Biomedical subjects

Aaron P Rapoport

Publications and source records attributed to Aaron P Rapoport.

12 recordsLinked to original sources

PubMed2007

Treatment and outcomes of post-transplant lymphoproliferative disease: a single institution study.

Post-transplant lymphoproliferative disorders (PTLD) complicate up to 10% of solid organ transplants. This retrospective study was conducted to review the PTLD experience among 2,300 recipients of solid organ or allogeneic bone marrow transplants from a single institution. Twenty-seven cases of PTLD were identified, leading to an overall incidence of 1.2%. Polymorphic B cell hyperplasia/lymphoma was the most common type. The median time to development of PTLD was 8.4 months. Ten patients had localized (stage I or II) disease, and 12 patients presented with B symptoms. Nine patients each were treated with systemic chemotherapy or surgical resection as part of the initial therapy. After a median follow-up duration of 2.6 years, the median survival has not been reached. There were no late relapses of PTLD, and 17 patients remain alive. Age, sex, organ source, LDH, stage, presence of extranodal disease, or presentation with B symptoms did not influence overall survival when examined by Cox proportional hazard model. Thirteen patients retained their graft function throughout PTLD treatment. This study confirms the ability to treat a significant proportion of PTLD patients with chemotherapy or surgical resection (depending on presentation), without sacrificing graft function in those receiving chemotherapy.

Adult↗

PubMed2006

Phase I trial of first-line bortezomib/thalidomide plus chemotherapy for induction and stem cell mobilization in patients with multiple myeloma.

BACKGROUND: In preclinical studies, bortezomib was shown to suppress tumor growth, sensitize malignant cells to apoptosis, and reverse chemotherapy resistance. PATIENTS AND METHODS: We evaluated the addition of escalating doses of bortezomib 0.7, 1, and 1.3 mg/m2 intravenously on days 1, 4, and 8 to DT-PACE (cisplatin 10 mg/m2, doxorubicin 10 mg/m2, cyclophosphamide 400 mg/m2, and etoposide 40 mg/m2 per day by intravenous continuous infusion on days 1-4) plus oral dexamethasone 40 mg on days 1-4 and thalidomide 200 mg on days 1-8 in newly diagnosed patients with multiple myeloma. Peripheral blood stem cells were collected after cycle 1. Twelve patients completed the study, and all received autologous stem cell transplantation (SCT). RESULTS: Hematologic toxicities were predictable, with 3 episodes of neutropenic fever. Grade >/= 2 nonhematologic toxicities included diarrhea (n = 1), deep vein thrombosis (n = 2), hypotension (n = 2), syncope (n = 1), and peripheral neuropathy (n = 3). The median number of CD34+ cells collected was 20.57 x 10 superset6 CD34+ cells/kg. After 2 cycles, 10 of 12 patients exhibited a partial response or better. Best response after autologous SCT, complete response/near complete response was exhibited in 9 patients, and partial response was exhibited in 3 patients. At a median of 20 months, 4 patients experienced relapse and 1 had died. Bortezomib/DT-PACE compared favorably with DT-PACE with regard to leukapheresis days, total CD34+ cell collection, and engraftment. CONCLUSION: This novel strategy of simultaneous proteasome inhibition in combination with thalidomide and chemotherapy was effective and safe, allowing for adequate stem cell collection and early autologous SCT; its impact on overall survival, especially in patients with high-risk myeloma, awaits further investigation.

Adult↗

PubMed2005

Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer.

Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.

Adoptive Transfer↗

PubMed2005

Expression of PDZ-binding kinase (PBK) is regulated by cell cycle-specific transcription factors E2F and CREB/ATF.

