Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell ...transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma.
We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score.
In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P=0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P=0.02). At 72 months, Kaplan-Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P=0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P=0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group.
Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530 .).
Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The incidence of cSCC is increasing globally and the prognosis of metastatic disease is poor. Currently ...there are no specific targeted therapies for advanced or metastatic cSCC. We have previously shown abundant expression of the complement classical pathway C1 complex components, serine proteases C1r and C1s in tumor cells in invasive cSCCs in vivo, whereas the expression of C1r and C1s was lower in cSCCs in situ, actinic keratoses and in normal skin. We have also shown that knockdown of C1s expression results in decreased viability and growth of cSCC cells by promoting apoptosis both in culture and in vivo. Here, we have studied the effect of specific IgG2a mouse monoclonal antibodies TNT003 and TNT005 targeting human C1s in five primary non-metastatic and three metastatic cSCC cell lines that show intracellular expression of C1s and secretion of C1s into the cell culture media. Treatment of cSCC cells with TNT003 and TNT005 significantly inhibited their growth and viability and promoted apoptosis of cSCC cells. These data indicate that TNT003 and TNT005 inhibit cSCC cell growth in culture and warrant further investigation of C1s targeted inhibition in additional in vitro and in vivo models of cSCC.
Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of ...the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.
Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (⩾18 ...years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.
Assessing patient eligibility for hematopoietic stem cell transplantation (HSCT) remains a complex, multifaceted challenge. Among these challenges, the paucity of comprehensive clinical data to guide ...decision making remains problematic coupled with unclear trade-offs between patient, disease and local HSCT center factors. Moreover, it is unclear that the modification of poor patient characteristics will improve post-HSCT outcomes. However, the use of Comorbidity Indices and Comprehensive Geriatric Assessments helps meet this challenge, but may be limited by overlapping patient characteristics. The increasing consideration for pre-HSCT psychosocial assessments and interventions remains to be studied. Ultimately, the decision to proceed with a HSCT remains interdisciplinary while considering the available evidence discussed in this review.
Chronic autoimmune demyelinating neuropathies are a group of rare neuromuscular disorders with complex, poorly characterized etiology. Here the authors describe a phenotypic, human‐on‐a‐chip (HoaC) ...electrical conduction model of two rare autoimmune demyelinating neuropathies, chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN), and explore the efficacy of TNT005, a monoclonal antibody inhibitor of the classical complement pathway. Patient sera is shown to contain anti‐GM1 IgM and IgG antibodies capable of binding to human primary Schwann cells and induced pluripotent stem cell‐derived motoneurons (MNs). Patient autoantibody binding is sufficient to activate the classical complement pathway, resulting in detection of C3b and C5b‐9. A HoaC model, using a microelectrode array with directed axonal outgrowth over the electrodes treated with patient sera, exhibits reductions in MN action potential frequency and conduction velocity. TNT005 rescued the serum‐induced complement deposition and functional deficits while treatment with an isotype control antibody has no rescue effect. These data indicate that complement activation by CIDP and MMN patient serum is sufficient to mimic neurophysiological features of each disease and that complement inhibition with TNT005 is sufficient to rescue these pathological effects and provide efficacy data included in an investigational new drug application, demonstrating the model's translational potential.
This manuscript presents a novel in vitro human‐on‐a‐chip system to 1) investigate multifocal motor neuropathy and chronic inflammatory demyelinating polyneuropathy patient sera‐mediated changes in peripheral motoneuron conduction velocity due to complement deposition. 2) A novel C1s inhibitor's ability to prevent complement deposition and reverse the conduction block. 3) An IND to the FDA is filed utilizing these results, which led to an authorization of a clinical trial.
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