBAMDex group. 50% TRS was 36 months in both groups without a detectable difference. 117 responders of stage II and III with stable disease were randomised to receive either IFN-alpha (5 x 10(6) IU, subcutaneous (S.C.) 3 times per week) or no maintenance treatment. The relapse rate in both groups was 50% after 13 months. No survival benefit for IFN alpha treated patients was observed (50% TRS: 45 months).

Pyridinium cross-links in multiple myeloma: correlation with clinical parameters and use for monitoring of intravenous clodronate therapy--a pilot study of the German Myeloma Treatment Group (GMTG).

The relevance of quantitative determinations of urinary deoxypyridinolines (DPY) and pyridinolines (PY), and of serum type I collagen carboxyterminal cross-linked telopeptides (ICTP), has been evaluated for patient monitoring in multiple myeloma (MM). In 178 untreated MM patients, a clear correlation was found between ICTP concentrations, bone destructions and serum calcium levels. Furthermore, serum ICTP, urinary DPY and PY concentrations were estimated before and during treatment in a further 33 MM patients randomly allocated to four groups receiving intravenous melphalan/prednisone (MivP) chemotherapy alone, or MivP in combination with three different doses of i.v. clodronate. 1800 mg of i.v. clodronate combined monthly with MivP induced a rapid and sustained reduction in bone resorption parameters to the normal range, a result not obtained with either MivP alone, or with a lower clodronate dose. While confirming the relevance of determining pyridinium cross-links for estimating bone resorption in MM, our data indicate that measurements of these parameters could be useful for dose finding and monitoring of bisphosphonate therapy.

High incidence of monoclonal immunoglobulins in patients after liver or heart transplantation.

Sera from 56 recipients of liver or heart transplants were investigated for monoclonal immunoglobulins (mIg) by immunofixation electrophoresis (IFE) at different times during 4 years after transplantation. Transient, changing, or stable mIgs were found in 18 patients. A significantly increased mIg incidence was observed in heart Tx patients, patients over 40 years of age, and those receiving azathioprine or antithymocyte globulin in addition to prednisolone and cyclosporine as immunosuppressive treatment. No correlations could be found between the presence of mIg and the number of rejection episodes or intercurrent infections. Such serum mIg represent monoclones of at least 1 x 10(9) cells of B lymphocyte lineage that apparently proliferate without adequate suppressive control. Since immunosuppressed allograft recipients are at risk of developing B cell lymphomas, such monoclones may be regarded as prelymphomas necessitating a careful follow-up in these patients.

Palliative radiotherapy in plasma cell myeloma.

Pain symptoms caused by bone lesions of multiple myeloma can be relieved by a local irradiation treatment. To estimate the influence of systemic treatment on the palliative effect of local radiotherapy the records of 70 myeloma patients treated with chemotherapy combined with or followed by local irradiation were reviewed. The local response rate, defined as complete pain relief at the irradiated site, was 80% in patients receiving irradiation during chemotherapy (melphalan and prednisone) and this palliative effect endured 31.8 +/- 3.6 months. If irradiation was started in the period without systemic treatment the local response rate was 39.6% and lasted 24.8 +/- 17.9 months. In sites treated with more than one radiotherapy course 94% response rate after the first treatment, 56% after the second treatment and no response after the third course was achieved. The duration of local pain control was positively related to the applied radiation dose. It is concluded that irradiation during concomitant chemotherapy is superior to radiotherapy performed in a period without systemic treatment. Local long-term palliation can only be achieved by a sufficient high radiation dose.

A plasma clot culture system for growing and antiproliferative drug sensitivity testing of myeloma stem cells.

An easy-to-perform clonogenic culture system for myeloma stem cells is presented which approaches the patient's in vivo situation more closely and therefore seems particularly well-suited for antiproliferative drug sensitivity assays. Bone marrow cells are propagated in clotted autologous or allogenic plasma that is enriched with 2-mercaptoethanol, insulin, and synthetic nucleotides and co-factors for nuclear synthesis, no feeder layer or conditioned medium is necessary. Clusters and colonies consisting of between 8 and 60 cells readily formed within 6-8 days after cloning yielding a plating efficiency between 0.12 and 2.16%. A linear relationship between the number of cells plated and colony formation was found from 10(5) through 2 X 10(6) cells plated. The successful growth rate for 65 tests from 53 patients amounted to 90.8%. Morphological and histochemical examination of the clusters revealed lymphoid cells at various stages of maturation ranging from lymphocytic and lymphoblastoid to lymphoplasmacytic and plasma cells. Tumor origin of the clones was demonstrated by immunofluorescence studies in which Ig-positive cells stained only for the heavy and light chain isotypes identical to those of the patient's serum paraprotein. Anti-idiotypic antisera confirmed the patient's specific malignant phenotype of the colonies formed. The technique of the assay is described in detail.

