James Cavet

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study

BACKGROUND Intravenous injection is the standard administration route of bortezomib; however, subcutaneous administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1·3 mg/m(2) dose and twice per week schedule in patients with relapsed multiple myeloma. METHODS This randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18 years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive up to eight 21-day cycles of bortezomib 1·3 mg/m(2), on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion. Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate (ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect. This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. FINDINGS 222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous group and 31 in intravenous group; ORR difference -0·4%, 95% CI -14·3 to 13·5), showing non-inferiority (p=0·002). After a median follow-up of 11·8 months (IQR 7·9-16·8) in the subcutaneous group and 12·0 months (8·1-15·6) in the intravenous group, there were no significant differences in time to progression (median 10·4 months, 95% CI 8·5-11·7, vs 9·4 months, 7·6-10·6; p=0·387) and 1-year overall survival (72·6%, 95% CI 63·1-80·0, vs 76·7%, 64·1-85·4; p=0·504) with subcutaneous versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26 [18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0·044), grade 2 or worse (35 [24%] vs 30 [41%]; p=0·012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0·026) was significantly less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated. INTERPRETATION Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with an improved safety profile. FUNDING Johnson & Johnson Pharmaceutical Research and Development, and Millennium Pharmaceuticals.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial

BACKGROUND Multicentric Castlemans disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castlemans disease. METHODS We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castlemans disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castlemans disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING Janssen Research & Development.

The fate of human Langerhans cells in hematopoietic stem cell transplantation.

Langerhans cells (LC) and other antigen-presenting cells are believed to be critical in initiating graft versus host responses that influence the outcome of allogeneic hematopoietic stem cell transplantation. However, their fate in humans is poorly understood. We have sought to define the effect of conditioning regimes and graft versus host disease (GVHD) on the survival of recipient LC and reconstitution of donor cells after transplant. Confocal microscopy of epidermal sheets shows that full intensity transplant (FIT) depletes LC more rapidly than reduced intensity transplant (RIT) at day 0, although the nadir is similar in both at 14–21 d. Recovery occurs rapidly within 40 d in the absence of acute GVHD, but is delayed beyond 100 d when GVHD is active. LC chimerism was determined in sex-mismatched transplants using a two-step Giemsa/fluorescence in situ hybridization assay on isolated cells. Acquisition of donor chimerism at 40 d is more rapid after FIT (97%) than RIT (36.5%), irrespective of blood myeloid engraftment. At 100 d, all transplants achieve at least 90% LC donor chimerism and over half achieve 100%. Complete donor chimerism is associated with prior acute cutaneous GVHD, suggesting a role for allogeneic T cells in promoting LC engraftment.

Donor interleukin 1 receptor antagonist genotype associated with acute graft-versus-host disease in human leucocyte antigen-matched sibling allogeneic transplants

Interleukin 1 (IL‐1) is involved in various autoimmune and inflammatory diseases. IL‐1 receptor antagonist (IL‐1Ra) is the naturally occurring antagonist to IL‐1α and ‐1β. Polymorphisms of IL‐1β have been associated with variations in IL‐1β production (nucleotides +3953 and −511). A variable number tandem repeat (VNTR) polymorphism in the IL‐1Ra gene has been associated (allele 2) with increased IL‐1Ra production. We examined these polymorphisms in human leucocyte antigen (HLA)‐matched allogeneic bone marrow transplant patients and donors. IL‐1Ra VNTR (allele 2) in the donor genotype was more frequent with milder acute graft‐versus‐host disease (aGvHD) grades 0–II (29 out of 59 transplants) than severe GvHD grades III–IV (2 out of 18 transplants) (P = 0·0032). This association was confirmed in a subgroup with cyclosporine monotherapy prophylaxis: donor possession of allele 2 was again associated with milder aGvHD, grades 0–II (19 out of 38 transplants), than grades III–IV (1 out of 14) (P = 0·0042) transplants. No association was found between the IL‐1β−511 or IL‐1β+3953 polymorphism and severity of GvHD. Recipient IL‐1Ra VNTR genotype (allele 2) showed a strong trend towards association with aGvHD severity (P = 0·0697). Thus, the donor genotype for the IL‐1Ra polymorphism has an apparent protective role against acute GvHD following transplantation and may be an additional factor for individual risk assessment for complications, including GvHD, post transplant.

Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes

The introduction of reduced‐intensity conditioning (RIC) has enabled the role of allogeneic transplantation to be re‐evaluated in Hodgkin lymphoma (HL). While T‐cell depletion reduces graft‐versus‐host disease (GvHD), it potentially abrogates graft‐versus‐tumour activity and increases infective complications. We compared the results in 67 sibling donor transplantations following RIC in multiply relapsed patients from two national phase II studies conditioned with fludarabine/melphalan. One used cyclosporine/alemtuzumab (MF‐A, n = 31), the other used cyclosporine/methotrexate (MF, n = 36) as GvHD prophylaxis. There was a small excess of chemorefractory cases in the MF cohort (P = NS). MF‐A resulted in significantly lower incidences of non‐relapse mortality, acute and chronic GvHD, but no significant excess of relapse/progression. Post donor lymphocyte infusion (DLI) disease responses occurred in 8/14 (57%) and 6/11 (55%) patients in the MF‐A and MF groups, respectively. Current progression‐free survival (CPFS) was superior with MF‐A (univariate analysis), with durable responses to DLI contributing to the favourable outcome (43% vs. 25%, P = 0·0356). Disease status at transplantation significantly influenced overall survival (P = 0·0038) and CPFS (P = 0·0014), retaining significance in multivariate analyses, which demonstrated a trend towards improved CPFS with T‐cell depletion (P = 0·0939). These data suggest that alemtuzumab significantly reduced GvHD without resulting in a deleterious impact on survival outcomes following RIC in HL, and that durable responses to DLI may be more common following the inclusion of alemtuzumab in the conditioning protocol.

Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin's lymphoma following autologous stem cell transplantation

This study compares outcome of reduced-intensity conditioned transplant (RIT) with outcome of conventional non-transplant therapy in patients with Hodgkins lymphoma relapsing following autograft. There were 72 patients in two groups who had relapsed, and received salvage therapy with chemotherapy±radiotherapy. One group (n=38) then underwent alemtuzumab-containing RIT. The second group—historical controls (n=34), relapsing before the advent of RIT—had no further high-dose therapy. This group was required to respond to salvage therapy and live for over 12 months post-relapse, demonstrating potential eligibility for RIT, had this been available. Overall survival (OS) from diagnosis was superior following RIT (48% at 10 years versus 15%; P=0.0014), as was survival from autograft (65% at 5 years versus 15%; P⩽0.0001). For the RIT group, OS at 5 years from allograft was 51%, and in chemoresponsive patients was 58%, with current progression-free survival of 42%. Responses were seen in 8 of 15 patients receiving donor lymphocyte infusions (DLI) for relapse/progression, with durable remission in five patients at median follow-up from DLI of 45 months (28–55). These data demonstrate the potential efficacy of RIT in heavily pre-treated patients whose outlook with conventional therapy is dismal, and provide evidence of a clinically relevant graft-versus-lymphoma effect.

Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation

We investigated the role of polymorphism of the vitamin D receptor (VDR) gene in HLA-matched sibling BMT for polymorphisms previously associated with human disease pathology. In intron 8 of the VDR gene, the B and A alleles of the BsmI and ApaI RFLPs were found to associate with reduced aGVHD when present in the patients genotype. Logistic regression analysis demonstrated that patient VDR genotype, along with previously identified IL-10−1064 and IFN-γ genotype to be risk factors for severe acute GVHD. The A allele also associates with increased likelihood of death when present in the donor genotype (AA vs Aa or aa, hazard ratio 2.03, P = 0.0232). In patients who received increased prophylaxis with multi-agent therapy, patients whose graft was from a donor with an AA genotype had a substantially worse survival than patients whose graft was from a donor with a non-AA genotype (hazard ratio 12.93, P < 0.0001). Analysis of VDR genotype in prospective BMT recipients could indicate patients at risk of severe aGVHD. Analysis of VDR genotype in prospective BMT donors may identify individuals who have greater transplant-related mortality, and also allow appropriately restricted use of increased immunosuppressive prophylaxis.

