sirolimus and fludarabine

Waldenström macroglobulinemia (WM) is a distinct B-cell lymphoproliferative disorder for which clearly defined criteria for the diagnosis, initiation of therapy, and treatment strategy have been proposed as part of the consensus panels of International Workshops on WM (IWWM). As part of the IWWM-7 and based on recently published and ongoing clinical trials, the panels updated treatment recommendations. Therapeutic strategy in WM should be based on individual patient and disease characteristics (age, comorbidities, need for rapid disease control, candidacy for autologous transplantation, cytopenias, IgM-related complications, hyperviscosity, and neuropathy). Mature data show that rituximab combinations with cyclophosphamide/dexamethasone, bendamustine, or bortezomib/dexamethasone provided durable responses and are indicated for most patients. New monoclonal antibodies (ofatumumab), second-generation proteasome inhibitors (carfilzomib), mammalian target of rapamycin inhibitors, and Bruton's tyrosine kinase inhibitors are promising and may expand future treatment options. A different regimen is typically recommended for relapsed or refractory disease. In selected patients with relapsed disease after long-lasting remission, reuse of a prior effective regimen may be appropriate. Autologous stem cell transplantation may be considered in young patients with chemosensitive disease and in newly diagnosed patients with very-high-risk features. Active enrollment of patients with WM in clinical trials is encouraged.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Clinical Trials as Topic; Consensus Development Conferences as Topic; Disease Progression; Everolimus; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Nitrogen Mustard Compounds; Pyrazines; Rituximab; Salvage Therapy; Sirolimus; Treatment Outcome; Vidarabine; Waldenstrom Macroglobulinemia

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Topics: Administration, Oral; Adolescent; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antilymphocyte Serum; Blood Platelets; Busulfan; Child; Female; Graft vs Host Disease; HLA Antigens; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Neutrophils; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Rituximab; Sirolimus; T-Lymphocytes; T-Lymphocytes, Regulatory; Tissue Donors; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult

Many patients with lymphoma relapse after autologous stem cell transplantation (AutoSCT). These patients are often considered for allogeneic stem cell transplantation (AlloSCT) if remission can be achieved. If a tandem approach was organized, some cases of relapse might be prevented. We conducted a phase II trial of tandem AutoSCT followed by reduced-intensity conditioning (RIC) AlloSCT for patients with high-risk lymphoma. High-dose chemotherapy was given with busulfan, cyclophosphamide, and etoposide. AlloSCT was composed of RIC with busulfan/fludarabine and tacrolimus, sirolimus, and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Donors were fully matched related or unrelated donors. AlloSCT was performed any time between 40 days and 6 months after AutoSCT. Forty-two patients were enrolled, and all patients underwent AutoSCT. RIC AlloSCT was performed in 29 patients. In the 29 patients who underwent tandem transplant, median time from AutoSCT to AlloSCT was 96 days (range, 48 to 169). The 6-month cumulative incidence of grades II to IV acute GVHD was 13.8% (90% confidence interval [CI], 5.3% to 26.3%). Cumulative incidence of chronic GVHD at 1 year was 37.9% (90% CI, 23.1% to 52.7%). Nonrelapse mortality at 2 years after AlloSCT was 11.1% (90% CI, 3.5% to 23.6%). At a median follow-up of 30 months (range, 17.1 to 51.5) for the entire group, the 2-year progression-free survival rate was 64% (90% CI, 50% to 75%) and the 2-year overall survival rate was 69% (90% CI, 43% to 85%). For the 29 patients who underwent tandem SCT, the 2-year progression-free survival rate was 72% (90% CI, 55% to 83%) and the 2-year OS rate was 89% (90% CI, 74% to 96%). Tandem AutoSCT-RIC AlloSCT appears to be safe and effective in patients with high-risk lymphoma. Prospective trials using such an approach in specific lymphoma subtypes are warranted.

