CD4(+) CD28(+) lymphocytes on day 5 after high-dose melphalan for multiple myeloma predict a low risk of infections during severe neutropenia and are associated with the number of reinfused T lymphocytes of the autologous stem cell graft

Background aimsNeutropenia following high-dose chemotherapy is associated with a substantial risk of infectious complications. The aim of this study was to identify variables in residual leukocyte subsets during neutropenia that are predictive for neutropenic fever.MethodsResidual leukocytes in the peripheral blood on day 5 after autologous blood stem cell transplantation were analyzed by three-color flow cytometry in 55 consecutive patients with multiple myeloma. Furthermore, the number of T cells transfused with the autografts was determined.ResultsNeutrophil counts at day 5 and neutrophil engraftment were similar in patients with and without neutropenic fever. Low absolute lymphocyte, CD4⁺ CD28⁺ and CD45RO⁺ CD28⁺ counts at day 5 were associated with neutropenic fever. T-cell counts at day 5 correlated with the CD3⁺ cell number in the graft.ConclusionsOur data show that the absolute lymphocyte, CD4⁺ CD28⁺ and CD45RO⁺ CD28⁺ counts play a role in host defense during severe neutropenia. The T-cell number in the graft may help to identify patients at high risk of neutropenic infections.     

T-cell subsets in multiple myeloma. Impact of cytostatic treatment

Blood leukocyte and lymphocyte counts, absolute and relative numbers of T-lymphocytes and T-cell subsets were studied in 45 patients with multiple myeloma and 18 healthy controls. No differences were found between untreated patients and controls. In the group of untreated patients similar results were obtained in patients with low-intermediate tumour cell mass as in patients with large tumour cell mass. In patients with large tumour cell mass studied during cytostatic therapy, leukocyte and lymphocyte counts, T-cells, OKT4+ cells and OKT4/OKT8 ratios were significantly lower than in untreated patients. Patients studied at varying intervals (2-28 mo.) after cessation of therapy still exhibited abnormal leukocyte and lymphocyte counts, numbers of T-cells, OKT4+ cells and OKT4/OKT8 ratios.     

Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer

Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.     

Functional regulatory T cells are collected in stem cell autografts by mobilization with high-dose cyclophosphamide and granulocyte colony-stimulating factor

High-dose cyclophosphamide (Cy) and G-CSF are widely used to mobilize hemopoietic stem cells for treating patients with high-dose chemotherapy and autologous stem cell transplantation (ASCT). Because lymphocyte count in the graft collected after Cy-G-CSF treatment is an independent survival factor after ASCT for patients with multiple myeloma, our purpose was to study how Cy-G-CSF treatment affects the phenotype and function of T cells in patients with multiple myeloma. Cy induced a 3-fold decrease of T cell counts with a slow and partial T cell recovery of one-third at the time of hemopoietic stem cell collection. Cy-G-CSF treatment did not affect the relative ratios of central memory, effector memory, and late effector CD4+ or CD8+ T cells, but a decrease in the percentage of naive CD4+ cells was observed. The percentages of CD25+ cells increased 2- to 3-fold in CD4+ and CD8+ T cells, the former including both activated CD25low and CD25high cells. CD4+CD25high cells were regulatory T cells (Treg) that expressed high levels of FOXP3, CTLA-4, and GITR and displayed in vitro suppressive properties. The recovery of Treg absolute counts after Cy-G-CSF treatment was higher than the recovery of other lymphocyte subpopulations. In conclusion, Cy-G-CSF treatment induces a severe T cell count decrease without deleting Treg, which are potent inhibitors of antitumor response. The present data encourage novel therapeutic strategies to improve T cell recovery following ASCT while limiting Treg expansion.     

Hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders: studies of granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-3 (IL-3) and Flt-3 ligand (Flt3L)

The levels of hematopoietic growth factors in patients receiving intensive chemotherapy for malignant disorders were investigated using a variety of approaches. Firstly, serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF and Flt3-ligand (Flt3L) were examined in acute leukemia patients with treatment-induced cytopenia and complicating bacterial infections. Increased serum levels of both G-CSF and Flt3-ligand (Flt3L) were detected when these patients developed therapy-induced leukopenia, whereas GM-CSF levels were low or undetectable. Development of complicating bacterial infections then increased the serum levels of both G- and GM-CSF, and the Flt3L levels remained high during the infections. Secondly, release of growth factors was characterized for clonogenic T cells that remained in the circulation of acute leukemia patients with chemotherapy-induced cytopenia. CD4(+) and CD8(+) T cells from these patients released high levels of GM-CSF, relatively low levels of IL-3 secretion having been detected, and only a minority of the clones released detectable amounts of Flt3L. Thus, circulating T cells may contribute to the high systemic growth factor levels in cytopenic patients. Thirdly, plasma levels of GM-CSF and interleukin-3 (IL-3) were examined in patients with malignant disorders who received chemotherapy plus G-CSF for stem cell mobilization. Increased levels of GM-CSF and Flt3L were detected both in the patients' plasma and in the stem cell grafts. Despite the increased growth factor levels in neutropenic patients with complicating infections, the occurrence of febrile neutropenia did not have a major impact on normal hematopoietic reconstitution (i.e. duration of treatment-induced neutropenia) after intensive chemotherapy for acute myelogenous leukemia.     

Effect of alemtuzumab-based T-cell depletion on graft compositional change in vitro and immune reconstitution early after allogeneic stem cell transplantation

Background aimsTo reduce the risk of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT), T-cell depletion (TCD) of grafts can be performed by the addition of alemtuzumab (ALT) “to the bag” (in vitro) before transplantation. In this prospective study, the authors analyzed the effect of in vitro incubation with 20 mg ALT on the composition of grafts prior to graft infusion. Furthermore, the authors assessed whether graft composition at the moment of infusion was predictive for T-cell reconstitution and development of GVHD early after TCD alloSCT.MethodsSixty granulocyte colony-stimulating factor-mobilized stem cell grafts were obtained from ≥9/10 HLA-matched related and unrelated donors. The composition of the grafts was analyzed by flow cytometry before and after in vitro incubation with ALT. T-cell reconstitution and incidence of severe GVHD were monitored until 12 weeks after transplantation.ResultsIn vitro incubation of grafts with 20 mg ALT resulted in an initial median depletion efficiency of T-cell receptor (TCR) α/β T cells of 96.7% (range, 63.5–99.8%), followed by subsequent depletion in vivo. Graft volumes and absolute leukocyte counts of grafts before the addition of ALT were not predictive for the efficiency of TCR α/β T-cell depletion. CD4^pos T cells were depleted more efficiently than CD8^pos T cells, and naive and regulatory T cells were depleted more efficiently than memory and effector T cells. This differential depletion of T-cell subsets was in line with their reported differential CD52 expression. In vitro depletion efficiencies and absolute numbers of (naive) TCR α/β T cells in the grafts after ALT incubation were not predictive for T-cell reconstitution or development of GVHD post- alloSCT.ConclusionsThe addition of ALT to the bag is an easy, fast and generally applicable strategy to prevent GVHD in patients receiving alloSCT after myeloablative or non-myeloablative conditioning because of the efficient differential depletion of donor-derived lymphocytes and T cells.     

Immunotherapy in multiple myeloma: Id-specific strategies suggested by studies in animal models

Multiple myeloma (MM) cells produce monoclonal immunoglobulin (Ig) which serves as a truly tumor-specific antigen. The tumor-specific antigenic determinants are localized in the variable (V)-regions of the monoclonal Ig and are called idiotopes (Id). We review here the evidence obtained in a T-cell receptor (TCR) transgenic mouse model that Id-specific, MHC class II–restricted CD4⁺ T cells play a pivotal role in immunosurveillance and eradication of MHC class II-negative MM cells. In brief, monoclonal Ig secreted by MM cells is endocytosed and processed by antigen-presenting cells (APCs) in the tumor. Such tumor-resident dendritic cell APCs in turn present Id peptide on their class II molecules to Id-specific CD4⁺ T cells which become activated and indirectly kill the MHC class II-negative myeloma cells. However, if the Id-specific CD4⁺ cells fail to eliminate the MM cells during their initial encounter, the increasing number of tumor cells secretes so much monoclonal Ig that T-cell tolerance to Id is induced. Extending these findings to MM patients, Id-specific immunotherapy should be applied at a time of minimal residual disease and when new Id-specific T cells have been educated in the thymus, like after high-dose chemotherapy and autologous stem cell transplantation.Abbreviations APC antigen-presenting cell - ASCT autologous stem cell transplantation - CDR complementarity-determining region - CFA complete Freunds adjuvant - DC dendritic cell - GM-CSF granulocyte-macrophage colony-stimulating factor - H heavy - Id idiotope or idiotype - Ig immunoglobulin - IL interleukin - L light - M-component monoclonal component - MGUS monoclonal gammopathy of undetermined significance - MHC major histocompatibility complex - MM multiple myeloma - MOPC mineral oil–induced plasmacytoma - TCR T-cell antigen receptor - V variableA. Corthay and B. Bogen are joint corresponding authors for this article.     

