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ABSTRACT: Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations
in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant
family history of unexplained erythrocytosis spanning four generations of the patient’s family was established. The family
history was also significant for an apparent increased rate of cerebrovascular disease in individuals with erythrocytosis.
The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair
down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied
widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family
history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45
for our patient.
KeywordsErythropoietin–EPOR–Polycythaemia–PFCP
International Journal of Hematology 04/2012; 93(4):542-544. · 1.27 Impact Factor
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Antonio Di Stasi, Siok-Keen Tey,
Gianpietro Dotti,
Yuriko Fujita,
Alana Kennedy-Nasser,
Caridad Martinez,
Karin Straathof,
Enli Liu,
April G Durett,
Bambi Grilley,
Hao Liu,
Conrad R Cruz,
Barbara Savoldo,
Adrian P Gee,
John Schindler,
Robert A Krance,
Helen E Heslop,
David M Spencer,
Cliona M Rooney,
Malcolm K Brenner
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ABSTRACT: Cellular therapies could play a role in cancer treatment and regenerative medicine if it were possible to quickly eliminate the infused cells in case of adverse events. We devised an inducible T-cell safety switch that is based on the fusion of human caspase 9 to a modified human FK-binding protein, allowing conditional dimerization. When exposed to a synthetic dimerizing drug, the inducible caspase 9 (iCasp9) becomes activated and leads to the rapid death of cells expressing this construct.
We tested the activity of our safety switch by introducing the gene into donor T cells given to enhance immune reconstitution in recipients of haploidentical stem-cell transplants. Patients received AP1903, an otherwise bioinert small-molecule dimerizing drug, if graft-versus-host disease (GVHD) developed. We measured the effects of AP1903 on GVHD and on the function and persistence of the cells containing the iCasp9 safety switch.
Five patients between the ages of 3 and 17 years who had undergone stem-cell transplantation for relapsed acute leukemia were treated with the genetically modified T cells. The cells were detected in peripheral blood from all five patients and increased in number over time, despite their constitutive transgene expression. A single dose of dimerizing drug, given to four patients in whom GVHD developed, eliminated more than 90% of the modified T cells within 30 minutes after administration and ended the GVHD without recurrence.
The iCasp9 cell-suicide system may increase the safety of cellular therapies and expand their clinical applications. (Funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; ClinicalTrials.gov number, NCT00710892.).
New England Journal of Medicine 11/2011; 365(18):1673-83. · 53.30 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant family history of unexplained erythrocytosis spanning four generations of the patient's family was established. The family history was also significant for an apparent increased rate of cerebrovascular disease in individuals with erythrocytosis. The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45 for our patient.
International journal of hematology 03/2011; 93(4):542-4. · 1.17 Impact Factor
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ABSTRACT: Hepatosplenic T-cell lymphoma (HSTL) is an aggressive lymphoma. In post-transplant immunosuppressed patients, HSTL is usually rapidly fatal. We report successful treatment of post-transplant HSTL in a 50-year-old renal allograft recipient by reducing immunosuppression and using intensive chemotherapy consisting of alternating cycles of HyperCVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) and MTX/HiDAC (methotrexate, Ara-C). Remission is ongoing at 8+ years. Literature review identified another 20 cases of HSTL in solid organ transplant recipients: median survival was 4 months; no other patients survived beyond 12 months. Bone marrow involvement was universal, but changes were often subtle: 6 of 12 cases had nondiagnostic examinations earlier on. High index of suspicion may lead to more timely diagnosis of this uncommon form of post-transplant lymphoproliferative disorder, and treatment with intensive chemotherapy such as HyperCVAD may be curative.
