Steven Pincus | Saint Louis University (original) (raw)

Papers by Steven Pincus

Biology of Blood and Marrow Transplantation, Feb 1, 2006

I 2 represents the precentage of unexplained heterogeneity.

PubMed, Feb 1, 1995

We report the occurrence of reversible cyclosporine-induced cortical blindness in three allogenei... more We report the occurrence of reversible cyclosporine-induced cortical blindness in three allogeneic bone marrow transplant recipients. Possible mechanisms involved in this rare complication, as well as the associated radiographic and pathologic findings, are discussed.

PubMed, Feb 1, 1997

High-dose chemotherapy is associated with a high complete response rate and possibly some surviva... more High-dose chemotherapy is associated with a high complete response rate and possibly some survival advantage in patients with metastatic breast cancer. We designed a clinical trial consisting of a two-step high-dose chemotherapy regimen followed by posttransplantation doxorubicin as the first chemotherapy treatment for metastatic disease. Twenty-one patients with metastatic breast cancer and no previous chemotherapy for metastatic disease were treated with high-dose cyclophosphamide (Cy; 5000 mg/m2), followed by granulocyte colony-stimulating factor. Peripheral blood stem cells were collected. Subsequently, patients received Cy (6000 mg/m2), thiotepa (500 mg/m2), and carboplatin (800 mg/m2) (CTCb) with hematopoietic rescue. Upon recovery of hematopoietic and gastrointestinal toxicity, three cycles of doxorubicin (Dox; 60 mg/m2) were delivered. After Cy, nine patients (45%) developed neutropenic fevers. There were no episodes of bacteremia. Patients received CTCb 37 days after starting Cy and had a hospital stay of 19 days. After CTCb, the median number of days to an absolute neutrophil count >5 x 10(9)/liter was 8, and the median number of days to a platelet count >20 x 10(9)/liter was 9. Neutropenic fevers occurred in 12 patients. There were no hemorrhagic complications. Fifty-five of the 63 planned courses of Dox were delivered. The median time from peripheral blood stem cell infusion to the first Dox cycle was 38 days. The median time to the second Dox cycle was 28 days, and to the last cycle was 30 days. Three episodes of neutropenic fevers were observed. Two patients developed herpes zoster. This regimen is feasible, with acceptable toxicity.

PubMed, Mar 1, 1996

Between July 1991 and January 1994, 52 patients with hematologic malignancies underwent BMT using... more Between July 1991 and January 1994, 52 patients with hematologic malignancies underwent BMT using BU/CY2 as conditioning regimen. Median patient age was 38 years. Eleven patients underwent autologous BMT, 22 HLA-identical allogeneic BMT, and 19 patients underwent a MUD or an allogeneic mismatched BMT. GVHD prophylaxis was with cyclosporine/methylprednisone in 26 patients; T cell depletion was used in 15 patients. VOD was observed in 7.5% of patients, IP in 12%, seizures in 4%. The overall incidence of grade II-IV acute GVHD was 35%. Delayed platelet engraftment was observed in seven of 11 patients who underwent autologous BMT. Graft failure was seen in seven of 19 (37%) patients who underwent MUD or allogeneic mismatched BMT. Six of the seven patients received T cell depletion as GVHD prophylaxis. BU/CY2 transplantation from an unrelated or family-mismatched donor with T cell depletion is associated with a high incidence of graft failure.

