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PubMed2006

Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation: influence of Campath dose on lymphoid recovery, mixed chimerism and survival.

Sixty-nine consecutive patients (median age 54 years) were prospectively enrolled in a single-institution protocol for allogeneic transplantation with adjusted non-myeloablative fludarabine-melfalan-based conditioning including cyclosporin A and MMF, and one of three modes of serotherapy. Thirty-one donors (45%) were unrelated. The first cohort of 29 had ATG (Thymoglobulin 2 mg/kg x 3 days), the subsequent 26 had Campath 30 mg x 3 days subcutaneously, and the final cohort of 14 had 30 mg Campath once. The groups were similar as regards age, diagnosis and risk factors. Campath-patients had no acute toxicity, fewer days with fever and antibiotics, and required fewer transfusions than ATG-treated patients. 3-d-Campath patients showed lower lymphocyte counts from day +4, and CD4+, CD8+, CD19+ and NK cells recovered slower than in ATG-treated patients. More Campath patients developed mixed chimerism that required DLI. 3-d-Campath induced more serious and opportunistic infections than ATG, which resulted in a greater non-relapse mortality and an impaired overall survival despite a low tumor-related mortality. The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3-d-Campath on immune recovery, severe infections and survival. Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity, but dose limitation to 30 mg once is recommended.

Adult↗
PubMed2005

Hematopoietic stem-cell transplantation from unrelated donors in elderly patients (age >55 years) with hematologic malignancies: older age is no longer a contraindication when using reduced intensity conditioning.

Allogeneic stem cell transplantation (SCT) is a potentially curative approach for patients with hematological malignancies. Reduced-intensity conditioning regimens allow SCT in elderly patients; however, there are only limited data on the feasibility and outcomes of unrelated donor SCT in these patients. In this study, we analyzed, retrospectively, data of 36 patients with various hematological malignancies and median age 58 years (range, 55-66), who were given unrelated donor SCT after reduced-intensity conditioning. The preparative regimen consisted of fludarabine combined with oral busulfan (8 mg/kg, n=8), intravenous busulfan (6.4 mg/kg, n=11), treosulfan (30 g/m(2), n=5) or melphalan (100-150 mg/m(2), n=12). Patients were also given serotherapy, ATG (n=32), or alemtuzumab (n=4). The probabilities of overall survival, disease-free survival, and nonrelapse mortality at 1 year after SCT were 52, 43, and 39%, respectively. Acute graft-versus-host disease (GVHD) grade II-IV and chronic GVHD occurred in 31 and 45%, respectively. Multivariable analysis determined that survival rates were higher in patients with chemosensitive disease (HR 4.5), and patients conditioned with intravenous busulfan or treosulfan (HR 3.9). Unrelated donor SCT is feasible in elderly patients, with outcomes that are similar to younger patients. Favorable outcome was observed in patients with myeloid malignancies, and those transplanted in remission and early in the course of disease. Age alone should not be considered a contraindication to unrelated donor SCT.

Aged↗
PubMed2003

Follow-up of patients with progressive multiple myeloma undergoing allografts after reduced-intensity conditioning.

Allogeneic stem cell transplantation (allo-SCT) after reduced-intensity conditioning was evaluated in 22 patients (median age 53, range 36-66 years) with multiple myeloma with progression after an autologous SCT. Seven patients received a transplant from a human leucocyte antigen (HLA)-identical sibling and 15 patients (68%) from an unrelated donor [including 3/22 (14%) from a HLA-mismatched unrelated donor]. Graft-versus-host disease (GVHD) prophylaxis consisted of serotherapy with antithymocyte globulin (ATG) and cyclosporine (CSA) (n = 12) or CSA plus mycophenolate mofetil (n = 10). Despite of heavy pretreatment, the transplant-related mortality (TRM) for all grafted patients was acceptable at 5/22 patients (23%). Seven of 21 patients (33%) that were evaluated developed grade II GVHD and one (5%) patient developed grade III/IV acute GVHD. Seven patients developed chronic GVHD (cGVHD), but only one was extensive. Eleven patients died of progressive disease within a median of 7 months (2-19 months) post transplant. Thirteen of all 22 patients (59%) achieved a partial or complete remission with six of these 13 patients (46%) remaining event free at a median of 24 months (range 8-36 months) post allografting. Estimated 2 year overall and event-free survival was, respectively, 25.5% and 22.0% for the whole patient group, and 62.5% and 57.1% for patients with chemosensitive disease. Chemorefractory disease prior to allogeneic stem cell transplantation (P = 0.0182) and absence of cGVHD (P = 0.069) were associated with shorter event-free survival. Thus long-term disease control can be achieved, but is restricted to patients responding to prior salvage chemotherapy.

