bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Study of Temsirolimus (CCI-779) in Patients with Advanced Leukemias.
Authors: Yee Karen W.L. , Garcia-Manero Guillermo , Thomas Deborah , Ravandi-Kashani Farhad , Verstovsek Srdan , Andreeff Michael , Dancey Janet E. , Giles Francis J. 
Published: April 2020

Abstract
Temsirolimus (CCI-779, Wyeth Pharmaceuticals) has been shown to inhibit proliferation of a variety of tumors and induce G1 cell cycle arrest by preventing activation of the serine/threonine kinase, mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/Akt pathway. Several lines of evidence implicate the PI3K/Akt/mTOR pathway in hematological malignancies. Interim results of a phase II study evaluating the efficacy and toxicity of single-agent temsirolimus in patients with advanced malignancies are presented. Temsirolimus was administered weekly, at a flat dose of 25 mg, as a 30-minute intravenous infusion. Treatment was continued until evidence of disease progression or unacceptable toxicity. To date, 8 patients have been enrolled and 7 are evaluable for efficacy and toxicity (one patient did not receive temsirolimus). Of these 7 patients, 5 had AML, 1 CML-myeloid blast crisis, and 1 ALL. Median age was 68 years (range, 21 to 87 years) and 5 were male. All patients had received prior therapy, median 2 regimens (range, 1 to 3 regimens). The median number of temsirolimus doses administered was 3 (range, 1 to 10) with a median time on study of 18 days (range, 3 to 89+ days). The most common temsirolimus-related adverse events were grade ≤ 2 and consisted of anorexia, nausea and/or vomiting and diarrhea, mucositis, dermatitis, hypertriglyceridemia, hyperglycemia, hypomagnesemia, hypocalcemia, hypokalemia, hypophosphatemia, and fatigue/asthenia. No patient developed nonspecific pneumonitis. Grade 3 toxicities included fatigue/asthenia (2), hyperglycemia (1), painful mucositis with dehydration and electrolyte abnormalities (1), diarrhea with hypokalemia (1), and hypophosphatemia (1). No patient experienced grade 4 toxicities or death from temsirolimus. No patient required dose reductions, but 2 did have dose delays due to grade 3 mucositis (1) and out-of-state hospitalization for pneumonia and atrial fibrillation (1). No patient achieved a complete remission. One patient with heavily pre-treated Philadelphia-negative precursor B-cell ALL had a transient 79% to 91% reduction in peripheral blood blasts 4 days after the first dose of temsirolimus that was maintained for 12 days prior to disease progression with involvement of the synovial fluid in bilateral knees. At the time of analysis, 6 of the 7 patients have discontinued treatment due to disease progression (4), patient refusal (1), or physician decision (1). Preliminary findings indicate that temsirolimus is relatively well-tolerated at a dose of 25 mg per week and may have biologic activity in ALL. Accrual onto the study is currently ongoing.
Down Syndrome Patients with Relapsed Acute Myelogenous Leukemia.
Authors: Loew Thomas W. , Gamis Alan , Smith Franklin O. , Massey Gita V. , Woods William G. , Hilden Joanne M. , Lange Beverly , Alonzo Todd A. , Chang Myron , Gerbing Robert B. 
Published: April 2020

Abstract
Down Syndrome (DS) is known to increase the risk of acute myelogenous leukemia (AML). Recent cooperative group clinical trials, POG 9421 and CCG 2891, using standard timing and cytarabine/daunomycin based chemotherapy achieved induction rates of 95% and 91%, respectively. 218 patients (57 on 9421, 161 on standard timing arm of 2891) were treated. Induction failures occurred in 17/218 (3/57 on 9421, 14/161 on 2891). Relapses occurred in 11% (24/218) [4/57 on 9421, 20/161 on 2891]. Analysis of these 24 patients demonstrate overall survival (OS) of 12% (3/24). One patient on 9421 relapsed with ALL and successfully underwent ALL chemotherapy. The remaining 23 patients had relapsed AML with OS of 8% (2/23), while 13 died of progressive disease, five of infection, two of toxicity and one of graft-versus-host disease. Median time to relapse from on-study was nine months (range 5-17). Median time to death from relapse was five months (range 1–18). Reinduction attempts were known to occur in 16 patients. Combination chemotherapy with cytarabine was the most common regimen. Seven patients achieved M1 marrows, one M2 and eight nonresponders. Mitoxantrone/cytarabine was used in 5/16 reinduction attempts with three M1 marrows, one M2 and one nonresponder. Of nine patients who underwent BMT (eight known allogeneic), two are long-term survivors (OS 22%). These patients relapsed 12 and 22 months post on-study. Both achieved second remission with induction therapy consisting of mitoxantrone/cytarabine and were consolidated with an allogeneic, related, haploidentical BMT using a busulfan/cyclophosphamide preparative regimen. Outcome for DS patients with relapsed AML is dismal. Mitoxantrone/cytarabine chemotherapy followed by allogeneic BMT may improve survival. Further evaluation of therapies is needed for this group of patients.