Annals of Oncology, Apr 1, 2001

Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase... more Combining topotecan with other cytotoxics has been problematic due to marrow suppression. A phase I trial was initiated to identify the optimal sequence and maximum-tolerated dose of topotecan in combination with paclitaxel and carboplatin. Patients with advanced cancer and performance status ECOG &amp;lt; or = 2. The starting dose was paclitaxel 175 mg/m2 day 1, carboplatin AUC 6.0 day 1, and topotecan 0.5 mg/m2 daily day 1-5 (early sequence). The next course of paclitaxel and carboplatin administration was delayed to day 5 (late sequence). Treatment was repeated every three weeks. After determining maximum-tolerated dose without cytokines, granulocyte colony-stimulating factor (G-CSF) was added and further dose escalation was pursued. Fifty-one patients were entered; men: women ratio 30:21. Dose-limiting toxicity (DLT) for the early sequence was neutropenia at doses paclitaxel mg/m2/carboplatin AUC 5/topotecan mg/m2 (PCT) 175/5/0.75 for four to five days. DLT for the late sequence was neutropenia at PCT doses of 175/5/ 1.0 for four days. G-CSF 5 microg/kg subcutaneously starting day 6 permitted further topotecan dose escalation. After adding G-CSF, late sequence DLT was neutropenia at doses 175/5/1.25 for four days. Forty-six patients were evaluable for response and of those, there were thirteen partial responses. The late sequence resulted in less toxicity and was better tolerated. The early sequence maximum-tolerated dose (MTD) was 175/6/0.5 for five days. The late sequence MTD was PCT 175/5/0.75 for five days. The late sequence MTD with G-CSF was 175/5/1.0 for four days. The recommended phase II PCT dose is the late sequence 175/5/1.0 for four days with G-CSF.

PubMed, Jun 1, 1995

Relapse after high-dose chemotherapy supported by peripheral blood stem cell transplantation (HDC... more Relapse after high-dose chemotherapy supported by peripheral blood stem cell transplantation (HDC-PBSCT) is the main cause of therapeutic failure in patients with lymphoma and breast cancer. Adoptive immunotherapy with activated natural killer (A-NK) cells and interleukin 2 might eliminate surviving residual tumor without adding to toxicity. Eleven patients with relapsed lymphoma and one with metastatic breast cancer were entered on a pilot clinical trial of HDC-PBSCT followed on day 2 after transplant by infusion of cultured autologous A-NK cells. Simultaneously, recombinant human interleukin 2 (rhIL-2) was initiated as a 4-day continuous i.v. infusion at 2 x 10(6) IU/m2/day, referred to as high-dose rhIL-2. Therapy with high-dose rhIL-2 was followed by a 90-day continuous i. v. infusion at 3 x 10(5) IU/m2/day, referred to as low-dose rhIL-2. All patients engrafted and nine completed treatment. Posttransplant days to a neutrophil count of 500/microliter and to a platelet count of 50,000/microliter were similar to comparable patients treated with HDC-PBSCT alone. Generation of A-NK cells for therapy was feasible in all patients except the three patients with Hodgkin's disease, whose cells did not proliferate in culture. Overall toxicity associated with early posttransplant transfer of A-NK cells and interleukin 2 did not differ from that observed with peripheral blood stem cell transplantation alone in comparable patients. There was early amplification of natural killer cell activity in the peripheral blood of four patients that appeared to result from the transfused A-NK cells. Adoptive transfer of A-NK cells and rhIL-2 during the pancytopenic phase after HDC-PBSCT was feasible and well tolerated, did not adversely affect engraftment, and resulted in amplified natural killer activity in the peripheral blood during the immediate posttransplantation period.

Gastroenterology, Apr 1, 2001

Cell Transplantation, 1993

The indications for bone marrow transplanta tion (BMT) continue to expand as supportive care impr... more The indications for bone marrow transplanta tion (BMT) continue to expand as supportive care improves and alternative stem cell sources have been exploited. The ap plication of allogeneic BMT has expanded to include unre lated histocompatibility antigen-matched donors and partially matched family donors. While the results of these transplants are not as good as those with sibling donors, these alternative donors allow curative therapy to be delivered to patients with leukemia, aplastic anemia, and immunodefi ciency diseases who otherwise would not be eligible for cu rative therapy. Autologous BMT has emerged as a curative therapy for patients with non-Hodgkin's lymphoma, Hodgkin's disease, acute myeloid leukemia, and acute lymphoblas tic leukemia. In addition, dose-intensive therapy with marrow or peripheral blood stem cell support to patients with Stage II, III, and IV breast carcinoma is under intense study in sin gle and multiple-institution studies. Important issues under active study are prophylaxis for graft-versus-host-disease, the role of marrow purging in autologous BMT, the use of cy tokine and chemotherapy-mobilized peripheral blood stem cells, and control of infectious diseases. This review summa rizes current results in both allogeneic and autologous bone marrow transplantation, issues in marrow graft manipula tions, issues in infectious disease control, the application of gene therapy to correct genetic disease through bone marrow or peripheral blood infusion, and current concepts in post-BMT immunization.