Active CMV disease does not always correlate with viral load detection

The use of quantitative cytomegalovirus (CMV) real-time polymerase chain reaction (RT-PCR) and preemptive ganciclovir therapy is replacing prophylaxis as the management of choice in high-risk patients undergoing stem cell transplantation (SCT). However, there are limited data defining its role in this setting. In the current retrospective single-centre study, quantitative RT-PCR was used to determine CMV in 577 consecutive patients undergoing SCT (172 allogeneic and 405 autologous) over a 5-year period. CMV RT-PCR was performed weekly until cessation of immunosuppression (allogeneic) or for 30 days post-SCT (autologous). Treatment was commenced after two consecutive positive results or a high copy on the first occasion (>1000 copies/ml, >3 log). The overall CMV reactivation rate in patients undergoing allogeneic SCT was 30%, with reactivation observed in 72% of high-risk patients (recipient positive patients). CMV end-organ disease was observed in eight patients (1%); of these, four were CMV RT-PCR negative at the time of diagnosis of end-organ CMV disease, with three remaining negative throughout the course of the disease. CMV-related mortality was recorded in three patients. The current data support a preemptive treatment strategy-based CMV RT-PCR, but indicate that in symptomatic patients, a negative CMV PCR result does not exclude CMV end-organ disease.

Polymorphisms of interleukin-1α constitute independent risk factors for chronic graft-versus-host disease after allogeneic bone marrow transplantation

Summary. The interleukin‐1 (IL‐1) family of cytokines is widely involved in inflammatory processes and diseases with an inflammatory component. Polymorphisms of the IL‐1α, IL‐1β and IL‐1Ra genes have been implicated in a number of autoimmune or inflammatory conditions, with polymorphism of the IL‐1Ra gene showing association with severity of graft‐versus‐host disease (GVHD) after allogeneic bone marrow transplantation (BMT). We compared the clinical outcomes (GVHD and survival) of 115 patients after human leucocyte antigen (HLA)‐identical sibling allogeneic BMT with their genotype for two polymorphisms present in the IL‐1α gene, which have been implicated in immune‐related pathology. Possession of allele 2 of the IL‐1α−889 polymorphism and allele 2 of the IL‐1α variable number tandem repeat (VNTR) polymorphism in the donor genotype was associated with the occurrence of chronic, but not acute GVHD. A local normal population was also genotyped for these polymorphisms, and subsequent analysis identified conserved haplotypes in this gene region. Haplotypes containing allele 2 at both IL‐1α−889 and IL‐1α VNTR loci were extremely uncommon, suggesting that both risk alleles would be inherited independently. Both loci could therefore function as independent disease association markers. The polymorphisms of the IL‐1α gene could be used to predict chronic GVHD in HLA‐matched sibling transplants alongside clinical risk factors.

Oestrogen receptor |[alpha]| gene polymorphism associates with occurrence of graft-versus-host disease and reduced survival in HLA-matched sib-allo BMT

Summary:Oestrogen receptors mediate the cellular response to oestrogens and related compounds and promote a wide range of effects on haemopoiesis. Polymorphisms of the oestrogen receptor genes have previously been associated with variation in bone mineral density, likelihood of fractures, risk of developing Alzheimers disease, endometrial cancer and response to hormone replacement therapy. We examined the polymorphisms in both ERα and ERβ genes in 108 patients receiving a bone marrow transplant from an HLA-matched sibling donor, and compared ER genotype with outcomes of occurrence of graft-versus-host disease (GVHD) and survival using logistic regression analysis. Polymorphism of ERα (presence of the PX haplotype (PvuII–XbaI RFLP) of intron 1), but not ERβ, in the patient genotype associates with occurrence of acute GVHD and with lower overall survival, following correction for known clinical and genotypic risk features. Analysis of ER genotype prior to transplant might therefore inform on a patients likelihood of developing post-transplant complications. Variation in transplant performance because of ER genotype suggests an underlying role for oestrogens in the pathophysiology of transplant-related complications, and suggests that oestrogen-related therapy may offer a new modality of post-transplant support.