A new conditioning regimen involving total marrow irradiation, busulfan and cyclophosphamide followed by autologous PBSCT in patients with advanced multiple myeloma.

The overall survival of patients with advanced multiple myeloma (MM) undergoing high-dose chemotherapy and autologous stem cell transplantation (SCT) depends mainly on the quality of response. Thus, to improve the response rate, a new intensified high-dose chemoradiotherapy was evaluated in a phase I/II study. After induction chemotherapy, 89 patients (median age 51 years, range 32-60 years) with MM stage II/III received a conditioning regimen with total marrow irradiation (9 Gy), busulfan (12 mg/kg) and cyclophosphamide (120 mg/kg) followed by SCT. Regimen-related toxicity according to WHO criteria and response rates defined by EBMT/IBMTR were analyzed. The main toxicity was mucositis grade III/IV in 76%, and fever grade >I in 75% of patients. Three patients developed reversible veno-occlusive disease. Transplant-related mortality was 2%. Among patients with de novo and pretreated MM, a CR rate of 48 and 41%, respectively, was documented. With a median follow-up of 45 months, the actuarial median durations of event-free survival (EFS) and overall survival (OS) after transplant were 29 and 61 months for the whole group, 36 and 85 months for patients with de novo MM, respectively. Thus, administration of this intensified conditioning regimen was associated with tolerable toxicity, a high response rate and long EFS and OS.

Cytostatic drug sensitivity test for human multiple myeloma, measuring monoclonal immunoglobulin produced by bone marrow cells in vitro.

An in vitro cytostatic drug sensitivity test for human multiple myeloma has been developed, predicting differences in sensitivity of the individual tumor to various anticancer drugs. Bone marrow preparations containing the tumor cells were incubated with cytostatic drugs and cultured for 10 days. Using an enzyme-linked immunosorbent assay we measured tumor products--monoclonal immunoglobulin and beta 2-microglobulin--in the culture supernatants. The reduction of these products in vitro due to the drugs administered was compared with the patients' further clinical course during treatment with different standard cytostatic drug regimens. We found a predictive value of more than 80% for this easily performed test.

Peripheral blood lymphocyte subpopulations in multiple myeloma.

Antisera raised against idiotypic determinants of myeloma proteins and macroglobulins have been used to differentiate peripheral blood lymphocytes populations from individual patients. I.D.-positive lymphocytes not resembling plasma cells have been regularly found in peripheral blood in these diseases. This lymphocyte population is heterogeneous with respect to non-tumor-specific surface markers, such as SRBC-, Fc- and C-receptors. Tumor specific idiotypic determinants will thus allow a more correct recognition of the total tumor cell compartment in these diseases.

[Multiple myeloma]. / Das multiple Myelom.

Multiple myeloma is a low-grade non-Hodgkin lymphoma. Treatment is palliative, and an individually adapted strategy for therapy is needed for each patient. A review about diagnostic methods for staging, prognostic factors and different aspects of therapy is presented.

[Therapy of multiple myeloma: indications and options]. / Therapie des multiplen Myeloms : Indikationen und Möglichkeiten.

The multiple myeloma (MM) has an incidence of 3-4/100,000 in the Caucasian population. MM has to be distinguished from smouldering MM and monoclonal gammopathy of uncertain significance (MGUS). In younger patients (<65 years) a good long-term remission is the aim of therapy, while in the elderly patients with comorbidities the aim is a good partial remission with good quality of life. In the elderly this can be achieved with a combination of melphalan and prednisone. High-dose chemotherapy, often as a tandem transplantation, is part of standard therapy of MM patients <65 years. However, allogeneic stem cell transplantation is the only curative approach. New substances approved for treatment of relapsed MM include bortezomib, thalidomide, and lenalidomide.

The role of alpha-interferon in multiple myeloma.