Earlier we reported that a novel mitotic protein kinase, PDZ-binding kinase (PBK), is expressed in primary hematopoietic neoplasms. Recent reports have suggested a role for PBK in mitotic progression. In the present study, we demonstrate that PBK is down regulated during doxorubicin induced growth arrest of HL60 promyelocytic leukemia cells at least partly due to cell cycle-specific transcriptional regulation. Furthermore, we show that transcriptional control is mostly due to binding of transcription factors E2F and CREB/ATF to two distinct binding sites within the PBK promoter. This was demonstrated by: (i) electrophoretic mobility shift assays showing transcription factor binding within the PBK promoter at the putative E2F (-146bp) and CREB/ATF (-312bp) binding sites; (ii) Western immunoblot analysis of knockdown extracts from siRNA inhibition of transcription factor expression showing that PBK protein expression is dependent upon the presence of these transcription factors; (iii) codistribution of CREB factor and PBK in cell lines of disparate tissue origin; and (iv) luciferase reporter assays showing that PBK promoter activity is dependent on factor binding at intact E2F and CREB/ATF sites. These findings may provide insight into the mechanisms that upregulate PBK expression in proliferative hematologic malignancies and down regulate its expression following growth arrest of leukemic cells.

Activating Transcription Factors↗

PubMed2005

Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients.

PURPOSE: Bcl-2 regulates the mitochondrial apoptosis pathway that promotes chemotherapy resistance. Bcl-2 antisense oligonucleotide, G3139, targets Bcl-2 mRNA. PATIENTS AND METHODS: G3139 was administered (3 to 7 mg/kg/d for 7 days) by continuous intravenous infusion. On day 4, patients started thalidomide (100 to 400 mg as tolerated) and dexamethasone (40 mg daily for 4 days) on 21-day cycles for three cycles. Stable and responding patients continued on 35-day cycles for 2 years. RESULTS: Thirty-three patients (median age, 60 years; range, 28 to 76 years) received 220 cycles. Patients received a median of three prior regimens including thalidomide (n = 15) and stem-cell transplantation (n = 31). The regimen was well tolerated; the median number of cycles per patient was eight (range, one to 16+ cycles). Toxicities included reversible increase in creatinine, thrombocytopenia, neutropenia, fatigue, anorexia, constipation, fever, neuropathy, edema, electrolyte disturbances, and hyperglycemia. Fifty-five percent of patients had objective responses, including two complete responses (CRs), four near CRs (positive immunofixation), and 12 partial responses; six patients had minimal responses (MRs). Of patients who received prior thalidomide, seven had objective responses, and three had MRs. The median duration of response was 13 months, and estimated progression-free and overall survival times were 12 and 17.4 months, respectively. Responding patients had significant increase in polyclonal immunoglobulin M (P = .005), indicating innate immune system activation. Western blot analysis of Bcl-2 protein isolated from myeloma cells before and after G3139 demonstrated a decrease of Bcl-2 levels in three of seven patients compared with six of nine patients using reverse transcriptase polymerase chain reaction. CONCLUSION: G3139, dexamethasone, and thalidomide are well tolerated and result in encouraging clinical responses in relapsed multiple myeloma patients.

Adult↗

PubMed2005

Catastrophic antiphospholipid syndrome: atypical presentation in the setting of chronic graft versus host disease: case report and review of the literature.

A 44-year-old female developed a catastrophic thrombotic syndrome following allogeneic stem cell transplantation for acute lymphoblastic leukemia. In the context of chronic graft versus host disease, she developed a lethal multi-system thrombotic state as evidenced by stroke, renal failure and cardiac thrombi in association with elevated anticardiolipin antibody. The case is discussed in the framework of the existing literature and derives clinical practice recommendations for this rare but clinically devastating entity.

Adult↗

PubMed2004

Phase I clinical trial of the inosine monophosphate dehydrogenase inhibitor mycophenolate mofetil (cellcept) in advanced multiple myeloma patients.