Topics: Adult; Aged; Allografts; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Disease-Free Survival; Female; Follow-Up Studies; Graft vs Host Disease; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Sirolimus; Stem Cell Transplantation; Survival Rate; Tacrolimus; Vidarabine

We treated 14 patients with GATA2 deficiency using a nonmyeloablative allogeneic hematopoietic stem cell transplantation regimen. Four patients received peripheral blood stem cells from matched related donors (MRD), 4 patients received peripheral blood stem cells from matched unrelated donors (URD), 4 patients received hematopoietic stem cells from umbilical cord blood donors (UCB), and 2 patients received bone marrow cells from haploidentical related donors. MRD and URD recipients received conditioning with 3 days of fludarabine and 200 cGy total body irradiation (TBI). Haploidentical related donor recipients and UCB recipients received cyclophosphamide and 2 additional days of fludarabine along with 200 cGY TBI. MRD, URD, and UCB recipients received tacrolimus and sirolimus for post-transplantation immunosuppression, whereas haploidentical recipients received high-dose cyclophosphamide followed by tacrolimus and mycophenolate mofetil. Eight patients are alive with reconstitution of the severely deficient monocyte, B cell, and natural killer cell populations and reversal of the clinical phenotype at a median follow-up of 3.5 years. Two patients (1 URD recipient and 1 UCB recipient) rejected the donor graft and 1 MRD recipient relapsed with myelodysplastic syndrome after transplantation. We are currently using a high-dose conditioning regimen with busulfan and fludarabine in patients with GATA2 deficiency to achieve more consistent engraftment and eradication of the malignant myeloid clones.

Topics: Adolescent; Adult; Allografts; Antineoplastic Agents; Bone Marrow Transplantation; Child; Cord Blood Stem Cell Transplantation; Female; Follow-Up Studies; GATA2 Transcription Factor; Genetic Diseases, Inborn; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Male; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vidarabine; Whole-Body Irradiation

Reduced-intensity conditioning (RIC) allo-SCT is a potentially curative treatment approach for patients with relapsed Hodgkin's or non-Hodgkin's lymphoma. In the present study, 37 patients underwent RIC allo-SCT after induction treatment with EPOCH-F(R) using a novel form of dual-agent immunosuppression for GVHD prophylaxis with CsA and sirolimus. With a median follow-up of 28 months among survivors, the probability for OS at 3 and 5 years was 56%. Treatment-related mortality was 16% at day +100 and 30% after 1 year of transplant. Acute GVHD grades II-IV developed in 38% of patients, suggesting that the regimen consisting of CsA and an ultra-short course of sirolimus is effective in the prevention of acute GVHD.

Topics: Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Etoposide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Immunosuppressive Agents; Lymphoma, Non-Hodgkin; Male; Middle Aged; Prednisolone; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Vincristine; Young Adult

Combination tacrolimus and sirolimus graft-versus-host disease (GVHD) prophylaxis for allogeneic transplant in patients conditioned with a fractionated total body irradiation-based regimen has shown encouraging results. We studied this prophylaxis combination in 85 patients receiving a matched-sibling transplant conditioned with 3 different regimens:fludarabine-melphalan (n = 46); total body irradiation-etoposide (n = 28), and busulfan-cyclophosphamide (n = 11). The conditioning regimens were completed on day -4. Sirolimus and tacrolimus were started on day -3 to avoid overlap with conditioning therapy. All patients engrafted, with a median time to neutrophil engraftment of 15 days. The cumulative incidence of acute GVHD grades II to IV and III to IV was 43% and 19%, respectively, with no significant difference by conditioning regimen. The 2-year cumulative incidence of chronic GVHD was 46%. With a median follow-up of 26 months, disease-free survival was 58% and overall survival, 66%. The day-100 and 2-year nonrelapse mortality was 4.8% and 10.2%, respectively. The overall incidence of thrombotic microangiopathy was 19%, and it was significantly higher with busulfan/cyclophosphamide (55%, P = .005). Tacrolimus plus sirolimus is an effective combination for acute GVHD prophylaxis and is associated with very low nonrelapse mortality. Thrombotic microangiopathy is a significant complication with this regimen, particularly in patients receiving busulfan/cyclophosphamide.

