H Waldmann

Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis

The elective treatment of patients with multiple sclerosis, using a humanized anti-leukocyte (CD52) monoclonal antibody (Campath-1H), has illuminated mechanisms that underlie the clinical course of the disease. Twenty-seven patients were studied clinically and by magnetic resonance imaging (MRI) before and for 18 months after a single pulse of Campath-1H. The first dose of monoclonal antibody was associated with a transient rehearsal of previous symptoms caused by the release of mediators that impede conduction at previously demyelinated sites; this effect remained despite selective blockade of tumor necrosis factor-alpha. Disease activity persisted for several weeks after treatment but thereafter radiological markers of cerebral inflammation were suppressed for at least 18 months during which there were no new symptoms or signs. However, about half the patients experienced progressive disability and increasing brain atrophy, attributable on the basis of MRI spectroscopy to axonal degeneration, which correlated with the extent of cerebral inflammation in the pretreatment phase. These data support the formulation that inflammation and demyelination are responsible for relapses of multiple sclerosis; that inflammatory mediators, but not tumor necrosis factor-alpha, cause symptomatic reactivation of previously demyelinated lesions; and that axonal degeneration, conditioned by prior inflammation but proceeding despite its suppression, contributes to the progressive phase of disability. These results provide evidence supporting the emerging view that treatment in multiple sclerosis must be given early in the course, before the consequences of inflammation are irretrievably established.

The window of therapeutic opportunity in multiple sclerosis: evidence from monoclonal antibody therapy.

AbstractFrom 1991–2002, we treated 58 patients with multiple sclerosis (MS) using the humanised monoclonal antibody, Campath–1H, which causes prolonged T lymphocyte depletion. Clinical and surrogate markers of inflammation were suppressed. In both the relapsing–remitting (RR) and secondary progressive (SP) stages of the illness, Campath–1H reduced the annual relapse rate (from 2.2 to 0.19 and from 0.7 to 0.001 respectively; both p < 0.001). Remarkably, MRI scans of patients with SP disease, treated with Campath–1H 7 years previously, showed no new lesion formation. However, despite these effects on inflammation, disability was differently affected depending on the phase of the disease. Patients with SPMS showed sustained accumulation of disability due to uncontrolled progression marked by unrelenting cerebral atrophy, attributable to ongoing axonal loss. The rate of cerebral atrophy was greatest in patients with established cerebral atrophy and highest inflammatory lesion burden before treatment (2.3 versus 0.7 ml/year; p = 0.04). In contrast, patients with RR disease showed an impressive reduction in disability at 6 months after Campath–1H (by a mean of 1.2 EDSS points) perhaps owing to a suppression of on–going inflammation in these patients with unusually active disease. In addition, there was a further significant, albeit smaller, mean improvement in disability up to 36 months after treatment.We speculate that this represents the beneficial effects of early rescue of neurons and axons from a toxic inflammatory environment, and that prevention of demyelination will prevent long–term axonal degeneration. These concepts are currently being tested in a controlled trial comparing Campath–1H and IFN–beta in the treatment of drug–naïve patients with early, active RR MS.

Respiratory virus infections in transplant recipients after reduced‐intensity conditioning with Campath‐1H: high incidence but low mortality

Summary. Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath‐1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45·7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4·1, P = 0·01] which were often recurrent in patients with severe acute or chronic graft‐versus‐host disease (GVHD) (OR 10·6, P = 0·03). Infection within the first 100 d (OR 5·0, P = 0·05) and PIV 3 (OR 9·2, P = 0·01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced‐intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T‐cell subset in this setting might also have been contributory factors.

Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM–CAMPATH conditioning: an effective regimen with low procedure‐related toxicity

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure‐related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti‐CD52 antibody CAMPATH‐1G from day −5 to day −1.