Acute Disease↗
PubMed2003

The outcome of unrelated donor stem cell transplantation for patients with multiple myeloma.

We performed a retrospective analysis of outcome in 45 patients with multiple myeloma receiving unrelated donor stem cell transplants (UD-SCT) in the UK between 1993 and 2002; 17 received myeloablative conditioning regimens and 28 received reduced intensity conditioning (RIC) protocols. Forty patients received pretransplant CAMPATH serotherapy. Forty-two of 45 patients had detectable disease at transplant, but 33 of 45 were chemoresponsive. Sixty per cent of patients had received a previous autograft. Myeloid engraftment was seen in 95% of recipients and was significantly faster in recipients receiving peripheral blood stem cells (P = 0.07) and RIC (P = 0.001). The incidence of severe (grade 3/4) acute graft versus host disease (aGvHD) was 5% (2/40). The 100-d non-relapse mortality was 18% (5/38) following RIC and 53% (9/17) following myeloablative regimens. Twenty-nine per cent of patients achieved a complete remission, 61% a partial remission, giving a 90% overall response rate. At median follow-up (513 d), overall survival was 40%: 54% in the RIC group (median follow-up: 489 d) and 18% in the myeloablative group (median follow-up: 560 d). In recipients of UD-SCT, RIC protocols that incorporated CAMPATH were associated with faster myeloid engraftment, less severe aGvHD and lower 100-d non-relapse mortality than myeloablative regimens, without a corresponding rise in relapse rate during the period of observation.

Adult↗
PubMed2002

Novel biologically based therapeutic strategies in myeloma.

Multiple myeloma remains incurable despite advances in conventional chemotherapy and wider applicability of high dose chemotherapy with single and/or tandem autologous peripheral blood stem cell transplantation. Although a complete remission rate of 41% and an event-free survival of 43 months have been reported after tandem transplantation, it is highly unlikely that further improvements in the outcome of multiple myeloma will be achieved by escalating cytotoxic chemotherapy alone. Novel biologically based therapies are therefore urgently required. Targeted therapeutic approaches based on: identification of genetic abnormalities in malignant plasma cells; interrupting growth of myeloma cells; triggering apoptotic signaling cascades in tumor cells; modulating growth and survival of multiple myeloma cells in the bone marrow microenvironment, i.e. angiogenesis and cytokine networks; enhancing allogeneic and autologous antimyeloma immunity; and characterizing newer myeloma antigens for serotherapy are under development. These therapies offer great promise, used alone/or in combination with conventional treatment approaches, to improve the outcome in this disease in newly diagnosed/refractory or relapsed patients with multiple myeloma.

Antineoplastic Agents↗
PubMedDate not supplied

[Unrelated donor stem cell transplantation in children: low toxicity using a GvHD-prophylaxis regimen with CSA, MTX, metronidazole,iv-immunoglobulin and ATG].