Topics: Adolescent; Adult; Busulfan; Child; Cyclophosphamide; Etoposide; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Melphalan; Middle Aged; Pilot Projects; Radiation Dosage; Siblings; Sirolimus; Survival Analysis; Tacrolimus; Thrombotic Microangiopathies; Tissue Donors; Transplantation Conditioning; Vidarabine; Young Adult

We assessed the combination of sirolimus, tacrolimus, and low-dose methotrexate as acute graft-versus-host disease (aGVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic peripheral blood stem cell (PBSC) transplantation from matched related (MRD, n = 46) and unrelated (URD, n = 45) donors. All patients received fludarabine and intravenous busulfan conditioning followed by transplantation of mobilized PBSC. The median time to neutrophil engraftment was 13 days. The cumulative incidence of grade II-IV and III-IV aGVHD were 16% and 7%, respectively. There was no difference in the incidence of aGVHD between MRD and URD cohorts. Two-year cumulative incidence of extensive chronic GVHD (cGVHD) was 40%. Relapse-free survival (RFS) at 2 years was 34%: 21% in MRD and 45% in URD. Overall survival (OS) at 2 years was 59%: 47% in MRD and 67% in URD. High levels (>90%) of donor derived hematopoiesis were achieved in 59% of patients early after transplantation. The addition of sirolimus to tacrolimus and low-dose methotrexate as GVHD prophylaxis following RIC with fludarabine and low-dose intravenous busulfan is associated with rapid engraftment, low rates of aGVHD, and achievement of high levels of donor chimerism.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility Testing; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Premedication; Sirolimus; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Acute lymphoblastic leukemia (ALL) is associated with poor survival in older adults, and allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning (RIC) has been an increasingly used strategy in this population. At City of Hope we conducted a retrospective analysis of 72 patients who underwent allogeneic HCT with fludarabine and melphalan (FluMel) as the conditioning regimen between 2005 and 2018, from either a matched sibling or fully matched unrelated donor while in complete remission. Tacrolimus and sirolimus (T/S) were used as graft-versus-host disease (GVHD) prophylaxis. Overall survival and progression-free survival at 4 years post-HCT were 58% and 44%, respectively. The cumulative incidences of relapse/progression and nonrelapse mortality at 4 years were 34% and 22%, respectively. Patients with Philadelphia chromosome-positive (Ph+) ALL had a significantly lower cumulative incidence of relapse/progression (20% versus 48% for patients with Ph-negative status, P = .007). In conclusion, RIC HCT with FluMel conditioning and T/S GVHD prophylaxis was associated with favorable outcomes in patients with Ph+ ALL and should be considered as a viable consolidative therapy for adult patients with ALL.

Topics: Aged; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Retrospective Studies; Sirolimus; Tacrolimus; Transplantation Conditioning; Vidarabine

In classical reduced-intensity conditioning (RIC) regimens, including the fludarabine and busulphan (BF) combination, sirolimus and tacrolimus (SIR-TAC) as graft vs host disease (GVHD) prophylaxis has shown acceptable results. The outcomes of SIR-TAC in a more intense RIC regimen as Thiotepa-fludarabine-busulfan (TBF) have been hardly investigated. This retrospective study included all consecutive patients receiving an allogeneic hematopoietic stem cell transplantation for myeloid malignancies (January 2009-2017) conditioned with either TBF or BF and receiving SIR-TAC. Patients receiving TBF presented higher non-relapse mortality (31.6 vs 12.3%,

Topics: Busulfan; Feasibility Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Sirolimus; Tacrolimus; Thiotepa; Transplantation Conditioning; Vidarabine

Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Biomarkers, Tumor; Disease Susceptibility; Female; Flow Cytometry; Gene Expression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Mutation; Sirolimus; Treatment Outcome; Vidarabine

Topics: Adenine; Antineoplastic Agents; Bendamustine Hydrochloride; Bortezomib; Chromosomes, Human, Pair 17; Cytarabine; Humans; Lenalidomide; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Mutation; Neoplasm Recurrence, Local; Piperidines; Pyrazoles; Pyrimidines; Rituximab; Sirolimus; Thalidomide; Tumor Suppressor Protein p53; Vidarabine