Incidence of Febrile Neutropenia Is Low and Unrelated to Day 1 Neutrophil Count in Hodgkin’s Lymphoma Treated with ABVD.
Authors: Chand Vikram K. , Ritchie Justine , Shannon Mary , Link Brian K. , Wooldridge James E. 
Published: April 2020

Abstract
BACKGROUND: When neutropenia without infection is encountered while treating Hodgkin’s Lymphoma (HL) with ABVD chemotherapy clinicians may choose to delay or reduce the chemotherapy dose or maintain the dose intensity and schedule with or without neutrophil growth factor support out of concern for neutropenic complications. We sought to determine the frequency of neutropenia and febrile neutropenia (FN) during ABVD chemotherapy.
METHODS: We examined the medical records of all patients seen at Univ. of Iowa diagnosed with HL between 1/1/1990 and 12/31/2002 treated with ABVD chemotherapy. We reviewed the charts with complete chemotherapy dosing records to determine the incidence of neutropenia, dose reduction, dose delay and chart record of febrile neutropenia (FN).
RESULTS: 218 patients were seen at UIHC with the diagnosis of HL. 104 patients were treated with ABVD chemotherapy. Adequate dosing data was available for 82 of these patients (894 treatments). On scheduled day of treatment (Day 1 and 15 of each cycle) at least Grade III neutropenia (ANC&lt;1000) was present in 51 pts and 165 (18.45%) treatments. Grade IV (ANC&lt;500) neutropenia was present in 28 pts and 56 (6.26%) treatments. Grade III/IV neutropenia was most frequent at treatment 2 (C1, D15) (n=32). Figure 1 illustrates the frequency of Grade III/IV neutropenia on day 1 of treatment. Dose modification (DM) defined as dose delay of &gt; 4 days and/or dose reduction to &lt; 80% of original doxorubicin dose following neutropenia occurred at only 10 of 165 treatments. No episodes of FN developed in this cohort. 155 treatments at the time of neutropenia were administered without dose reduction or dose delay. Growth factor support was co-administered in 55 (36.77%) of these treatments and the remaining treatments at the time of neutropenia (73.23%, n=100) were administered without growth factor support. One episode of FN developed in each of these subsets. No FN was observed following the 56 treatments administered with an ANC &lt; 500, including 54 managed without DM (32 with GCSF support and 22 without). 672 treatments were administered with ANC ≥ 1000 resulting in 6 episodes of FN. DM was observed in 78 of these 672 treatments with 3 subsequent episodes of FN. 57 treatments (4 with DM, 23 with GCSF, 20 without GCSF, 14 unknown GCSF) had no available ANC data and were associated with one episode of FN. FN developed a total of 9 times in 8 of 82 patients over 894 treatments.
CONCLUSION: Among HL patients treated with ABVD chemotherapy we found a high frequency of neutropenia - most commonly following treatment 1. We found a very low incidence of FN that was independent of neutropenia at the time of chemotherapy administration. Dose modification for neutropenia without infection at the time of ABVD administration is not required to reduce risk of FN, and should be avoided in settings where maintaining dose intensity is considered valuable.
Biological Effects of Rabbit Anti-Thymocyte Immunoglobulin (rATG, Thymoglobulin®) in T-Cell Non-Hodgkin’s Lymphoma Cell Lines.
Authors: Hernandez Francisco J. , Reddy Nishita , Nallapareddy Sujatha , Czuczman Myron S. 