BACKGROUND: Unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) is accepted as a therapy for leukaemic diseases and varying inborn diseases if a suitable related donor cannot be found. The goal of immunosuppressive therapy with UD-HSCT is an effective prevention of graft-versus-host-disease (GvHD) on one hand. On the other hand an optimal balance with immunocompetence of the transplanted bone marrow is desirable in order to prevent graft failure, infection and, in the case of leukaemic diseases, potentially control the underlying disease. PATIENTS AND METHODS: Between 1992 and 2000 49 patients aged 11 months to 16.7 years received an UD-HSCT in Hamburg. Underlying diseases were leukaemia or MDS in 35, of these ALL in 21, hemophagocytic lymphohistiocytosis (HLH) in 9, immunodeficiency or inborn error of metabolism in 5 patients. GvHD-prophylaxis consisted of a combination of Cyclosporin A (CSA), methotrexate (MTX), metronidazole, IgM-enriched iv-immunoglobulin (ivIg) (Pentaglobin(R)) or ivIgG and anti-thymocyte-globulin (ATG). Within the same time span 10 patients with ALL received a matched related donor HSCT (MRD-HSCT). GvHD-prophylaxis in these patients was done without ATG in 8 of 10 cases. UD-HSCT were analyzed for survival, relapse and toxicity. Probability of survival of the patients with ALL after UD-HSCT was compared with results of MRD-HSCT in children with ALL. RESULTS: The Kaplan-Meier estimates of three year overall-survival (OS) were 74 % for all patients. Probability of disease-free survival (DFS) at three years was 62 % for leukaemia/MDS-patients and 100 % for the HLH-patients. Acute GvHD (aGvHD) grades II or III occurred in 51 % of patients. Chronic GvHD (cGvHD) occurred in 22 % of patients. There were 5 cases of treatment-related mortality (TRM). Probability of DFS for patients with ALL at three years was 65 % after UD-HSCT and 30 % in the patients after MRD-HSCT. CONCLUSIONS: UD-HSCT in children is an effective and safe therapy. A GvHD-prophylaxis regimen combining the standard immunosuppressive agents CSA and MTX with ivIg, metronidazole and serotherapy using ATG may result in a low incidence of severe GvHD-complications and low TRM rate without increase in relapse rates.

Adolescent↗
PubMed1990

Vaccination with a live retrovirus: the nature of the protective immune response.

We tested 3'-azido-3'-deoxythymidine (zidovudine) combined with interferon alpha as chemoprophylaxis after exposing mice to Rauscher murine leukemia virus. Therapy started 4 hr after inoculation and administered for 20 days prevented viremia and disease in all 234 mice tested. When the animals were rechallenged with live virus after cessation of therapy, 96% were resistant. The nature of this protective immune response was analyzed: Passive serotherapy of naive mice challenged subsequently with Rauscher murine leukemia virus was only protective at a high dose of immune serum. Immune, but not naive, T cells alone were fully protective against virus challenge. We conclude that vaccination with a live retrovirus that cannot replicate because of pharmacological blockade induces a T-cell response capable of protecting against a lethal retrovirus-induced disease.

Animals↗
PubMed2002

Chronic lymphocytic leukaemia--the haematologic basis for diagnosis and treatment.

Clinically diagnosis may be incidental when absolute lymphocytosis is uncovered at routine medical examination. More usually there is a recurrent sinopulmonary infection reflecting a varying degree of humoral and cellular immune deficiency. Autoimmune phenomena may result in haemolytic anaemia or thrombocytopenia. Expanding tumour bulk underlies the lymphadenopathy which may be prominent. Diagnosis is confirmed on morphology of the smear where atypical variants need to be distinguished from other indolent lymphoproliferative disorders. Immunophenotyping is indispensable in classification. Prognosis is predicated by cytogenetics and markers of tumour biology that include beta-2 microglobulin and peripheral blood lymphocyte doubling time. Management is dictated by symptoms and signs of progression superimposed upon performance status that includes age. Disease that is asymptomatic and truly indolent, particularly in the elderly, qualifies for a careful watch-and-wait policy. In other circumstances stratification to therapy requires entry into peer-reviewed protocols if optimal outcome is to be achieved. Established regimens, of demonstrably equal efficacy, are pulsed single-agents exemplified by chlorambucil or combinations of cyclophosphamide with vincristine and prednisone. The purine analogues, particularly when administered with an alkylating agent and mitoxantrone, are emerging as superior options. In selected patients any properly accredited program will make provision for escalation in chemotherapy requiring haematopoietic stem cell transplantation on the one hand or use of serotherapy with CD52 antibodies on the other. Less commonly, but in a defined subgroup, immunoglobulins directed against membrane CD20 may be effective. Perspective for the generalist is anchored in recognising that the previous cavalier approach to drug medication, with or without radiotherapy, is unwise whereas integrated management is now the international standard of practice. The previous anachronism of dabbling by occasional therapists is to be deprecated since this will generally deny patients access to proper diagnosis and risk-adjusted multi-disciplinary treatment.