The effect of the serotherapy regimen used and the marrow cell dose received on rejection, graft-versus-host disease and outcome following unrelated donor bone marrow transplantation for leukaemia.

unrelated donor (ud) transplantation is the only potentially curative therapy for many leukaemia patients but is associated with a high mortality and morbidity. we sought to identify factors that could be optimised to improve outcome following ud transplantation in adults. data was retrospectively analysed on 55 patients sequentially receiving ud transplants for cml or acute leukaemia (al), all of whom received serotherapy for the prevention of gvhd and rejection. all patients received standard conditioning regimens. the first 28 patients transplanted also received combined pre- and post-transplant serotherapy with campath 1g (days −5 to +5) and standard dose csa plus mtx as gvhd prophylaxis (protocol 1). the subsequent 27 patients received a 5-day course of pre-transplant serotherapy alone either with atg (cml patients) or campath 1g (al patients) on days −5 to −1 inclusive, with high-dose csa plus mtx (protocol 2). the incidence of acute gvhd was low with no patient receiving either protocol developing >grade 2 disease. The use of protocol 2 and the administration of a bone marrow cell dose above the median (2.17 × 108/kg) were the most important factors predicting engraftment (P = 0.03 and P = 0.001, respectively) but this only remained significant for cell dose in multivariate analysis (P = 0.03). Overall survival for the group was 45% at 3 years and was influenced by both age (P = 0.02) and disease status at transplantation (P = 0.001). Receiving a cell dose above the median was also associated with a trend towards better survival (P = 0.08), due primarily to a reduction in the TRM to 8.2% compared with 54.5% in those receiving a lower cell dose (P = 0.002). We conclude that pre-transplant serotherapy alone is highly effective at preventing acute GVHD following UD BMT and that additional post-transplant serotherapy does not confer any benefit. Furthermore, a high marrow cell dose infused has a major effect in reducing transplant-related mortality following UD BMT. Bone Marrow Transplantation (2000) 25, 411–417.

CAMPATH-IH in multiple sclerosis.

In a pilot study, seven patients with multiple sclerosis were treated with CAMPATH-1H which targets the CD52 antigen present on lymphocytes and monocytes. There was a substantial reduction in disease activity as measured by gadoliunium-enhancing lesions on MRI. Encouraged by this result a further seven patients have been treated with CAMPATH-1H; four also received anti-CD4 antibody. Lymphopaenia developed rapidly and was sustained for at least one year. In 12 patients, the first infusion of antibody was characterised by significant exacerbation or re-awakening of pre-existing symptoms lasting several hours. These clinical effects of antibody treatment correlated with increased levels of circulating cytokines. Peak levels of tumour necrosis factor alpha (TNFα) and interferon gamma (IFNγ) occurred at 2 h whereas the rise in interleukin-6 (IL-6) was significantly delayed and peaked at 4 h after starting antibody treatment The neurological symptoms could not be attributed directly to pyrexia and were not provoked (in one patient) by an artificial rise in temperature. In the remaining two patients, a single pre-treatment with intravenous methylprednisolone (500 mg) prevented both the transient increase in neurological symptoms and the cytokine release. Our results suggest that soluble immune mediators contribute to symptom production in multiple sclerosis by directly or indirectly blocking conduction through partially demyelinated pathways.

In vivo CAMPATH-1H prevents GvHD following nonmyeloablative stem-cell transplantation

BACKGROUND We have investigated a novel nonmyeloablative conditioning regimen in 44 patients with hematological malignancies. The median patient age was 41 years. Many of the patients had high-risk features, including 19 patients with a previous failed transplant. METHODS Recipient conditioning consisted of CAMPATH-1H 20 mg/day on Days -8 to -4, fludarabine 30 mg/m(2) on Days -7 to -3 and melphalan 140 mg/m(2) on Day -2. Thirty-six recipients received unmanipulated G-CSF mobilized PBSC from HLA identical siblings and eight received unmanipulated BM from MUD. GvHD prophylaxis was with CYA alone for 38 patients and CYA plus MTX for six sibling recipients. RESULTS Forty-two of the 43 evaluable patients had sustained engraftment. Results of chimerism analysis using microsatellite PCR indicate that 18 of 31 patients studied were full donor chimeras, while the other patients were mixed chimeras in one or more lineages. At a median follow-up of 9 months (range, 3-29 months) 33 patients remain alive in CR, or with no evidence of disease progression. Seven patients relapsed or progressed post-transplant and four of them subsequently died. Four patients died from regimen-related complications. There were no cases of Grades III-IV acute GvHD. Only two patients developed Grade II acute GvHD and only one had chronic GvHD. The estimated probability of non-relapse mortality at 1 year was 11%.Results: Although longer follow-up is needed to establish the long-term remission rates, this study demonstrates that this nonmyeloablative preparative regimen is associated with durable engraftment, minimal toxicity and low incidence of GvHD.