Waldenström macroglobulinemia (WM) is a B-cell neoplasm manifested by the accumulation of clonal immunoglobulin (Ig)M-secreting lymphoplasmacytic cells. MYD88 and CXCR4 warts, hypogammaglobulinemia, infections, myelokathexis syndrome-like somatic mutations are present in >90% and 30% to 35% of WM patients, respectively, and impact disease presentation, treatment outcome, and overall survival. Familial predisposition is common in WM. Asymptomatic patients should be observed. Patients with disease-related hemoglobin <10 g/L, platelets <100 × 10(9)/L, bulky adenopathy and/or organomegaly, symptomatic hyperviscosity, peripheral neuropathy, amyloidosis, cryoglobulinemia, cold-agglutinin disease, or transformed disease should be considered for therapy. Plasmapheresis should be used for patients with symptomatic hyperviscosity and before rituximab for those with high serum IgM levels to preempt a symptomatic IgM flare. Treatment choice should take into account specific goals of therapy, necessity for rapid disease control, risk of treatment-related neuropathy, immunosuppression and secondary malignancies, and planning for future autologous stem cell transplantation. Frontline treatments include rituximab alone or rituximab combined with alkylators (bendamustine and cyclophosphamide), proteasome inhibitors (bortezomib and carfilzomib), nucleoside analogs (fludarabine and cladribine), and ibrutinib. In the salvage setting, an alternative frontline regimen, ibrutinib, everolimus, or stem cell transplantation can be considered. Investigational therapies under development for WM include agents that target MYD88, CXCR4, BCL2, and CD27/CD70 signaling, novel proteasome inhibitors, and chimeric antigen receptor-modified T-cell therapy.

Topics: Adenine; Adult; Aged; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; B-Lymphocytes; Bendamustine Hydrochloride; Boronic Acids; Bortezomib; Cladribine; Cyclophosphamide; Everolimus; Gene Expression; Genetic Predisposition to Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunoglobulin M; Male; Middle Aged; Molecular Targeted Therapy; Myeloid Differentiation Factor 88; Nitrogen Mustard Compounds; Oligopeptides; Piperidines; Plasmapheresis; Pyrazines; Pyrazoles; Pyrimidines; Receptors, CXCR4; Rituximab; Sirolimus; Transplantation, Autologous; Vidarabine; Waldenstrom Macroglobulinemia

A 9-month-old boy with life-threatening multiresistant pure red cell anemia/autoimmune hemolytic anemia within the frame of a possible, undiagnosed immune-mediated disease was initially treated with prednisone. Further-line therapies of the following 7 relapses included immunoglobulins, rituximab, cyclophosphamide, and alentuzumab followed by other maintenance treatments as cyclosporine, methotrexate, and mycophenolate. After all the administered therapies failed, the patient was successfully treated by splenectomy followed by fludarabine and then sirolimus as maintenance treatment. Relapses might have been caused by the lack of a complete debulking of triggering cells and/or ineffective maintenance therapy. Splenectomy and sirolimus may have played a complementary role in the management of both situations.

Topics: Anemia, Hemolytic, Autoimmune; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Resistance; Humans; Infant; Male; Red-Cell Aplasia, Pure; Sirolimus; Splenectomy; Treatment Outcome; Vidarabine

Oral mucositis (OM) is a side effect of intensive chemotherapy and radiation and has been reported to affect 75-100% of hematopoietic stem cell transplantation (HSCT) recipients. The purpose of this study was to compare the incidence of OM in patients conditioned with myeloablative conditioning (MAC) to reduced-intensity conditioning (RIC) and to determine the effect of a new oral care protocol.. The study involved 171 HSCT recipients, with hematological malignancies transplanted between 2007 and 2011. Median age of the patients was 50 years (range 12-71). Ninety-nine (58%) received RIC and 72 received MAC. Clinical features of OM were recorded from day -3 before to day +25 after HSCT using the World Health Organization (WHO) scoring system and the oral mucositis assessment score (OMAS).. Overall, 87% of the patients developed OM of any severity, which peaked on days 10-11. The mean WHO score was 1.7. In multivariate analysis, the severity of OM was associated with MAC (relative hazard (RH) 1.57, 95% confidence interval (CI) 1.37-1.80, p < 0.001), all donor-recipient gender combinations except female-to-male (RH = 1.26, 95% CI 1.10-1.4, p = 0.001), and early year of HSCT (RH = 0.84, 95%CI 0.7-0.96, p = 0.013). There was a correlation between long hospitalization and OM (day 15, r = 0.31, p < 0.001). There was a good correlation between the WHO and OMAS scoring systems for OM (r = 0.74, p < 0.001).. Oral mucositis was reduced in patients treated with RIC and in patients treated during recent years, when oral care was intensified. Increased scores of OM prolonged hospitalization.

Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Cyclophosphamide; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Multivariate Analysis; Oral Hygiene; Prednisone; Sirolimus; Stomatitis; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation; Young Adult

Posttransplant lymphoproliferative disease (PTLD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. We describe here the case of a boy with history of induction failure of a T-cell acute lymphoblastic leukemia, who presented a life-threatening situation of nonengraftment and rituximab-refractory PTLD after the first hematopoietic stem cell transplantation. We decided to use an unusual strategy of combining a nonmyeloablative conditioning (fludarabine and cyclophosphamide) with a calcineurin inhibitor-free GvHD prophylaxis (sirolimus and mycophenolate mofetil). This strategy had permitted the control of an Epstein-Barr virus PLTD in umbilical cord blood transplantation without further reactivation.

Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Calcineurin; Child; Combined Modality Therapy; Drug Resistance, Neoplasm; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Rituximab; Sirolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Chronic lymphocytic leukemia (CLL) remains incurable; therefore searching for new therapeutic strategies in this disease is necessary. An important mechanism of tumor development is neoangiogenesis. A potent antiangiogenic factor, bevacizumab (Avastin, AVA), has been poorly explored in CLL so far. In the current study we assessed cytotoxic activity of AVA alone or in combinations with drugs routinely used in this disease.. Cells isolated from 60 CLL patients were treated with AVA alone or in combination with anti-CD20 monoclonal antibody (MoAb), rituximab (RIT), anti-CD52 MoAb, alemtuzumab (ALT), 2-CdA (2-chlorodeoxyadenosine), FA (fludarabine), MAF (mafosfamide) or RAPA (rapamycin). Cytotoxicity was assessed by propidium iodide staining. Apoptosis was evaluated using annexin-V and TUNEL assays. Additionally, a drop of mitochondrial potential (DYm) as well as expression of apoptosis-regulating proteins Bax, Bak, Bid, Bad, Bcl-2, Mcl-2, XIAP, FLIP, Akt and Bcl-2-A1 were determined by flow cytometry.. At the dose of 40 μg/ml, after 48 hours of incubation, AVA induced significant cytotoxicity against CLL cells. The drug triggered apoptosis, with activation of caspase-3 and -9, but not caspase-8, along with a drop of DYm. Incubation with AVA induced significant overexpression of proapoptotic Bak and Bad as well as downregulation of antiapoptotic Mcl-2 and Akt proteins. Combination of AVA with RIT, ALT or RAPA significantly increased cytotoxicity when compared with the effects of single drugs.. In conclusion, this is the first report showing proapoptotic activity of AVA against CLL cells. Combination of AVA with RIT, ALT or RAPA may be a promising therapeutic strategy, which requires confirmation in further studies.

Topics: Alemtuzumab; Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bevacizumab; Caspase 3; Caspase 9; Cladribine; Cyclophosphamide; Down-Regulation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Proteasome Inhibitors; Rituximab; Sirolimus; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vidarabine