Antineoplastic Agents↗
PubMedDate not supplied

Acquired immune deficiency syndrome (AIDS): speculations about its etiology and comparative immunology.

Acquired immune deficiency syndrome (AIDS) in many aspects resembles formerly recognized immune deficiencies, but in its complexity and presumed viral etiology, it is a unique entity. Examples of overlapping features of AIDS and immune defects, infectious complications, and neoplasms are discussed. It is not known what are the exact underlying mechanisms that permit or prohibit infectious and neoplastic complications among the immunodeficiency syndromes compared, but both overlapping and differing features of these entities are significant enough to hold a clue for future understanding. AIDS resembles feline leukemia as this latter syndrome was described 10 years ago. The retrovirus causing feline leukemia is highly immunosuppressive; preleukemic and viremic cats often succumb to opportunistic infections. If patients with early AIDS harbor retroviruses related to the human T cell leukemia virus in their organs (lymph nodes, bone marrow), serotherapy with monoclonal antibodies directed to this virus may stop and reverse the severe immunosuppression, thus preventing the development of opportunistic infections.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Exacerbation of Lyme arthritis in beige mice.

Borrelia burgdorferi-induced disease susceptibility was explored in disease-resistant C57/BL6 (B6) and -susceptible C3H/He (C3H) mice with and without the beige (bg) mutation, which is associated with granulocyte and NK cell dysfunction. Both B6 and C3H mice had more prevalent and severe arthritis than their congenic partners, and B6-bg mice developed arthritis equal in severity to that in C3H mice. Spirochetes were visualized in joint tissue of B6-bg mice but not B6 mice. No differences in spirochete isolation from tissues or immunoglobin titers to B. burgdorferi were noted between groups. Depletion of granulocytes with cyclophosphamide and macrophages with silica in B6 and C3H mice modified arthritis susceptibility, but depletion of NK cells by serotherapy in B6 mice had no effect on disease. This study demonstrates that innate genetic resistance to Lyme arthritis in mice can be overcome by a single gene mutation, which is probably mediated through granulocyte function.

Animals↗
PubMed1977

In vivo suppression of EL 4 lymphomas by rabbit antitumor sera.

Three of more than 50 batches of rabbit antisera raised against the mouse EL 4 lymphoma could inhibit the growth of the tumor in the syngeneic C57BL/6J mice either after exposure of the tumor cells to the antitumor globulin (ATG) in vitro or after the administration of ATG in mice preinoculated with various numbers of EL 4 cells, even though the ATG was not cytotoxic to the tumor cells in the presence of complement. The outcome of immunotherapy with ATG in tumor-bearing C57BL/6J mice depended on the tumor load, the interval between tumor inoculation and the institution of therapy, the total dose, and the schedule of administration of ATG. Complete tumor suppression could be obtained in a proportion of mice preinoculated with 10(5) EL 4 cells, i.e., 10(4) times more than the minimum number of EL 4 cells necessary for 100% tumor takes. Whole-body irradiation (400 rads) or complement depletion of tumor host by cobra venom factor had no effect on tumor suppression by ATG. No evidence of immunity against the EL 4 lymphoma could be detected in EL 4-bearing mice that survived after serotherapy. Anti-EL 4 sera raised in goats and goat and rabbit antisera raised against a lymphoma in the AKR mice have, so far, failed to show any tumor inhibition.

Animals↗
PubMed1989

Direct expression in E. coli of a functionally active protein A--snake toxin fusion protein.