Published: April 2020

Abstract
Monoclonal antibodies (mAbs) have emerged as powerful adjuncts in the treatment of patients with B-cell lymphoproliferative disorders. While the treatment of B-cell lymphomas has incorporated mAbs and other biological agents into standard chemotherapy regimens, the treatment options for patients with T-cell lymphomas remain relatively limited. There exists a dire need to develop targeted therapies for T-cell lymphomas. Thymoglobulin® (rATG) is a rabbit polyclonal antibody targeting various receptors present on T-cell lymphocytes. When administered at high doses, rATG is known to deplete various subsets of T-cell lymphocytes and induce tolerance in solid organ or bone marrow transplant settings. Using several pre-clinical models, we evaluated the biological effects of rATG against various T-cell lymphoma cell lines. Experiments were conducted in HH, H9, Loucy and HT102 cell lines. A B-cell mantle cell lymphoma cell line was used as a control (MJ). rATG-induced cell-growth inhibition was measured by [3H]-Thymide incorporation assays and measured at 24 and 48 hours. Induction of apoptosis in T-cell lines following rATG exposure was determined by annexin-V/propidium iodine staining and quantified by flow cytometric analysis. Standard functional assays for ADCC/CMC were performed using rATG (5 or 25mg/ml) in 51Cr-labeled T-cells. We found that rATG inhibited DNA synthesis in all the T-cell lines tested. No biological effect was observed in the B-cell mantle cell lymphoma line. Treatment with rATG at either 5 or 25mg/ml resulted in a 30 to 50% growth inhibition when compared to isotype or vehicle controls (P&lt;0.05). Induction of apoptosis was demonstrated in 30 to 40% of T-cell lymphoma cells 24 hrs following exposure to ATG. Biological effects of rATG were dose-dependent. In addition, rATG induced significant ADCC and CMC in T-cell lymphoma cell lines. In conclusion, our data demonstrate that rATG is active against a variety of T-cell lymphoma cell lines in vitro. Anti-tumor effects of rATG are mediated by induction of direct signaling and via the activation of the innate immune system. Additional in vivo studies using T-cell lymphoma are underway and will be presented at the annual meeting.
Preferential Induction of B Cell Apoptosis Using Photodynamic Therapy.
Authors: Krosl Gorazd , Dube Pascale , Dallaire Nancy , Vaillancourt Marc , Roy Denis-Claude 
Published: April 2020

Abstract
Apoptotic cell death in cancer cells promotes antigen presentation and favors the development of an anti-tumor vaccination effect. While lymphoma cells can easily be obtained from lymph nodes or peripheral blood, these malignant cells usually co-localize with normal hematopoietic T lymphocytes, rendering the selective induction of apoptosis in malignant B cells particularly difficult. We have found that photodynamic therapy (PDT) using the photosensitizer 4–5 dibromorhodamine methyl ester (TH9402) and visible light (514 nm) can be used to preferentially eliminate malignant B-lineage non-Hodgkin’s lymphoma cells (mean of 3–4 logs) over T lymphocytes. As a rhodamine derivative, TH9402 cellular efflux is mediated through the P-glycoprotein (Pgp) pump. However, the preferential elimination of B cells over resting T cells could not be ascribed to Pgp inactivation and we found no difference in intracellular retention of TH9402 between B and T cells. In order to understand the molecular events leading to such high B cell susceptibility to PDT, we then investigated the nature of death pathways involved. To determine whether apoptosis was the preponderant mechanism leading to the rapid elimination of B cells, we measured the binding of Annexin V (AnnV) in 7-aminoactinomycin D (7AAD) negative (i.e. live) B and T cells using flow cytometry, and quantified DNA fragmentation and caspase 3 and 9 activity in isolated CD3+ and CD19+ PDT treated and untreated cells. We found that B cells demonstrated high levels of apoptosis after PDT, with 53±1.3% (mean±SE) AnnexinV+/7AAD- cells compared to 30±1.9% in T cells (p&lt; 0.05). The extent of DNA fragmentation, as determined by the TUNEL reaction, was extensive in B cells (33.7±9.8%)(mean±SE) but not T cells (2.3±0.1%) when measured at 4 hours post PDT (p&lt;0.01). After PDT, catalytic caspase 3 levels were also 4-fold higher in CD19+ cells than CD3+ cells (p&lt;0.01). In contrast, caspase 9 levels remained low for both cell types. The induction of apoptosis translated into the elimination of more than 90% of B cells within 4 hours after PDT, while the majority of T cells were not affected. Importantly, similar elimination of B-lineage cell lines and patient cells was observed, using a limiting dilution assay, whether cells overexpressed the anti-apoptotic bcl-2 protein or not. Thus, these results indicate that the predominant caspase 3 apoptotic pathway is specifically implicated in PDT-induced B cell death, and its early activation explains the rapid and profound sensitivity of B lymphocytes to PDT. This strategy could promote tumor cell vaccination in the context of autologous TH9402-purged stem cell transplantation for patients with B-lineage malignancies. In addition, preferential B cell targeting could take advantage of the crucial immunomodulatory role of apoptosis for the treatment of patients with autoimmune B cell disorders.