Endometrial cancer, one of the most common gynecologic malignancies, is increasing in Japan, nearly doubling over the last decade. High-grade disease patients are often resistant to conventional chemotherapy with platinum agents; therefore, discovery of efficacious new drugs in this setting is required to benefit chemorefractory cases. The 50% growth-inhibitory (GI50) concentration of 27 clinically relevant drugs was measured in the NCI60 panel of cell lines. Gene expression data were analyzed using Bayesian binary regression, to first generate a response signature for each drug and then to calculate individual susceptibility scores using in vivo endometrial cancer data (GSE2109; http://www.ncbi.nlm.nih.gov/geo) and in vitro data (GSE25458), as well as to identify candidate drugs for chemorefractory cases. Using these candidates, cell proliferation, apoptosis and caspase assays were performed in vitro. The tumor growth-inhibitory effect of the candidate was also assessed in vivo using nude mice. Through microarray analysis, fludarabine and temsirolimus showed higher susceptibility scores in high-grade cases compared to cisplatin, doxorubicin and paclitaxel. Fludarabine significantly inhibited cell proliferation and increased apoptosis in the cisplatin-resistant endometrial cancer cell line, HEC1A, relative to HEC50B (p < 0.001). Fludarabine treatment also enhanced caspase-3/7 activity in HEC1A relative to HEC50B cells (p < 0.001), and inhibited the growth of HEC1A xenograft tumors relative to cisplatin (p < 0.05). These results support that identification and use of genomic signatures can lead to identification of new therapeutic candidates that may prove beneficial to chemoresistant cases. Fludarabine may be useful in targeting high-grade, chemorefractory endometrial cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bayes Theorem; Biomarkers, Tumor; Blotting, Western; Carboplatin; Cell Proliferation; Cisplatin; Doxorubicin; Drug Resistance, Neoplasm; Endometrial Neoplasms; Female; Follow-Up Studies; Gene Expression Profiling; Humans; Middle Aged; Neoplasm Grading; Neoplasm Staging; Oligonucleotide Array Sequence Analysis; Paclitaxel; Prognosis; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; Survival Rate; Tumor Cells, Cultured; Vidarabine

We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD; of these 35 were extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.

Topics: Adult; Aged; Chemoprevention; Dose-Response Relationship, Drug; Drug Combinations; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Incidence; Male; Melphalan; Middle Aged; Myelodysplastic Syndromes; Retrospective Studies; Sirolimus; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

Topics: Adult; Aged; Antilymphocyte Serum; Cord Blood Stem Cell Transplantation; Fetal Blood; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia; Melphalan; Middle Aged; Sirolimus; Tacrolimus; Transplantation Conditioning; Vidarabine

This retrospective study reviews the results of our experience with the occurrence of CMV DNAemia in islet cell transplanted cynomolgus monkeys subjected to different immunosuppressive protocols, including induction treatment with thymoglobulin (TMG), with a combination of thymoglobulin and fludarabine (FLUD), with cyclophosphamide, or with daclizumab. CMV DNA in the peripheral blood (CMV DNAemia) of 47 monkeys was quantified by real-time PCR on a weekly to biweekly basis. As compared to other immunosuppressive regimens, and in association with greater decreases in WBC, lymphocyte, CD3+CD4+, and CD3+CD8+ lymphocyte counts, frequent CMV DNAemia occurred earlier (within the first month posttransplant), and was of greater severity and duration in recipients of TMG ± FLUD. Treatment of recipients with alternative induction agents that resulted in less dramatic reductions in WBC and lymphocyte counts, however, resulted in occurrence of CMV DNAemia after postoperative day 60. The frequency, average intensity, duration, and area under the curve (AUC) for CMV DNAemia in animals receiving TMG ± FLUD were 75-100%, 4.02 ± 1.75 copies/ng DNA, 23.0 ± 5.3 days, and 367.0 ± 121.1 days × copies/ng DNA, respectively; corresponding values in animals receiving other treatments (0-44%, 0.19 ± 0.10 copies/ng DNA, 0.5 ± 0.3 days, and 75.4 ± 40.2 days × copies/ng DNA, respectively) were significantly different. The value of WBC, T and B cells at the nadir of cell depletion greatly affects the occurrence of CMV DNAemia. No animals developed CMV DNAemia within the next 3 weeks when the lowest value of WBC, lymphocyte, CD3+, CD3+CD4+, CD3+CD8+, or CD20+ cells was above 4500, 1800, 300, 200, 150, or 300 cells/μl, respectively. Oral valganciclovir prophylaxis did not completely prevent the appearance of CMV DNAemia.

Topics: Analgesics, Non-Narcotic; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Antiviral Agents; Cytomegalovirus; Daclizumab; DNA, Viral; Ganciclovir; Humans; Immunoglobulin G; Immunosuppressive Agents; Islets of Langerhans Transplantation; Leukocytes; Macaca fascicularis; Organometallic Compounds; Organophosphorus Compounds; Retrospective Studies; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation, Homologous; Valganciclovir; Vidarabine

We report on a patient with relapsed chronic lymphocytic leukemia (CLL) treated with the novel mTOR inhibitor RAD001 within a phase II clinical trial. Although the patient initially responded to therapy, RAD001 was discontinued after 32 weeks due to progression and fludarabine-based chemotherapy was started. The patient subsequently developed a rapidly fatal Epstein-Barr-virus-associated lymphoproliferative disorder, clonally unrelated to the CLL. The clinical course suggests caution when using newer immunosuppressive drugs for treatment of CLL, especially in the context of additional purine analog therapy.