American Journal of Clinical Oncology, Apr 1, 1996

This study was designed to establish the toxicity and response rates o observed with a combinatio... more This study was designed to establish the toxicity and response rates o observed with a combination of high-dose cyclophosphamide, carboplatin, and etoposide with stem cell rescue in patients with breast carcinoma. Eligibility criteria included metastatic or locally advanced breast carcinoma ; aged < or equal to 60 years; performance status Eastern Cooperative Oncology Group (ECOG) 0-1; and creatinine clearance > or equal to 65 ml/min. Chemotherapy consisted of cyclophosphamide 25 mg/kg i.v. X 4 days, etoposide 400 mg/m(2) i.v. X 4 days, and carboplatin 375 mg/m(2) X 4 days. Bone marrow or peripheral blood stem cells were reinfused 48 h after completion of chemotherapy. Seventeen patients were treated in this study. The major toxicity was gastrointestinal (grades I and II). Fevers associated with neutropenia were observed in all the patients, but no episodes of bacteremia were documented. Hematopoietic toxicities were acceptable. No toxic deaths were observed. Six patients had chemotherapy-sensitive disease at time of transplant, nine had refractory disease, and two were untested. A response rate of 62% with 18% complete response (CR) was achieved. Two patients are free of disease at +7 and +9 months after transplantation. The combination of high-dose cyclophosphamide, carboplatin, and etoposide is well tolerated with a response rate comparable to previously reported high-dose chemotherapy regimens. However, in a poor prognostic risk group, namely patients with chemoinsensitive disease, this therapeutic approach seems to be of no advantage over standard chemotherapy.

Transplantation and Cellular Therapy

Biology of Blood and Marrow Transplantation, 2020

In the first two years after full implementation, 1073 potential related donors were referred to ... more In the first two years after full implementation, 1073 potential related donors were referred to the Donor Services group. All but 40 (3.7%) of these were able to be pre-screened. Those who were not pre-screened were primarily international potential donors or non-responsive to phone contact. Of the remaining 1033 donors, 441 (42.6%) had prescreens requiring clinical review. After this review, 112 donors (11%) were deferred prior to typing. An additional 30 (3%) were preemptively disqualified from donating one product type (either PBSC or marrow) at time of pre-screen, and 15 (1.5%) were noted to have issues that may defer them if they were selected. The most common reasons for deferral were multiple complex medical issues (25%), severe cardiac issues and/ or treatment with blood thinners (23%), and recent cancer history (13%). The rate of deferral after PE dropped from 11% to 5% (p < .01). Conclusion: The donor pre-screening process has been beneficial for our center. Fewer HLA kits were sent out to donors not meeting medical criteria for clearance, and more donors were deferred prior to coming on site. Additionally, donor PE visits were streamlined as medical record requests and additional testing could be ordered prior to the visit allowing us to see greater donor volume (18% increase) without expanding resources. Finally, important information about the donor was able to be communicated to the recipient team prior to donor selection, helping them optimize donor selection.

Biology of Blood and Marrow Transplantation, 2018

Expansion of functional human hematopoietic stem cells (HSCs) has the potential to significantly ... more Expansion of functional human hematopoietic stem cells (HSCs) has the potential to significantly improve patient outcomes in HSC transplantation and increase the dose of HSCs in gene therapy. Though several approaches have been reported to increase HSC number, a direct comparison of the various methods to expand transplantable HSCs has not been published and clinical outcome data for the various methods remains incomplete. Here, we compared several small molecule approaches reported to expand human HSCs including HDAC inhibitors (BG45,

Biology of Blood and Marrow Transplantation, 2017

of relapse 23%). With a median follow-up of 402 days (range 53-769), the probability of event-fre... more of relapse 23%). With a median follow-up of 402 days (range 53-769), the probability of event-free survival for the whole cohort was 77 % (SE 9.3). Immune reconstitution kinetics showed a robust NK cells recovery in the immediate posttransplant period. B cell compartment also showed a near optimum recovery by approximately 6 months. However, T cell subset recovery lagged behind NK cells and B cells. In conclusion haplo-identical transplantation using TCR α/β and CD 19 depleted graft is a safe approach resulting in excellent engraftment rate and may be associated with reduced risk of acute GVHD and relapse. Infectious complications especially viral infections are common.