Phase I Clinical Trial of Glivec in Combination with Tetra-Arsenic Tetra-Sulfide in the Treatment of CML Patients in Advanced Phase.
Authors: Li Jun-Min , Wang Ai-Hua , Sun Hui-Ping , Shen Yang , Zhao Rui-Hua , Gu Bai-Wei , Chen Bing , Xing Wen , Shen Zhi-Xiang , Wang Zhen-Yi , Chen Sai-Juan , Chen Zhu 
Published: April 2020

Abstract
OBJECTIVE: To evaluate the safety and efficacy of Glivec in combination with As4S4 in the treatment of advanced CML patients.
PATIENTS AND METHODS: 9 Ph+ CML patients in advanced phase were entered into the study. The first 3 patients received Glivec 400mg/d plus As4S4 150mg/kg/d (day 1–14, each month). If no patient were to experience grade 3/4 CTC toxicity after one month of treatment, the dose of Glivec would be increased to 600mg. All the patients were treated and followed up for 6 months. Adverse events, hematological, cytogenetic, molecular response and real-time RT-PCR were evaluated in each regular visit.
RESULTS: From Dec.2003 to June.2004, 9 patients consisting of 6 males and 3 females were enrolled in this trial, 5 in accelerated phase and 4 in blast crisis, aged 22–53 years (median 33). The first 3 patients received Glivec 400mg/d plus As4S4, and other 6 patients received increased dosage of Glivec to 600mg/d. By the time of report, 6 patients had finished the study. 7/9 patients (77.8%) achieved complete hematological response (CHR). 2 patients relapsed after 4 and 5 months of treatment, respectively, and 2 patients withdrew from the study after 1 and 2 months respectively to receive chemotherapy due to progression of the disease. Notably, 3 of these 4 patients had complex cytogenetic abnormalities. Cytogenetic response was observed in 3 patients (33.3%), including 2 major cytogenetic response (1 complete response) and 1 minor response. No molecular response was obtained so far in any patients. Bcr-Abl fusion transcript copy number was measured by real-time RT-PCR in 3 patients, 1 patient with CCR had 3140 fold reduction of BCR-ABL DoseN. Non-hematologic toxicities such as gastrointerstinal discomfort, edema, liver dysfunction and myalgia/bone pain were common and mild (grade 1/2). Grade 3/4 hematological toxicities including neutropenia, thrombocytopenia and anemia occurred in 3 patients.
CONCLUSIONS: Glivec in combination with As4S4 has potential effect in advanced CML with acceptable toxicities. Further investigation will be performed to compare the efficacy of Glivec/As4S4 combinative therapy with Glivec mono-therapy in advanced CML.
Immunogenecity of CML-DC Is Maintained upon Imatinib Mesylate: Implication for Vaccination Regimens.
Authors: Westers Theresia M. , Janssen Jeroen J.W.M. , Snoijs Niels C.L. , van de Loosdrecht Arjan A. , Ossenkoppele Gert J. 