Functional characterization of T lymphocytes derived from patients with acute myelogenous leukemia and chemotherapy-induced leukopenia

T-cell–targeting immunotherapy is now considered in acute myelogenous leukemia (AML). Immunotherapy seems most effective for patients with a low AML cell burden, and a possible strategy is therefore to administer immunotherapy early after intensive chemotherapy when patients have a low leukemia cell burden and severe treatment-induced cytopenia. To further investigate this possible therapeutic approach we used a whole blood assay to characterize the proliferative responsiveness (³H-thymidine incorporation) of circulating T cells from AML patients with severe treatment-induced leukopenia, i.e., peripheral blood leukocyte counts <0.5×10⁹/l. This assay will reflect both quantitative and qualitative differences. Responses were compared for 17 AML patients, 6 patients with acute lymphoblastic leukemia (ALL), and a group of 21 healthy controls. Most circulating leukocytes in the AML patients were T lymphocytes, whereas B lymphocytes and monocytes usually constituted <10%. Anti-CD3-stimulated proliferation was significantly lower for AML patients compared with healthy controls. However, proliferation in response to anti-CD3 + anti-CD28 did not differ for AML patients and healthy controls, an observation suggesting that T cells from AML patients have an increased responsiveness in the presence of optimal costimulation that compensates for the quantitative T-cell defect. In contrast, the responses were significantly lower for ALL than for AML patients. We conclude that the remaining T-cell population in AML patients with severe chemotherapy-induced cytopenia show an increased proliferative responsiveness and may represent a therapeutic target when antileukemic immunotherapy is tried in combination with intensive chemotherapy.     

Nodular hepatic lesions secondary to myeloma IgA presenting as fever of unknown origin

A 45 year old male presented with IgA multiple myeloma s/p (status post) autologous hematopoietic stem cell transplantation; and with a history of six weeks of fever and constitutional symptoms. Liver tests showed an infiltrative pattern, with ultrasound evidence of multiple nodular lesions. A laparoscopic biopsy identified circumscribed myeloma foci. This is the first reported case of myeloma nodular liver lesions causing a fever of unknown origin.     

Comparison of CD4+ T-cell subset distribution in chronically infected HIV+ patients with various CD4 nadir counts

Infection with HIV-1 causes CD4⁺ T-cell dysfunction, including unresponsiveness to antigenic stimuli. To understand the mechanism of virally induced T-cell dysfunction, we investigated changes occurred in functional CD4⁺ T-cell subsets in the peripheral CD4⁺ T-cell pool in chronically infected aviremic individuals treated with antiretroviral therapy. We phenotypically defined CD4⁺ T-cell subsets by surface markers and determined the frequency of each subset by flow cytometry. A substantially low naïve and elevated effector subsets were observed in chronically infected patients with nadir CD4 counts <100 cells/μl. The skewed distribution persisted in these patients even after their CD4 counts increased, and the subset imbalance was still observed in all four subsets after years of successful antiretroviral therapy. They also showed a limited recovery of CD4⁺ T-cell counts compared to those who maintained at least 250 CD4⁺ T cells/μl after 3–11 years of successful treatment since CD4 nadir time points. The difference was pronounced in the absolute numbers of naïve and T_EM cells. Our results suggested a significant and prolonged impact of nadir CD4 counts on the balanced distribution of the functional CD4⁺ T-cell subsets and may explain partially why antiretroviral therapy needs to be initiated while patients' CD4 counts remain relatively high.     