American Journal of Hematology 05/2008; 83(4):330-3. · 4.67 Impact Factor
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ABSTRACT: Addback of donor T cells following T cell-depleted stem cell transplantation (SCT) can accelerate immune reconstitution and be effective against relapsed malignancy. After haploidentical SCT, a high risk of graft-versus-host disease (GVHD) essentially precludes this option, unless the T cells are first depleted of alloreactive precursor cells. Even then, the risks of severe GVHD remain significant. To increase the safety of the approach and thereby permit administration of larger T cell doses, we used a suicide gene, inducible caspase 9 (iCasp9), to transduce allodepleted T cells, permitting their destruction should administration have adverse effects. We made a retroviral vector encoding iCasp9 and a selectable marker (truncated CD19). Even after allodepletion (using anti-CD25 immunotoxin), donor T cells could be efficiently transduced, expanded, and subsequently enriched by CD19 immunomagnetic selection to >90% purity. These engineered cells retained antiviral specificity and functionality, and contained a subset with regulatory phenotype and function. Activating iCasp9 with a small-molecule dimerizer rapidly produced >90% apoptosis. Although transgene expression was downregulated in quiescent T cells, iCasp9 remained an efficient suicide gene, as expression was rapidly upregulated in activated (alloreactive) T cells. We have demonstrated the clinical feasibility of this approach after haploidentical transplantation by scaling up production using clinical grade materials.
Biology of Blood and Marrow Transplantation 09/2007; 13(8):913-24. · 3.87 Impact Factor
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ABSTRACT: Gene-marking studies were the first gene-transfer protocols approved for human use. Their intent was not directly therapeutic but rather to track the behavior and fate of cells in vivo, and to use this information to improve treatment protocols. For more than fifteen years, gene-marking studies using retroviral vectors have provided invaluable information about the biology of human hematopoietic cells and T lymphocytes, and have helped guide cell therapies intended to treat malignant disease. Although the safety record of marking studies has been impeccable, the development of leukemia by immunodeficient children treated with retroviral vectors cast a pall over the entire field and essentially brought the era of pure gene-marking studies to an abrupt end. Paradoxically, the impetus these events gave to studying retroviral integration sites in host cell DNA emphasized the additional information that marker studies could provide about the behavior of cells at the clonal level. As confidence has slowly returned, marker studies have reappeared, usually as components of gene therapy protocols in which a marker gene or sequence is incorporated to allow the modified cells to be tracked or imaged in vivo. Hence, gene marking continues to have much to offer in terms of our understanding of the behavior, fate, and safety of gene-modified cells in vivo.
Molecular Therapy 05/2007; 15(4):666-76. · 6.87 Impact Factor
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ABSTRACT: Adoptive T-cell therapy has definite clinical benefit in relapsed leukaemia after allogeneic transplant and in Epstein-Barr virus-associated post-transplant lymphoproliferative disease. However, the majority of tumour targets are weakly immunogenic self-antigens and success has been limited in part by inadequate persistence and expansion of transferred T cells and by tumour-evasion strategies. Adoptive immunotherapy presents the opportunity to activate, expand and genetically modify T cells outside the tolerising environment of the host and a number of strategies to optimize the cellular product, including gene modification and modulation of the host environment, in particular by lymphodepletion, have been developed.
Immunology and Cell Biology 07/2006; 84(3):281-9. · 3.66 Impact Factor
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ABSTRACT: Re-treatment with rituximab for B-cell non-Hodgkin's lymphoma (NHL) relapsing after previous rituximab therapy has recently been shown to be clinically efficacious. Although the mechanism of resistance to rituximab re-treatment in non-responding patients is unknown, it is possible that loss of CD20 expression in the relapsed NHL could be important in some patients. We examined the incidence and nature of CD20 negative relapses following rituximab therapy in aggressive B-cell NHL treated at our institution. Of a total of 18 patients who received rituximab, 13 have relapsed, with 10 patients subsequently undergoing repeat tissue biopsy. Six of these 10 patients (60%) were shown to have lost CD20 expression by either immunohistochemistry and/or flow cytometry. Furthermore, three of the six patients who relapsed with CD20-negative NHL also suffered relapses at unusual anatomical sites. We conclude that loss of CD20 expression in aggressive B-cell NHL relapsing post-rituximab therapy is common. As such, repeat tissue biopsy should be undertaken to document CD20 expression by both flow cytometry and immunohistochemistry prior to considering repeated courses of rituximab in relapsed aggressive lymphomas.
British Journal of Haematology 12/2002; 119(2):412-6. · 4.94 Impact Factor
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