Alpha-interferon (Ifn-alpha) has anti-tumor activity in vivo when used as a single agent in multiple myeloma (MM). However, the mechanisms responsible for this activity have not been clarified so far. Ifn-alpha has been therapeutically tested in a number of clinical trials for remission induction, maintenance therapy, and in different combinations with chemotherapy or steroids. The results of these trials are partially controversial and do not undoubtedly support Ifn-alpha treatment in any of these indications. However, meta-analyses using individual patient data or published results of the trials revealed small but significant advantages for MM patients treated with Ifn-alpha monotherapy for maintenance or in combination with conventional chemotherapy for remission induction. These advantages weigh against reduction of quality of life due to adverse effects commonly seen in Ifn-alpha treated MM patients and in addition relatively high treatment costs. Future efforts should be made to find prognostic factors determining effectiveness of Ifn-alpha therapy. Furthermore, the outcome of Ifn-alpha treatment should be improved by new therapy strategies based on a better understanding of the pathophysiological mechanisms influenced by Ifn-alpha in MM.

[Prognostic factors and standard therapy of multiple myeloma]. / Prognostische Faktoren und Standardtherapie des multiplen Myeloms.

Multiple myeloma (MM) is a B-cell non-Hodgkins lymphoma with a neoplastic proliferation of plasma cells in the bone marrow. In different studies median survival time has been measured between 19 and 50 months. Several prognostic factors help to subdivide the patient population in risk groups. The treatment is palliative until now and the individual concept of therapy includes chemotherapy, radiotherapy and other treatment modalities. Evidence of progressive or symptomatic disease is usually required for initiation of chemotherapy.

[Induction and maintenance therapy in multiple myeloma. Results of a multicenter study]. / Induktions- und Erhaltungstherapie beim multiplen Myelom. Ergebnisse einer multizentrischen Studie.

In a prospective study by the German Myeloma Treatment Group, 320 untreated patients with multiple myeloma, stage II and III, were randomized into 2 groups receiving courses of either MP or VCMP as induction treatment every 6 months. 72% of the patients evaluable by TCM changes remitted, 21% showed a no change, and progress occurred in 7%. The corresponding results in BJ and nonsecretory myelomas were 56% remissions, 11% no change, 33% progress. The response rates were equal in both treatment groups. The overall survival was 60% after 4 years. However, MP-treated patients lived significantly longer than patients in the VCMP group. After successful remission induction, patients were randomized into one group with maintenance treatment using the induction scheme Q 8 weeks, and another group without further chemotherapy. Although the relapse rate of the latter group was significantly higher, differences between both groups concerning survival have not been observed.

Tumor-directed cytotoxicity in multiple myeloma--the basis for an experimental treatment approach with interleukin 2.

There is growing evidence that in multiple myeloma (MM) tumor-directed immune responses exist, might influence tumor progress and could be putative targets for immunotherapeutic approaches. Peripheral blood T lymphocytes are capable of suppressing monoclonal immunoglobulin production of autologous myeloma plasma cells in vitro. This activity can be enhanced by stimulation with mitogens, OKT3 monoclonal antibody or interleukin 2 (IL-2), and is obviously mediated by cytolytic T lymphocytes as demonstrated in a cytotoxicity assay using purified MM plasma cells as targets. The lytic activity is significantly higher when the effectors are prestimulated with irradiated autologous MM plasma cells. Based on these results 18 MM patients of advanced stages with tumor progress received 9 x 10(6) IU/m2 recombinant IL-2 (Proleukin) twice daily on days 1 and 2 and 0.9 x 10(6) IU/m2 twice daily for five subsequent days per week s.c. from days 3-56 (q 12 weeks). During therapy the number of eosinophils increased 15-fold, CD4+ T lymphocytes were activated as demonstrated by CD25 antigen expression and CD56+ natural killer (NK) cells expanded in the peripheral blood. NK cell activity and lymphokine-activated killer cell activity were significantly enhanced. IL-2 therapy induced endogenous IL-2 production and elevated soluble IL-2 receptor serum concentrations. Tumor response was observed in 6/17 evaluable patients. These data indicate that low-dose IL-2 treatment can stimulate immune enhancement in MM patients despite their characteristic tumor-induced immunodeficiency, and has proven to have limited efficacy in advanced MM patients.