Immunomodulatory drugs improve the immune environment for dendritic cell-based immunotherapy in multiple myeloma patients after autologous stem cell transplantation

Multiple myeloma (MM) is characterized by a malignant proliferation of plasma cells in the bone marrow with associated organ damage. Although the prognosis of MM has improved recently, the disease remains incurable for the large majority of patients. The eradication of residual disease in the bone marrow is a main target on the road toward cure. Immune cells play a role in the control of cancer and can be tools to attack residual MM cells. However, the myeloma-associated immune deficiency is a major hurdle to immunotherapy. We evaluated ex vivo the effects of low doses of the immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide on several immune cell types from MM patients after autologous stem cell transplantation and with low tumor burden. We observed that these drugs increased CD4⁺ and CD8⁺ T-cell proliferation and cytokine production, enhanced the lytic capacity of cytotoxic T lymphocytes and reduced the suppressive effects of regulatory T cells on CD8⁺ T-cell responses. In addition, we found that functional dendritic cells (DCs) can be generated from mononuclear cells from MM patients. The presence of IMiDs improved the quality of antigen-specific T cells induced or expanded by these DCs as evidenced by a higher degree of T-cell polyfunctionality. Our results provide a rationale for the design of early phase clinical studies to assess the efficacy of DC-based immunotherapy in combination with posttransplant maintenance treatment with IMiDs in MM.     

CD34(+)-selected stem cell boost for delayed or insufficient engraftment after allogeneic stem cell transplantation

BACKGROUND: Poor graft function without rejection may occur after stem cell transplantation (SCT). CD34(+) stem cell boost (SCB) can restore marrow function but may induce or exacerbate GvHD. We therefore investigated the feasibility and efficacy of CD34(+)-selected SCB in some patients with poor graft function. We present the results for eight patients (median age 46 years) transplanted initially for myelofibrosis, acute leukemia, myeloma and NHL. Six patients had received HLA-matched and two mismatched grafts (PB, BM; n=5, 3). After a median of 128 days post-transplant, the median leukocyte and platelet counts were, respectively, 2.05/nL and 18/nL. None had achieved platelet counts >50/nL even though donor chimerism was >95% in seven recipients. METHODS: Positive selection of CD34(+) stem cells was performed on a CliniMACS device, observing GMP and achieving a median of 98.5% purity. The patients received a median of 1.7 x 10(6)/kg CD34(+) cells and 2.5 x 10(3)/kg CD3(+) T lymphocytes. RESULTS: Hemograms at days +30, +60 and +90, respectively, showed steadily increasing median leukocyte (2.55, 3.15 and 4.20/nL) and platelet (29, 39 and 95/nL) counts. After a median follow-up of 144 days, five patients remained alive. No patient had developed acute or chronic GvHD. One patient died of leukemic relapse and two others of systemic mycosis. DISCUSSION: These preliminary results point to the possibility of safely improving graft function using CD34(+) positively selected stem cells without necessarily increasing the incidence of GvHD in patients with poor graft function post-SCT. Experience with more patients and longer follow-up should clarify the optimal role for this procedure.     

Immunogenicity of dendritic cells pulsed with MAGE3, Survivin and B-cell maturation antigen mRNA for vaccination of multiple myeloma patients

The introduction of autologous stem cell transplantation (SCT) and novel drugs has improved overall survival in multiple myeloma (MM) patients. However, minimal residual disease (MRD) remains and most patients eventually relapse. Myeloma plasma cells express tumor-associated antigens (TAA), which are interesting targets for immunotherapy. In this phase 1 study, we investigated the safety and immunological effects of TAA-mRNA-loaded dendritic cell (DC) vaccination for treatment for MRD in MM after SCT. Mature monocyte-derived DCs were pulsed with keyhole limpet hemocyanin (KLH) and electroporated with MAGE3, Survivin or B-cell maturation antigen (BCMA) mRNA. Twelve patients were vaccinated three times with intravenous (5–22 × 10⁶ DCs) and intradermal vaccines (4–11 × 10⁶ DCs), at biweekly intervals. Immunological responses were monitored in blood and delayed-type hypersensitivity (DTH) biopsies. All patients developed strong anti-KLH T-cell responses, but not KLH antibodies. In 2 patients, vaccine-specific T cells were detected in DTH biopsies. In one patient, we found MAGE3-specific CD4⁺ and CD8⁺ T cells, and CD3⁺ T cells reactive against BCMA and Survivin. In the other patient, we detected low numbers of MAGE3 and BCMA-reactive CD8⁺ T cells. Vaccination was well tolerated with limited toxicity. These findings illustrate that TAA-mRNA-electroporated mature DCs are capable of inducing TAA-T-cell responses in MM patients after SCT.     