Biology of Blood and Marrow Transplantation, 2016

receiving bulk HPC infusion. In addition, CD4+ cell count on day 180, TRM and relapse rates were ... more receiving bulk HPC infusion. In addition, CD4+ cell count on day 180, TRM and relapse rates were similar between the two groups. We also observed that with current mobilization techniques it was unlikely that more than 60% of normal donors would be able to collect more than 7x10E6 CD34+ cells/kg recipient weight for adult recipients.

Journal of Hematotherapy, 1997

Transplantation of marrow from unrelated donors is associated with an increased incidence and sev... more Transplantation of marrow from unrelated donors is associated with an increased incidence and severity of graft-versus-host disease (GVHD). In an attempt to minimize GVHD without compromising engraftment, unrelated donor marrow was depleted of lymphocytes by counterflow centrifugal elutriation (CCE), and a fixed dose of 0.5 x 10(6) CD3+ T cells/kg, as measured in real time by flow cytometry, was added back to the graft. Patients received cyclosporine (CYA) and corticosteroids for GVHD prophylaxis and to facilitate engraftment. In the first cohort (study I), 7 patients received busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) (CY) and one patient received CY (200 mg/kg) + 1260 cGy fractionated TBI. Of 6 who were evaluable for both engraftment and rejection, 4 rejected their graft. The study was terminated, and the protocol was modified (study II) by the addition of antithymocyte globulin (ATG) to the pre-BMT and post-BMT therapy. Twelve patients received CY + TBI as above plus ATG given pre-BMT and post-BMT. Ten of twelve who received ATG engrafted. Twelve patients from studies I and II were evaluable for acute GVHD. Two developed grade I acute GVHD. Two patients developed grade II acute GVHD, 2 patients developed grade III GVHD, and 1 patient developed grade IV acute GVHD. Two of three cases of acute GVHD (> grade II) occurred later than day 100 after BMT concomitant with reduction of immunosuppressive therapy. The rate of engraftment was significantly higher in study II (p = .054). In numbers of CD34+ cells infused, numbers of CFU-GM infused, and numbers of nucleated cells did not correlate with engraftment. We conclude that (a) in contrast to the results seen in recipients of marrow from HLA-matched sibling donors, the depletion of unrelated donor marrow of all but 0.5 x 10(6) CD34+ cells/kg together with CYA + corticosteroids was not sufficient to facilitate engraftment. The use of a more immunosuppressive regimen containing TBI and ATG appeared to improve engraftment. (b) The reduction of the graft T cell dose to 0.5 x 10(6) CD34+ cells/kg resulted in a higher incidence of acute GVHD than that seen in recipients of marrow from genotypically identical donors whose marrow was similarly processed.