Sustained remission of severe resistant autoimmune neutropenia with Campath-1H

We report the course of a patient with severe autoimmune neutropenia in whom only transient responses occurred with corticosteroids, antilymphocyte globulin and granulocyte‐colony stimulating factor, and who was resistant to treatment with azathioprine, cyclosporin and intravenous immunoglobulin. A 10 d course of intravenous Campath‐1H monoclonal resulted in a sustained haematological response. The long‐lasting effect of Campath‐1H may be due to its remarkable ability to induce a profound and prolonged peripheral blood T lymphopenia.

Excessive T cell depletion of peripheral blood stem cells has an adverse effect upon outcome following allogeneic stem cell transplantation

We evaluated the outcome of two modes of T cell depletion for HLA-identical sibling stem cell transplants in 34 consecutive adult patients: group A (n = 11) received PBSC post CliniMACs immuno-magnetic enrichment of CD34+ cells and group B (n = 23) received bone marrow following in vitro incubation with CAMPATH-1M and complement. All patients received an identical conditioning regimen which consisted of in vivoCAMPATH-1H 20 mg over 5 days, thiotepa 10 mg/kg, cyclophosphamide 120 mg/kg and 14.4 Gy TBI. No additional graft-versus-host disease prophylaxis was given. The mean T cell dose administered was 0.02 ± 0.05 × 106/kg for group A and 2.8 ± 2.8 106/kg for group B (P < 0.001). With a median follow-up of 28 months overall survival was 36.4% for group A at 12 months compared to 78.3% for group B (P = 0.001). Transplant-related mortality in group A at 12 months was 63.6% as compared to 18.0% in group B (P = 0.003). Most of the procedure-related deaths in group A occurred secondary to infection. These results suggest that extensive in vitro T cell depletion of peripheral blood stem cells in combination with in vivo T cell depletion may have profound effects upon the incidence of infections following allogeneic stem cell transplantation and this may adversely effect transplant-related mortality. Bone Marrow Transplantation (2001) 28, 827–834.

Myeloablative conditioning is well tolerated by older patients receiving T-cell-depleted grafts

Summary:Older age has been linked to increased transplant-related mortality from graft-versus-host disease (GvHD). Depletion of T cells from stem cell grafts seems to protect from complications of GvHD particularly in older patients. After myeloablative conditioning, patients with haematological malignancies received allogeneic grafts from HLA identical siblings. For GvHD prophylaxis, PBPC grafts were treated ex vivo with anti-CD52, and therapeutic doses of cyclosporin until day +90. Survival of patients younger or older than the population age median was analysed. In all, 62 consecutive patients with a median age of 42.5 years were studied. Death was procedure related in 17% and from relapse of malignancy in five. At a median, follow-up is 662 (7–2316) days, 74% survive disease free. The rate of haematopoietic recovery and treatment-related mortality was similar in both groups. A total of 73% of 30 individuals in the younger group and 75% (P=0.8) in the older cohort survive at a median follow-up of 444 and 806 days (P=0.4). GvHD occurred in 13% and was the only adverse factor for survival (P<0.04). Myeloablative conditioning is well tolerated up to the age of 59 in patients receiving T-cell-depleted grafts. This information is useful to more precisely select patients who would benefit most from reduced intensity conditioning schedules.