Collection and freezing of blood stem cells in acute nonlymphoblastic leukemia

Blood-derived hemopoietic stem cells were collected using a continuous (10 patients) or a semi-continuous flow separator (2 patients) in some patients with acute non-lymphocytic leukemia. For ten out of those patients, five to seven leukaphereses were performed during a short period (median = 11 days) of marrow recovery following severe aplasia induced by an intensive chemotherapy. The mean number of CFU-GM cells collected per leukapheresis and per patient respectively was 6.7 X 10(4)/kg and 38.5 X 10(4)/kg. This latter number was similar to that obtained during a marrow harvest performed for a bone marrow transplantation, suggesting that high numbers of hemopoietic stem cells can be collected from the peripheral blood in leukemic patients and used for autologous transplantation.     

The serum IL-12:IL-6 ratio reliably distinguishes infectious from non-infectious causes of fever during autologous stem cell transplantation

BACKGROUND: Fever during neutropenia and after neutrophil engraftment (post-engraftment fever) occurs commonly during autologous transplantation (ASCT), but infections are infrequently identified. Tests that reliably exclude infection may reduce the cost and toxicity of unnecessary diagnostic testing and empiric treatment. We assessed whether serum levels of inflammatory cytokines could distinguish infectious from non-infectious causes of fever in patients undergoing ASCT. METHODS: Serum levels of IL-1beta, IL-2, IL-6, IL-8, IL-10, IL-12(p70), TNF-alpha and IFN-gamma were measured by sandwich ELISA at multiple pre-determined times and at the onset of the first fever during neutropenia and after neutrophil engraftment in patients with hematologic malignancies undergoing ASCT. Standard clinical criteria were used to assess for the presence of infection. RESULTS: Seventy-two febrile episodes occurred in 54 of 65 enrolled patients; 29 (40%) of the episodes occurred after neutrophil engraftment. Infections were identified as the cause of 28% and 24% of the neutropenic and post-engraftment febrile episodes, respectively. The level of IL-12 decreased and that of IL-6 increased significantly during fever because of infection, such that the IL-12:IL-6 ratio accurately excluded infection. The area under the ROC curve for the IL-12:IL-6 ratio was 0.88 (95% CI 0.79-0.97). The sensitivity, specificity, positive predictive and negative predictive values associated with a cut-off ratio of 4.1 were 95%, 75%, 60%, and 97%, respectively. DISCUSSION: The IL-12:IL-6 ratio effectively discriminates infectious from non-infectious causes of fever during ASCT. It may be useful in assessing the probability of infection in patients with post-engraftment fever.     

Immunological and virological aspects of autologous stem cell transplantation in HIV+ patients

Autologous stem cell transplantation (ASCT) is an effective therapeutic option in patients with human immunodeficiency virus-associated lymphomas (HIV-L). This review will focus on the experimental and clinical data regarding the effects of ASCT on the reconstitution of lymphocyte subsets, T-cell repertoire and thymic function in HIV-L patients. Current data on the kinetics of reactivation of HIV, Epstein-Barr virus, cytomegalovirus and hepatitis C virus during mobilization and after reinfusion of stem cells will be also analyzed.     

Effect of chemotherapy on T-lymphocyte subsets in B-cell proliferative disorders

The T-cell subset distribution and the activity markers of 41 patients with multiple Myeloma, Waldenstr?m's macroglobulinaemia and benign monoclonal gammopathy were repeatedly analysed using monoclonal antibodies (T3, T4, T8, anti-TAC, anti DR) and rosetting techniques. In myeloma and macroglobulinaemia the relative and absolute numbers of T4+ cells were diminished while the absolute number of T8+ cells was not decreased. No significant difference between stage I and III of the myeloma disease was seen. The diminished number of T4+ cells in myeloma was partly due to the effect of chemotherapy. Chemotherapy-induced lymphopenia resulted in a drop of circulating T4+ cells and an inverted T4/T8 cell ratio. Untreated patients with myeloma were not significantly different from patients with benign gammopathy. Patients with macroglobulinaemia differed from patients with myeloma as they had an increased absolute T8 cell count and a significantly elevated percentage of TAC+ (= IL 2 receptor expressing) cells. In macroglobulinaemia chemotherapy affected also the T8+ cell subset. Thus, patients with macroglobulinaemia, but not with myeloma appear to have activated T8+ cells in their circulation.     