British Journal of Haematology, May 1, 1996

Activated natural killer (A-NK) cells, a subset of CD56 dim CD3lymphocytes, are obtained from PBM... more Activated natural killer (A-NK) cells, a subset of CD56 dim CD3lymphocytes, are obtained from PBMC of normal donors by adherence to plastic and culture in the presence of IL2. In this study we tested the feasibility of generating A-NK cells in patients with Ph + chronic myeloid leukaemia (CML). Cultures obtained from patients with early chronic phase (ECP; n=7) contained a mean (6SD) of 83 6 7% of CD56 + CD3cells, and those from patients with advanced chronic phase (ACP; n=7) contained 27 6 33% CD56 + CD3cells. In three patients with leukaemia in a blastic phase (BP) it was only possible to obtain one culture enriched in CD56 + CD3cells (81%). Cellular aggregates of myeloid cells and large granular lymphocytes were observed in early A-NK cell cultures. Paired freshly-adherent and cultured A-NK cells were tested for the presence of BCR/abl mRNA by RT-PCR. The BCR/abl + cells were detected in all 12 preparations of the freshly adherent A-NK cells tested. In 6/12 the BCR/abl + cells were no longer detectable by RT-PCR on day 14 of culture. Both proliferation and antileukaemic cytotoxicity were significantly higher (P = 0. 002 and P = 0. 029, respectively) in the BCR/ablcultures than those in the six BCR/abl + cultures. 5/6 BCR/ablcultures were highly enriched in A-NK cells on day 14, and 1/6 contained predominantly CD56 + CD3 + cells. Only 2/6 BCR/abl + cultures were enriched in A-NK cells on day 14, but they had poor cytotoxicity and a low proliferative index. Myeloid cells (CD33 +) were more frequently detected in the BCR/abl + than BCR/abl-A-NK cell cultures (P = 0. 028). These observations suggest that: (1) populations of benign A-NK cells can be generated from the peripheral blood of CML patients; (2) the ability to generate A-NK cells is impaired in patients with advanced CML; and (3) the ability to generate A-NK cells with antileukaemic activity correlates with the disappearance of BCR/abl + cells from these cultures. Keywords: chronic myelogenous leukaemia, BCR/abl, activated natural killer (A-NK) cells, elimination of BCR/abl + targets, generation of A-NK cells in CML. Chronic myelogenous leukaemia (CML) is a clonal disorder in which neoplastic transformation of a stem cell results in the proliferation and accumulation of myeloid cells and their precursors. The hallmark of CML, found in >95% of patients, is the Philadelphia chromosome (Ph 1) derived from a reciprocal translocation between chromosome 9 and 22, t(9:22)(q34:q11) (Nowell & Hungerford, 1960; Rowley, 1973), which gives rise to a fused BCR/abl gene (Shtivelman et al, 1985). The disease may have a biphasic or triphasic course, with an initial chronic phase, which lasts approximately 3 years (although it may last considerably longer) and is easily controlled with therapy. It eventually progresses to a poorly-defined accelerated phase, lasting less than 1-1. 5 years but sometimes longer, and then to a blastic phase, leading to death generally within 3-6 months. 20-25% of patients die from complications of accelerated phase, and another 20-25% may develop a blastic phase without the intermediate accelerated phase (Kantarjian et al, 1993).

Blood, 1985

A human renal carcinoma from a patient with erythrocytosis, serially transplanted into athymic nu... more A human renal carcinoma from a patient with erythrocytosis, serially transplanted into athymic nude mice, was grown in primary monolayer cell cultures. After reaching confluency, the cultured cells formed multicellular hemicysts (domes), which became more abundant as the cultures approached saturation density. Erythropoietin (Ep) production by this renal carcinoma in culture was only slightly increased at the time of semiconfluency but showed a marked increase after the cultures reached confluency, in parallel with dome formation. Dibutyryl adenosine 3',5'-cyclic monophosphate significantly (P less than .01) stimulated Ep production and dome formation in the semiconfluent and confluent cultures of the renal carcinoma.

Bone Marrow Transplantation, 2008

Biology of Blood and Marrow Transplantation, 2006

received immunotherapy. The reasons for not receiving immunotherapy included transplant related d... more received immunotherapy. The reasons for not receiving immunotherapy included transplant related death (6%), inadequate recovery for acute toxicity (16%), failure to obtain insurance coverage (8%), progression of disease (8%), and patient's/physician's choice (10%). The median time to start therapy was 70 days (range 32-100 days). There were no immunotherapy related deaths. By NCI Common Toxicity Criteria, the following grade 3-4 toxicities were seen: grade 4 hematological (n ϭ 4), grade 3 infection (n ϭ 3), grade 4 circulatory (n ϭ 1), grade 4 gastrointestinal (n ϭ 1), grade 3 neurological/neuro-central (n ϭ 1), and grade 3 dermatology (n ϭ 1). The most common toxicity was erthyema/induration at injection sites. For all patients, the median follow-up is 50 months. If one compares the outcome of patients who survived transplant and did not have early relapse as to whether they received immunotherapy or not, the following outcomes were seen. The survival rate is 63% versus 43% for patients with inflammatory disease. For stage IV disease the median survival without immunotherpy was 20 months versus 39 months with immunotherapy. Median time to disease progression was 18 months with immunotherpy and 12 months without immunotherapy. Immunotherapy with IL-2 and GM-CSF is well tolerated after ASCT. Immunotherapy appears to impact on survival but relapse still remains a problem for patients with advanced breast cancer after ASCT.