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1.
Acta Haematol ; 143(2): 146-154, 2020.
Article in English | MEDLINE | ID: mdl-31434076

ABSTRACT

BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.


Subject(s)
Bortezomib/therapeutic use , Multiple Myeloma/drug therapy , Vorinostat/therapeutic use , Bortezomib/adverse effects , Disease-Free Survival , Drug Administration Schedule , Female , Gastrointestinal Diseases/etiology , Hematopoietic Stem Cell Transplantation , Humans , Male , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Survival Rate , Transplantation, Autologous , Treatment Outcome , Vorinostat/adverse effects
3.
Leukemia ; 31(12): 2560-2567, 2017 12.
Article in English | MEDLINE | ID: mdl-28555084

ABSTRACT

DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Azacitidine/analogs & derivatives , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Azacitidine/therapeutic use , Biomarkers , Cytarabine , Decitabine , Drug Resistance, Neoplasm , Etoposide , Female , Humans , Leukemia, Myeloid, Acute/mortality , Male , Middle Aged , Mitoxantrone , Neoplasm Grading , Recurrence , Treatment Outcome , Young Adult
5.
Bone Marrow Transplant ; 52(1): 59-65, 2017 Jan.
Article in English | MEDLINE | ID: mdl-27427921

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.


Subject(s)
Adenine Nucleotides/administration & dosage , Arabinonucleosides/administration & dosage , Busulfan/administration & dosage , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/mortality , Leukemia, Myeloid, Acute/therapy , Transplantation Conditioning , Adult , Aged , Allografts , Clofarabine , Disease-Free Survival , Female , Humans , Induction Chemotherapy , Male , Middle Aged , Survival Rate
8.
Bone Marrow Transplant ; 51(1): 67-71, 2016 Jan.
Article in English | MEDLINE | ID: mdl-26367217

ABSTRACT

We aimed to examine whether doses of melphalan higher than 200 mg/m(2) improve response rates when used as conditioning before autologous transplant (ASCT) in multiple myeloma (MM) patients. Patients with MM, n=131, were randomized to 200 mg/m(2) (mel200) vs 280 mg/m(2) (mel280) using amifostine pretreatment. The primary end point was the proportion of patients achieving near complete response (⩾nCR). No treatment-related deaths occurred in this study. Responses following ASCT were for mel200 vs mel280, respectively, ⩾nCR 22 vs 39%, P=0.03, ⩾PR 57 vs 74%, P=0.04. The hazard of mortality was not statistically significantly different between groups (mel200 vs mel280; hazard ratio (HR)=1.15 (95% confidence interval (CI), 0.62-2.13, P=0.66)) nor was the rate of progression/mortality (HR=0.81 (0.52-1.27, P=0.36)). The estimated PFS at 1 and 3 years were 83 and 46%, respectively, for mel200 and 78 and 54%, respectively, for mel280. Amifostine and mel280 were well tolerated, with no grade 4 regimen-related toxicities and only one grade 3 mucositis (none with mel200) and three grade 3 gastrointestinal (GI) toxicities (two in mel200). Hospitalization rates were more frequent in the mel280 group (59 vs 43%, P=0.08). Mel280 resulted in a higher major response rate (CR+nCR) and should be evaluated in larger studies.


Subject(s)
Melphalan/administration & dosage , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Stem Cell Transplantation , Transplantation Conditioning , Adult , Aged , Autografts , Disease-Free Survival , Female , Humans , Male , Middle Aged , Multiple Myeloma/pathology , Survival Rate
10.
Blood Cancer J ; 5: e302, 2015 Apr 10.
Article in English | MEDLINE | ID: mdl-25860293

ABSTRACT

Bone marrow-derived mesenchymal stromal cells (BM-MSCs) play a fundamental role in the BM microenvironment (BME) and abnormalities of these cells may contribute to acute myeloid leukemia (AML) pathogenesis. The aim of the study was to characterize the cytokine and gene expression profile, immunophenotype and cytogenetics of BM-MSCs from AML patients compared to normal BM-MSCs from healthy donors. AML BM-MSCs showed decreased monocyte chemoattractant protein-1 levels compared to normal BM-MSCs. AML BM-MSCs expressed similar ß1 integrin, CD44, CD73, CD90 and E-cadherin compared to normal BM-MSCs. Cytogenetic analysis revealed chromosomal aberrations in AML BM-MSCs, some overlapping with and others distinct from their corresponding AML blasts. No significant difference in gene expression was detected between AML BM-MSCs compared to normal BM-MSCs; however, comparing the differences between AML and MSCs from AML patients with the differences between normal hematopoietic cells and normal MSCs by Ingenuity pathway analysis showed key distinctions of the AML setting: (1) upstream gene regulation by transforming growth factor beta 1, tumor necrosis factor, tissue transglutaminase 2, CCAAT/enhancer binding protein alpha and SWItch/Sucrose NonFermentable related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4; (2) integrin and interleukin 8 signaling as overrepresented canonical pathways; and (3) upregulation of transcription factors FBJ murine osteosarcoma viral oncogene homolog and v-myb avian myeloblastosis viral oncogene homolog. Thus, phenotypic abnormalities of AML BM-MSCs highlight a dysfunctional BME that may impact AML survival and proliferation.