PURPOSE: Inosine monophosphate dehydrogenase (IMPDH) inhibitors have been used to induce leukemia blast cell differentiation but have not been tested in multiple myeloma for activity. Currently, available IMPDH inhibitor, mycophenolate mofetil (MMF), which is known as an immunosuppressant, was shown to induce apoptosis in myeloma cell lines. On the basis of our preclinical studies, we designed a clinical study to test our hypothesis that MMF has antimyeloma activity. EXPERIMENTAL DESIGN: A Phase I MMF dose escalation study was conducted in relapsed and refractory myeloma patients who had documented disease progression by myeloma markers or bone marrow plasmacytosis to determine the maximum tolerated dose, toxicities, and efficacy of the drug. To assess the activity of IMPDH inhibition in the myeloma cells of patients, we measured intracellular nucleotide triphosphate levels by high-performance liquid chromatography-based analysis and examined the correlation with clinical response. RESULTS: Among the 11 study patients, MMF was generally well tolerated and was administered up to a maximum dose of 5 g/day. The most common toxicity was grade 1 fatigue (n = 4, 36%). One patient had a partial response (3 g/day), four patients had stable disease, and six patients had progression of disease. There was a statistically significant difference in the intracellular dGTP level changes between the stable disease/partial response group versus progression of disease. CONCLUSIONS: MMF at 1 to 5 g/day daily dose is well tolerated by patients with relapsed and refractory multiple myeloma patients. Positive correlation between clinical response and depletion of intracellular dGTP level was shown. Future drug development to target this enzyme maybe useful in treating myelomas.

Aged↗

PubMed2004

Double minute chromosomes in monoblastic (M5) and myeloblastic (M2) acute myeloid leukemia: two case reports and a review of literature.

Double minutes (dmin) are small, paired chromatin bodies that lack a centromere and represent a form of extrachromosomal gene amplification. Although they have been found in a variety of solid tumors, their presence in hematological malignancies, especially acute myeloid leukemia (AML), is rare. In addition, the presence of dmin may be a mechanism for upregulated oncogene expression and is generally associated with a poor prognosis. We describe two patients who had dmin at initial presentation of AML, including the first case of M5a with C-MYC amplification on dmin, and another case with C-MYC amplification as the only cytogenetic finding. We review here a total of 33 cases with dmin in AML. C-MYC was amplified by the dmin in 25 cases, while other putative oncogenes were amplified in the other 8.

Adult↗

PubMed2003

Timed sequential therapy of acute myelogenous leukemia in adults: a phase II study of retinoids in combination with the sequential administration of cytosine arabinoside, idarubicin and etoposide.

Clinical outcome in acute myeloid leukemia (AML) is unsatisfactory. One strategy to augment cytotoxicity is TST. All-trans retinoic acid (ATRA) down-regulates bcl-2 expression and heightens AML sensitivity to cytosine arabinoside (ara-C)-induced apoptosis in vitro. We designed a trial of ATRA plus ara-C-based TST in an attempt to enhance drug-induced apoptosis and clinical outcome. Between January 1998 and February 2000, 63 patients received induction TST (oral ATRA days 1-6, ara-C and idarubicin days 2-4, VP-16 days 9-11) followed by consolidation TST (ATRA, ara-C and idarubicin followed by a second ara-C infusion days 11-13). Complete remission (CR) was 60%, with higher rates for patients of <60 years (79%), de novo AML (70%), and non-adverse cytogenetics (81%). Median disease-free survival (DFS) for CR patients was 11.2 months (32% at 3+ years). For patients <60 years with de novo AML and non-adverse cytogenetics who underwent two-cycle TST, DFS was 67% at 3+ years. However, patients of age equal to 60 years and those with poor-risk disease features still have poor CR and DFS, despite the addition of ATRA.

Adult↗

PubMed2003

Flavonoid effects on normal and leukemic cells.

Quercetin and flavopiridol, both flavonoids which influence oxidative milieu, proliferation, and apoptosis of various cell types, were examined for their effects on acute myelogenous leukemic cells and normal progenitors. Both quercetin and flavopiridol inhibited the growth and viability of various acute myelogenous leukemia (AML) cell lines and AML blasts isolated afresh from patients with AML of various subtypes. The effects on inhibition of proliferation and decreased viability were also significant in normal CD34+ cells isolated from normal marrow donors. In certain AML cases, the effects of flavopiridol appeared to be mediated through activation of caspase 3, offering one possible mechanism for the apoptosis evident after exposure to flavopiridol as measured by annexin V expression. These flavonoid compounds might find use in various therapeutic settings in AML.