Published: April 2020

Abstract
Chronic myeloid leukemia (CML) is characterized by the presence of the Philidelphia chromosome which encodes for the fusion protein bcr-abl, a constitutively active tyrosine kinase. Imatinib mesylate (Gleevec, Novartis) is an inhibitor of the kinase activity of bcr-abl and therefore a treatment modality for CML. High rates of cytogenetic responses are found, although in many patients minimal residual disease (MRD) is detected by molecular techniques. Immunotherapy using leukemic dendritic cell (DC) based vaccination might be a feasible approach to eradicate MRD. In a pilot study on CML-DC-based vaccination in advanced CML DTH responses towards CML cells were achieved. (Ossenkoppele et al., Leukemia, 2003, 17, 1424). However, little is known about the effects of Imatinib mesylate on bcr-abl positive CML-DC during vaccination. In this study we investigated effects of Imatinib on culture of CML-DC, their viability, T cell stimulating and migratory capacity in vitro in 17 patients. Imatinib hardly affected the immunophenotypical profile of CML-DC. Expression of CD40, CD80, CD83, HLA-DR and chemokine receptors (CCR5, CCR7, CXCR4) remained stable during overnight exposure. Only the fluorescence intensity of CD86 was significantly higher (1–10μM, p=0.043) and that of CD54 significantly decreased in the highest Imatinib concentration tested (p=0.043). Exposure of Imatinib-free cultured CML-DC to Imatinib significantly reduced the recovery of viable cells and hence the DC yield in a dose-dependent manner (5.3–26% reduction after 20h. for 1–10μM, p=0.043). Migration of mature CML-DC towards CCL19 (MIP3β) was significantly improved in the presence of 1 and 5μM Imatinib which implies increased ability to reach the lymph nodes (p=0.043, mean 27, 36 and 34% migration for 0, 1 and 5μM Imatinib, respectively). Imatinib did not affect T cell stimulating capacity of CML-DC, except at concentrations higher than 3μM (p=0.028). No significant changes were observed for Imatinib exposure of CD34+ DC isolated from normal subjects. In conclusion, Imatinib at low concentrations maintains the immunogenecity of CML-DC. Since Imatinib plasma levels in CML patients are 1.5 and 3.0μM upon 400 and 800mg daily, respectively, our data justify continuation of Imatinib treatment during CML-DC-based vaccination regimens.
Disease Models and Transformation Mechanisms Mediated by MLL-AF4 Family Oncoproteins in Human Leukemia.
Authors: So Chi Wai Eric , Wong Piu , Lin Min , Cleary Michael L. 
Published: April 2020

Abstract
The Mixed Lineage Leukemia (MLL) gene codes for a histone methyltransferase that is required for hematopoietic development. As a consequence of chromosomal translocations, MLL is fused with over 40 different genes to yield in-frame fusion proteins in acute leukemias. AF4, the most common fusion partner, accounts for 40% of MLL leukemias. The AF4-related proteins, LAF4 and AF5q31, are also fusion partners for MLL in rare cases of leukemia, whereas a fourth family member, FMR2, is a candidate protein for fragile X mental retardation syndrome. MLL fusions with AF4 family proteins manifest as acute biphenotypic or lymphoblastic leukemias that are associated with a poor prognosis, but the lack of appropriate disease models has hampered progress in understanding their underlying molecular mechanisms. Here we report that each of the MLL-AF4 family fusion proteins (the leukemia associated MLL-AF4, MLL-LAF4, and MLL-AF5q31 as well as an artificial MLL-FMR2) is capable of altering the growth and self-renewal properties of primary murine hematopoietic stem/progenitor cells in a serial methylcellulose culture myeloid replating assay. However, significant differences were observed in their respective oncogenic potentials. Cells transduced with MLL-LAF4, MLL-AF5q31 and MLL-FMR2 rapidly expanded during serial replatings, adapted to growth in liquid culture, and induced leukemias in syngeneic recipient mice within 6 months. Conversely, bone marrow cells transduced with MLL-AF4 yielded modest numbers of blast-like colonies in the third round of plating, only transiently expanded in vitro, and quickly underwent terminal differentiation. MLL-LAF4 and MLL-AF5q31 were also capable of enhancing the self-renewal of transduced cells with B lymphoid progenitor phenotypes. A structure/function analysis demonstrated that the previously reported transcriptional transactivation domains of AF4 family proteins were neither necessary nor sufficient for in vitro transformation. Furthermore, the recently reported AF9 interaction motif that is conserved in all AF4 family proteins was also shown to be dispensable for in vitro transformation. These data indicate that transactivation per se, and interaction with AF9 in particular, are not absolutely required for the oncogenic actions of MLL-AF4 family proteins. Conversely, a minimal transformation domain was mapped to the highly conserved carboxy-terminal homology domain shared among all AF4 family proteins, including the Drosophila homolog Lilliputian, and shown to be necessary and sufficient for transformation. Taken together, our studies establish transformation models for MLL-AF4 family fusion proteins and provide critical mechanistic insights into their underlying molecular mechanisms.