We constructed a recombinant expression plasmid encoding a protein A--neurotoxin fusion protein. The fused toxin is directly expressed in the periplasmic space of Escherichia coli and can be purified in the milligram range by a single immuno-affinity step. The LD50 values of the fused toxin and native toxin are 130 and 20 nmol/kg mouse respectively. The Kd values characterizing their binding to the nicotinic acetylcholine receptor (AcChoR) are respectively 4.8 +/- 0.8 and 0.07 +/- 0.03 nM. In contrast, the fused and native toxins are equally well recognized by a toxin-specific monoclonal antibody which recognizes the AcChoR binding site. The lower toxicity of the fused toxin might result, therefore, from a steric hindrance, due to the presence of the bulky protein A moiety (mol. wt = 31 kd) rather than to a direct alteration of the 'toxic' site. The fused toxin is more immunogenic than native toxin, since 1 nmol of hybrid toxin and 14 nmol of native toxin give rise to comparable titers of antitoxin antibodies which, furthermore, are equally potent at neutralizing neurotoxicity. The work described in this paper shows that the use of fused toxins may be of paramount importance for future development of serotherapy against envenomation by snake bites.

Animals↗
PubMed1996

Severe envenoming by the Indian red scorpion Mesobuthus tamulus: the use of prazosin therapy.

We describe the clinical course and outcome in 46 victims of severe scorpion envenoming treated with prazosin (P), and compare them with earlier patients treated with conventional therapy (C) (n = 45) and nifepidine (N) (n = 28). The incidence of complicating left ventricular failure was 29% for C, 35% for N and 6.5% for P; that of acute pulmonary oedema was 46% for C, 14% for N and zero for P; mortality was 25% for C, 3.5% for N and zero for P. Although this is a historical study, prazosin appears to significantly reduce morbidity and shorten recovery time. Experience in other countries suggests that antivenom is helpful in controlling many of these problems, but in rural India serotherapy remains largely unavailable, and prazosin is a mainstay of treatment.

Adolescent↗
PubMed1993

Hematopoietic engraftment and graft failure after bone marrow transplantation.

PURPOSE: This article reviews the complex process of establishing functional long-term hematopoiesis required for successful clinical bone marrow transplantation. The failure to establish sustained hematopoiesis, either primary or secondary graft failure, is defined and multiple etiologic factors involved are discussed. DESIGN: Data from published studies of experimental and clinical BMT, as well as in vitro stem cell biology, were used to elucidate the elements required for establishing functional hematopoiesis. These include pleuripotential hematopoietic stem cells; homing of stem cell to the hematopoietic micro-environment; hematopoietic stroma and secreted cytokines acting synergistically to promote expansion and hematopoietic differentiation of the stem cells; and, in the setting of allogeneic transplantation, immunological tolerance between the host and the graft, without which graft rejection or graft-vs.-host disease may occur. CONCLUSIONS: The factors influencing the establishment of functional hematopoiesis and the risks for graft failure vary with the type of transplant performed. In an autologous transplant, damage to the stem cells or to the stromal microenvironment can contribute to prolonged time to engraftment or primary graft failure. In contrast, the hematopoietic stem cells are normal in both syngeneic and allogeneic transplantation. However, in the latter, because of immunological disparity between the host and recipient, there can be either primary or secondary graft failure due to a host-vs.-graft phenomenon, graft rejection. Classic graft rejection is an immunologic phenomenon mediated by residual host immunocompetent cells, either T cells or NK cells, depending on the allogeneic disparity between host and donor. T cell depletion and increased HLA disparity are risk factors for rejection. Numerous strategies have attempted to decrease the risk of rejection; most have focused primarily on increased immunosuppression of the host either with additional radiation, chemotherapy or in vivo anti-T cell serotherapy. Recent attempts have explored preventing rejection by manipulating donor cell composition of the infused graft.

Animals↗
PubMed2006

Understanding and making use of human memory B cells.

The work of our laboratory has focused on the study of human memory B cells. Using an in vitro approach we dissected the triggering requirements of B cells and unveiled a distinct role for TLRs in the activation of naive versus memory B cells. Using an ex vivo approach we analyzed the dynamics of memory B cells and ASCs and the kinetics of serum antibodies during secondary immune responses and in steady state conditions and used these quantitative data to build up a model of serological memory. According to this model memory B cells behave as ;stem cells' capable of generating plasma cells and antibodies in an antigen-dependent as well as in an antigen-independent fashion. Finally we developed an efficient method to interrogate human memory B cells and to isolate human monoclonal antibodies. This method can be exploited for the production of neutralizing antibodies for serotherapy and for "analytic vaccinology".