Adult↗

PubMed2003

Thrombotic microangiopathy in blood and marrow transplant patients receiving tacrolimus or cyclosporine A.

BACKGROUND: Cyclosporine A (CSA) and tacrolimus (FK-506) are both associated with thrombotic microangiopathy (TMA) in allogeneic BMT recipients, although it is not known which drug is more likely to cause the syndrome. The optimal treatment of BMT-associated TMA is also not known. STUDY DESIGN AND METHODS: To estimate the risks, predisposing factors, and outcomes of TMA, data were analyzed from two cohorts of BMT patients who had received CSA or FK-506 in our institution with the same clinical definition for TMA. TMA was diagnosed in 11 of 55 patients (CSA, 3 of 24; FK-506, 8 of 31). RESULTS: The daily risk of developing TMA was 0.12 percent for patients receiving CSA and 0.26 percent for those receiving FK-506 (p = 0.16, chi-square). Among patients receiving FK-506, sibling donor BMT recipients were as likely to develop TMA as matched unrelated donor recipients. Serum CSA and FK-506 concentrations were not elevated above the therapeutic range in most patients with TMA. The blood urea nitrogen to serum creatinine ratio was elevated in patients with TMA. Despite daily plasmapheresis, 9 of 11 patients died without resolution of TMA; however, the causes of death were multifactorial, including GVHD. Histologic evidence for TMA was absent in 1 patient who died with persistent clinical signs attributed to microangiopathy. CONCLUSIONS: In this study, a high incidence of TMA was found in patients receiving either CSA or FK-506 following BMT, with uniform diagnostic criteria and strict monitoring. Neither drug showed elevated levels in most patients with TMA. Plasmapheresis was unsuccessful in reversing most cases of TMA.

Adult↗

PubMedDate not supplied

Protein expression of PDZ-binding kinase is up-regulated in hematologic malignancies and strongly down-regulated during terminal differentiation of HL-60 leukemic cells.

PBK/TOPK is a recently identified 322 amino acid serine/threonine kinase that is phosphorylated during mitosis and may include p38 MAPK among its targets. Previous work has shown up-regulated expression of PBK/TOPK mRNA in a variety of tumor cell lines and fetal tissues, suggesting a role for this kinase in malignant cell proliferation. In this paper, PBK/TOPK protein expression was examined in a variety of primary hematologic neoplasms: PBK/TOPK was readily detected in 9 of 12 AML samples (75%), in 3 of 3 ALL samples, and in 1 sample each of a plasmacytoma and blastic type mantle cell lymphoma where it was strongly expressed. In contrast, PBK/TOPK was only weakly expressed in 2 samples of G-CSF-mobilized peripheral blood stem cells that were enriched in CD34+ progenitors by immunoselection. Furthermore, when HL-60 myeloid leukemic cells were differentiated with phorbol ester (TPA), PBK/TOPK protein expression was strongly down-regulated by 24 h. Under these same conditions, phosphorylated c-Myc was rapidly down-regulated (by 4 h), while the levels of cyclin D1 and phosphorylated p38 were constant. Notably, of 5 clinical samples that strongly expressed PBK/TOPK, 4 also strongly expressed phosphorylated c-Myc, while only 1 of 3 PBK/TOPK negative samples expressed phosphorylated c-Myc. These data show that PBK/TOPK protein is up-regulated in a variety of hematologic malignancies and may be involved in leukemic cell growth. Additional studies are warranted to determine if PBK/TOPK would be a valuable target for novel therapeutics. To this end, we also describe the derivation of clones of 293 (human embryonic kidney) cells, which carry an inducible kinase-defective mutant of PBK/TOPK. This model may be useful for studying the effects of down-regulated PBK/TOPK function.

Cell Differentiation↗