Sepsis, low platelet nadir at mobilization and previous IFN use predict stem cell mobilization failure in patients with multiple myeloma

BACKGROUND: Successful stem cell mobilization is a prerequisite for autologous blood cell transplantation. We analyzed factors that may predict the success of stem cell mobilization in patients with multiple myeloma (MM). METHODS: We analyzed 124 consecutive patients and compared those who failed to mobilize a sufficient amount of CD34(+) cells (peak blood CD34(+) cell count <20x10(6)/L) (n=20) with those with successful mobilization (n=104). The peak blood CD34(+) cell count after mobilization was used as the marker of mobilization success against which the various predictive factors were tested. RESULTS: In univariate analysis the best predictive factors for mobilization failure were the number of different chemotherapy regimens (P<0.001), number of chemotherapy cycles (P<0.001), time from diagnosis to mobilization (P<0.001) and previous use of IFN (P<0.001). The distributions of treatment responses at mobilization were similar in the groups with successful and unsuccessful mobilization, and were CR or VGPR in 10% of all patients, PR in 54% and stable or progressive disease in 36%. Regarding the mobilization-related factors, lower leukocyte nadir (P<0.001), longer duration of leukocyte counts <1x10(9)/L (P<0.001), lower platelet nadir (P=0.001), longer duration of platelet counts <20x10(9)/L (P<0.001) and the occurrence of sepsis after the mobilization therapy (P=0.001) were significantly associated with mobilization failure. In multivariate analysis, the amount of earlier chemotherapy cycles (P=0.002), low platelet nadir (P=0.020), occurrence of sepsis at mobilization (P=0.040) and previous use of IFN (P=0.052) remained as significant predictive factors for mobilization failure. DISCUSSION: Predicting the success of stem cell mobilization beforehand may have important practical consequences. By identifying those patients who will fail to mobilize stem cells, unnecessary mobilization and collection attempts can be avoided.     

Cyclosporine-induced deterioration in patients with AIDS.

Eight patients with AIDS (acquired immune deficiency syndrome) but free of life-threatening infection were treated with the immunosuppressive drug cyclosporine for a mean of 53.9 days. The serum cyclosporine levels were maintained in the desired therapeutic range. All eight patients experienced severe toxic symptoms, which necessitated discontinuation of cyclosporine therapy in six. The serum levels of creatinine, urea and potassium rose during treatment and fell after therapy was stopped. The total leukocyte count, hemoglobin level, platelet count, total T-cell count, and T4- and T8-cell counts all fell markedly during treatment. The total leukocyte count, platelet count, and T4- and T8-cell counts rose after therapy was stopped, but the hemoglobin level remained low. No patient experienced resolution of symptoms during therapy, and the condition of all patients improved after treatment was stopped. The results of this pilot study indicate that cyclosporine does not alleviate, and may worsen, the symptoms and laboratory findings in patients with AIDS.     

The impact of new emerging drugs in the treatment of multiple myeloma: is there still a role for PBSC transplantation?

High-dose therapy with the rescue of autologous stem cells represents today the standard approach for multiple myeloma patients aged <65 years. Several studies, in fact, have demonstrated the superiority of high-dose therapy with respect to conventional chemotherapy in younger patients. Peripheral blood stem cells (PBSCs) provide a rapid and effective hematopoietic recovery after the administration of supra maximal chemotherapy and mainly for this reason have become the preferred source of stem cells for autologous transplantation. Recently, however, a number of new drugs have appeared in the armamentarium of the hematologist. Among these, thalidomide has been the first antiangiogenetic drug effectively adopted firstly in refractory-relapsed patients and now also as first line treatment with better results respect to VAD or VAD-like regimens. Inhibitors of proteasome, such as bortezomib, and other immunomodulatory agents, such as lenalidomide, have been also studied more recently in myeloma patients. In particular, bortezomib has shown to be very effective as single agent or in combination with high-dose dexamethasone. In this review, we try to define the potential role of these new drugs, how and when they can be included in the therapeutic program designed for younger and older patients, and mostly if and how these new agents could jeopardize the central role of autologous stem cell transplantation in the treatment of multiple myeloma.