Animals↗
PubMed2005

Increased incidence of EBV-related disease following paediatric stem cell transplantation with reduced-intensity conditioning.

The incidence of Epstein-Barr virus (EBV) viraemia and lymphoproliferative disease (LPD) was studied in a consecutive cohort of 128 paediatric patients undergoing stem cell transplantation (SCT) with reduced-intensity conditioning (RIC; n = 65) or conventional-intensity conditioning (CIC; n = 68). Following CIC, six of 68 (8%) developed viraemia; all remained asymptomatic. EBV viraemia (23 of 65 patients = 35%, P < 0.001) and LPD (10 of 65 = 15%, P < 0.001) were significantly more frequent following RIC. Of the 23 RIC patients who developed viraemia, eight remained asymptomatic, five had symptomatic viraemia (fever +/- rash), and 10 patients developed LPD, two of whom died. An absolute lymphocyte count of <0.3 x 10(9)/l at the time of onset of viraemia was strongly predictive of development of LPD (P < 0.05) in this group. The incidence of viraemia was significantly higher in patients receiving serotherapy with antithymocyte globulin (ATG; 15 of 43, 35%) than Campath (12 of 73, 16.4%, P < 0.05). Primary immunodeficiency and acute graft-versus-host disease were associated with EBV viraemia in univariate analysis, but were not independent risk factors. In conclusion, EBV viraemia and LPD appear to be significantly more common in children following RIC SCT, particularly with selective depletion of recipient T cells relative to B cells following the use of ATG. This probably reflects the profound immunosuppression following RIC SCT, together with the incomplete ablation of recipient-derived B cells.

Adolescent↗
PubMed1996

Recognition of CD52 allelic gene products by CAMPATH-1H antibodies.

Cloning of the CD52 from a B-lymphocyte tumour cDNA library revealed two closely related sequences differing only at two amino acids C-terminal to the proposed point of glycosylphosphatidylinositol (GPI)-linkage. When transfected into CHO cells only one of these sequences gave high-level expression of the antigen recognized by the prototypic anti-CD52 antibody CAMPATH-1 whereas in JURKAT cells good expression levels were obtained with both sequences. Fusion of the sequence from the second sequence to DNA encoding the extracellular domain of CD4 indicated that this sequence was capable of directing GPI linkage. The possible implications for the function of CD52 and serotherapy with anti-CD52 antibodies are discussed.

Alemtuzumab↗
PubMed2006

Intrathecal vs. intramuscular administration of human antitetanus immunoglobulin or equine tetanus antitoxin in the treatment of tetanus: a meta-analysis.

BACKGROUND: Mortality caused by tetanus is still a serious health problem in developing countries. Apart from immunization, early treatment with equine antitetanus serum (ATS) or human tetanus immunoglobulin (TIG) is the real treatment that can avoid death. On pathophysiological grounds intrathecal administration would be preferred because of high concentrations of the antiserum in cerebrospinal fluid and thus around the nerve roots. Many studies concluded on its effectiveness whereas others did not find any superiority of this method. However, most of those studies were not random and/or had no sufficient weight. OBJECTIVE: To assess the efficacy of intrathecal therapy with ATS in neonates and adults. METHODS: Meta-analysis: Clinical trials were identified by searching Medline, the Cochrane library and Current Contents. Published randomized studies in English or French comparing intrathecal therapy and intramuscular therapy (IMS) were analysed with Revman, R, and Stata software. Treatment effects were evaluated by relative risk (RR) between intrathecal vs. intramuscular administration. RESULTS: A total of 942 patients were included in 12 trials, 484 in the intrathecal group and 458 in the intramuscular one. The combined RR of mortality for intrathecal vs. IMS was 0.71 (95% CI, 0.62-0.81). The superiority of intrathecal therapy also emerged when the analysis was performed in subcategories of both adults and neonates and for high and low dose of intrathecal serotherapy. Intrathecal administration of ATS or TIG is more beneficial than intramuscular administration in the treatment of tetanus.

Adult↗