Allogeneic donor CCR5 Δ32 homozygous haemopoietic cell transplantation (HCT) provides the only evidence to date of long-term control of HIV infection. However, availability of conventional CCR5 Δ32 ...homozygous donors is insufficient to develop this as a therapeutic strategy further.
We present a 37-year-old patient with HIV-1 infection and aggressive lymphoma who had disease progression after five lines of radiochemotherapy including an autologous HCT, and in the absence of matched sibling donors, received an allogeneic HCT with four of six HLA-matched CCR5 Δ32 homozygous cord blood cells (StemCyte, Covina, CA), supported with purified CD34+ cells from a haploidentical sibling. Blood or tissue samples were obtained before and weekly after HCT to monitor transplant and HIV infection, including chimerism analysis, CCR5 genotyping and viral tropism, viral isolation and sequence, viral reservoir analysis, immune activation and proliferation, and ex-vivo cell infectivity assays. Combined antiretroviral therapy continued during the procedure.
The patient's HIV was CCR5-tropic by genotypic and phenotypic analyses. Baseline latent reservoir tests showed HIV DNA copies in bulk and resting CD4 T cells and in gut-associated lymphoid tissue, CD4 T-cell-associated HIV RNA, replication competent viral size of 2·1 copies per 10(7) CD4 T cells, and single copy assay of 303 copies per mL. After HCT, plasma HIV DNA load was undetectable by ultrasensitive analyses. Upon cord blood full chimerism, the patient's CCR5 Δ32 homozygous CD4 T cells responded to proliferation and activation stimuli and became resistant to infection by the patient's viral isolate and by laboratory-adapted HIV-1 strains. Death related to lymphoma progression regretfully prevented long-term monitoring of the patient's viral reservoir.
CCR5 Δ32 homozygous cord blood reconstitution can successfully eliminate HIV-1 and render the allogeneic graft recipient's T lymphocytes resistant to HIV infection. Thus, they build on the evidence available to strongly support the use of cord blood as a strategic platform for a broader application of non-functional CCR5 transplantation to other infected individuals.
Spanish Secretariat of Research, the American Foundation for AIDS Research (amfAR).
Background Primary cutaneous marginal zone B-cell lymphomas are low-grade lymphomas running an indolent course. Skin relapses have been frequently reported but little information about disease-free ...survival (DFS) is available. Objective We sought to evaluate relapse rate and DFS in patients with primary cutaneous marginal zone B-cell lymphomas. Methods Clinical features, European Organization for Research and Treatment of Cancer/International Society for Cutaneous Lymphomas stage, light chain restriction, clonality, treatments, skin relapses, DFS, stage progression, extracutaneous disease, and outcome are analyzed in a series of 137 patients. Results Patients were classified as solitary lesion (T1) (n = 70; 51%), regional skin involvement (T2) (n = 40; 29%), and generalized skin lesions (T3) (n = 27; 20%). Surgical excision, local radiotherapy, or a combination were the initial treatment in 118 patients (86%). In 121 of 137 patients (88%) a complete remission was observed after initial treatment, including 99 of 106 patients (93%) with solitary or localized disease and 22 of 31 patients (71%) with multifocal lesions. Cutaneous relapses were observed in 53 patients (44%). Median DFS was 47 months. Patients with multifocal lesions or T3 disease showed higher relapse rate and shorter DFS. No significant differences were observed between surgery and radiotherapy, but surgery alone was associated with more recurrences at initial site. Overall survival at 5 and 10 years was 93%. Six patients (4%) developed extracutaneous disease during follow-up. Limitations This was a case series retrospective study. Conclusion Our results support long-term follow-up in patients with primary cutaneous marginal zone B-cell lymphomas. Disseminated skin lesions have higher relapse rate and shorter DFS suggesting further investigation on systemic therapies in such a group of patients.
Objective To review and summarize the information available on the effectiveness and safety of biological therapies in refractory Felty's syndrome (FS). Methods We describe a case of FS with severe ...neutropenia and recurrent bacterial infections unresponsive to disease-modifying antirheumatic drug treatment and long-term administration with granulocyte colony-stimulating factor, in which treatment with rituximab (RTX) was useful and resulted in a sustained neutrophil response. Current evidence on the use of biological therapies in FS is also analyzed through a systematic review of the English-language literature, based on a PubMed search. Results Available data on the use of biological therapies in refractory FS are based only on several case reports and are limited to the use of RTX and some anti-tumor necrosis factor α agents (etanercept, infliximab, and adalimumab). Including the case described here, data are available on 8 patients treated with RTX. A sustained increase in the absolute neutrophil count (>1500/mm3 ) was observed in 62.5% (5/8) of these patients after 1 cycle of treatment. In most of them, the hematological response was accompanied by a parallel improvement in biological markers of inflammation and other clinical manifestations of FS (arthritis, recurrent infections, systemic symptoms, etc). After a median follow-up of 9 months (range, 6-14), only 1 of these patients relapsed and neutropenia reappeared; in this patient, retreatment was rapidly effective. No significant adverse events related to RTX therapy were reported. Experience with anti-tumor necrosis factor agents is limited to 6 patients, none of whom presented any sustained increase in neutrophil count. Conclusions Although it is not yet possible to make definite recommendations, the global analysis of all cases reported to date only supports the use of RTX as a second-line therapy in patients with refractory FS.