Subject(s)
Bone Marrow/pathology , Chromosome Aberrations , Leukemia, Myeloid, Acute/genetics , Mesenchymal Stem Cells , Tumor Microenvironment/genetics , Adult , Aged , Animals , Cell Differentiation/genetics , Cell Proliferation/genetics , Cytogenetic Analysis , Female , Gene Expression Regulation, Leukemic , Humans , Leukemia, Myeloid, Acute/pathology , Male , Mice , Middle Aged , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/genetics , Protein Glutamine gamma Glutamyltransferase 2 , Transcriptome
13.
Tissue Antigens ; 83(4): 295-6, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24456416

ABSTRACT

HLA-B*44:101 and HLA-B*57:48 are characterized by amino acid substitutions in the alpha 2 domain.


Subject(s)
Alleles , Databases, Nucleic Acid , HLA-B Antigens/genetics , Base Sequence , Humans , Molecular Sequence Data , Protein Structure, Tertiary , White People
14.
Bone Marrow Transplant ; 49(4): 492-5, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24419523

ABSTRACT

Allo-SCT can result in long-term remission in patients with multiple myeloma (MM), although its overall role in disease management remains controversial. We evaluated lenalidomide monotherapy response and tolerability among 18 patients with MM who progressed or relapsed after Allo-SCT, who were enrolled a median of 12 months (range 3-104) following transplant. Treatment duration of lenalidomide was 8 months (range 1-57). Ten patients required dose reductions from 25 to 5-20 mg at a median of three cycles (range 1-12): eight for neutropenia, one for thrombocytopenia and one for myalgias and weakness. Serious adverse events (N=5) included H1N1 influenza (2), bacterial pneumonia (2) and fever, myalgia and hypoxia. Two patients died at 3 and 5 months of gastrointestinal or hepatic GVHD occurring within 1 month of dosing. Responses included complete response (CR) (5), very good partial response (2), partial response (PR) (3), minimal response (1) and stable disease (2) for an overall response rate (≥ PR) of 56%. Ten patients discontinued therapy for progressive disease (PD) at a median of 8.5 (1-43) months. Six patients died from PD. Five patients remained on therapy at 39 months (range 14-57), with four in CR. Lenalidomide for relapse of MM after Allo-SCT can result in extended disease control (>12 months) in 50% of patients.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Hematopoietic Stem Cell Transplantation/methods , Multiple Myeloma/therapy , Thalidomide/analogs & derivatives , Adult , Aged , Angiogenesis Inhibitors/adverse effects , Disease Progression , Female , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/etiology , Lenalidomide , Male , Middle Aged , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/therapy , Prospective Studies , Remission Induction , Thalidomide/administration & dosage , Thalidomide/adverse effects , Transplantation Conditioning , Transplantation, Homologous
18.
Tissue Antigens ; 78(4): 292-4, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21707538

ABSTRACT

The novel HLA-C allele HLA-C*07:147 contains one nucleotide substitution in exon 2 leading to an amino acid change in the alpha 1 domain from phenylalanine to leucine.


Subject(s)
Alleles , Amino Acid Substitution , HLA-C Antigens/genetics , Mutation, Missense , Humans , Protein Structure, Tertiary
20.
Gene Ther ; 17(10): 1244-52, 2010 Oct.
Article in English | MEDLINE | ID: mdl-20485382

ABSTRACT

One of the major hurdles for the development of gene therapy for Fanconi anemia (FA) is the increased sensitivity of FA stem cells to free radical-induced DNA damage during ex vivo culture and manipulation. To minimize this damage, we have developed a brief transduction procedure for lentivirus vector-mediated transduction of hematopoietic progenitor cells from patients with Fanconi anemia complementation group A (FANCA). The lentiviral vector FancA-sW contains the phosphoglycerate kinase promoter, the FANCA cDNA, and a synthetic, safety-modified woodchuck post transcriptional regulatory element (sW). Bone marrow mononuclear cells or purified CD34(+) cells from patients with FANCA were transduced in an overnight culture on recombinant fibronectin peptide CH-296, in low (5%) oxygen, with the reducing agent, N-acetyl-L-cysteine (NAC), and a combination of growth factors, granulocyte colony-stimulating factor (G-CSF), Flt3 ligand, stem cell factor, and thrombopoietin. Transduced cells plated in methylcellulose in hypoxia with NAC showed increased colony formation compared with 21% oxygen without NAC (P<0.03), showed increased resistance to mitomycin C compared with green fluorescent protein (GFP) vector-transduced controls (P<0.007), and increased survival. Thus, combining short transduction and reducing oxidative stress may enhance the viability and engraftment of gene-corrected cells in patients with FANCA.


Subject(s)
Fanconi Anemia Complementation Group A Protein/genetics , Fanconi Anemia/therapy , Genetic Therapy/methods , Lentivirus/genetics , Acetylcysteine/metabolism , Acetylcysteine/pharmacology , Bone Marrow Cells/cytology , Bone Marrow Cells/metabolism , Fanconi Anemia/pathology , Genetic Vectors/administration & dosage , Genetic Vectors/genetics , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/metabolism , Humans , Mitomycin/pharmacology , Transduction, Genetic
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