Topics: Aged; Epstein-Barr Virus Infections; Everolimus; Fatal Outcome; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoproliferative Disorders; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Vidarabine

To investigate the inflammatory signal transduction of high mobility group box-1 protein (HMGB1) induced inflammatory response in rat peritoneal macrophages.. Peritoneal macrophages obtained from male Wistar rats were seeded in 24-well (1 x 10(6) cells/well) tissue culture plates. The cells were incubated for 3 days before they were stimulated with HMGB1, and treated with Fludarabine [the specific inhibitor of signal transducer and activator of transcription 1 (STAT1)] or Rapamycin (the specific inhibitor of STAT3). The time-dependent and dose-dependent responses between HMGB1 stimulation and tumor necrosis factor-alpha (TNF-alpha) gene expression as well as release were analyzed respectively. Moreover, the effect of Fludarabine and Rapamycin on TNF-alpha mRNA expression and protein release were also observed.. (1) After HMGB1 challenge, TNF-alpha mRNA expressions were up-regulated markedly, peaked at 24 hours, and decreased at 36 hours. When HMGB1 was used at a concentration of 10 microg/ml, TNF-alpha mRNA expression increased most markedly. (2) HMGB1 could induce TNF-alpha release in rat peritoneal macrophages, with peaking at 4 hours and decreasing at 8 hours later. When the concentration of HMGB1 stimulation increased from 5 microg/ml to 25 microg/ml, TNF-alpha release was persistently enhanced. (3) It was also showed that TNF-alpha mRNA expression was significantly inhibited by treatment of either Fludarabine (100 micromol/L) or Rapamycin (25 ng/ml), while TNF-alpha release was not markedly suppressed.. STAT1 and STAT3 might be involved in the regulation of TNF-alpha gene expression, but not in TNF-alpha early release (< 24 hours) induced by HMGB1 stimulation in rat peritoneal macrophages.

Topics: Animals; Cells, Cultured; Drug Interactions; HMGB1 Protein; Macrophages, Peritoneal; Male; Rats; Rats, Wistar; Signal Transduction; Sirolimus; STAT1 Transcription Factor; STAT3 Transcription Factor; Transcription, Genetic; Tumor Necrosis Factor-alpha; Vidarabine

Non-myeloablative conditioning has extended the use of allogeneic haematopoietic transplant to many previously ineligible patients. We added the immunosuppressive and antitumour agent sirolimus (rapamycin) to an established transplant regimen of fludarabine 25 mg/m(2) days -7 through -3 and cyclophosphamide 1000 mg/m(2) days -7 and -6, with tacrolimus and methotrexate immunoprophyllaxis. A total of 23 patients with acute myelogenous leukaemia (AML) were treated, with a median age of 59 years (range: 28-72) at transplant. Only seven patients in total were in complete remission prior to transplantation. Nine patients were in chemotherapy-refractory progression and seven were primarily refractory to induction therapy. Six patients received matched sibling, 11 unrelated donor, 1-5/6 matched and five haploidentical (haplo - three of six or four of six matched) transplants. The haplo-recipients also received antithymocyte globulin, all patients engrafted. Only two, both recipients of haploidentical cells, have died from transplant-related causes. Twelve of 23 patients survived at 198-1162-d post-transplant (median 578). Four of 12 survivors relapsed at 83, 88, 243 and 508 d and three were in remission after chemotherapy and donor lymphocyte infusion. Although follow up is short, this data suggests that non-myeloablative haematopoietic cell transplantation with sirolimus (rapamycin)-based immunosuppression may provide disease control over several years in some patients with advanced and poor prognosis AML.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Chronic Disease; Cyclophosphamide; Disease Progression; Follow-Up Studies; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Middle Aged; Sirolimus; Survival Analysis; Treatment Outcome; Vidarabine