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1.  Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors 
The New England journal of medicine  2012;367(16):10.1056/NEJMoa1203517.
Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.
We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).
The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P = 0.29), with an absolute difference of 5 percentage points (95% CI, −3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P = 0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P = 0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.
We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute–National Cancer Institute and others; number, NCT00075816.)
PMCID: PMC3816375  PMID: 23075175
2.  Myelodysplastic Syndromes 
PMCID: PMC3768131  PMID: 21233243
NCCN Clinical Practice Guidelines; NCCN Guidelines; myelodysplastic syndromes; chronic myelomonocytic leukemia; refractory anemia; cytopenias; treatment
3.  Use of Cytomegalovirus Intravenous Immune Globulin for the Adjunctive Treatment of Cytomegalovirus in Hematopoietic Stem Cell Transplant Patients 
Pharmacotherapy  2010;30(6):554-561.
Study Objective
To describe characteristics and clinical outcomes of hematopoietic stem cell transplant (HSCT) patients who received adjunctive Cytomegalovirus Intravenous Immune Globulin (CMV-IVIG) for probable or proven cytomegalovirus (CMV) disease.
Retrospective cohort study.
A large, university-affiliated, tertiary-care medical center.
Thirty-five adult HSCT patients receiving at least one dose of CMV-IVIG for adjunctive treatment of probable or proven CMV disease over an eight-year period.
Measurements and Main Results
All-cause mortality at hospital discharge was the primary outcome. All patients received an allogeneic HSCT. Twenty-six patients had pneumonitis (74%), nine had enteritis (26%), and 29 had CMV viremia (83%). All patients received concomitant antiviral therapy; 31 (89%) received ganciclovir and 14 (40%) received foscarnet. All-cause mortality at hospital discharge was 49%. Patient characteristics associated with mortality included requiring intubation for CMV pneumonia (79% of non-survivors vs. 25% of survivors, p=0.016) and earlier disease onset following HSCT (median of 48 days for non-survivors vs. 106 days for survivors, p<0.001). In multivariable analysis, only requiring intubation for CMV pneumonia remained a significant risk factor for increased mortality. CMV-IVIG was attributed with a low rate of adverse events; mild hypertension (5.7%) and erythema/chills (2.9%) were most common.
The mortality rate in our population is similar to previous reports in the literature, and may be somewhat lower than rates reported with antiviral monotherapy. Our analysis suggests that factors associated with mortality include the need for intubation and, possibly, earlier onset of CMV disease following HSCT. CMV-IVIG appears to be well-tolerated in HSCT patients. These findings support further trials of CMV-IVIG efficacy in this setting.
PMCID: PMC3668347  PMID: 20500045
Cytomegalovirus intravenous immune globulin; Cytomegalovirus disease; Hematopoietic stem cell transplantation
4.  Recognizing and managing the expanded risk of tumor lysis syndrome in hematologic and solid malignancies 
Tumor lysis syndrome (TLS) is widely recognized as a serious adverse event associated with the cytotoxic therapies primarily used in hematologic cancers, such as Burkitt lymphoma and acute lymphoblastic leukemia. In recent years, TLS has been more widely observed, due at least in part to the availability of more effective cancer treatments. Moreover, TLS is seen with greater frequency in solid tumors, and particularly in bulky tumors with extensive metastases and tumors with organ or bone marrow involvement. The consequences of TLS include the serious morbidity and high risk of mortality associated with the condition itself. Additionally, TLS may delay or force an alteration in the patient’s chemotherapy regimen. The changing patterns of TLS, as well as its frequency, in the clinical setting, result in unnecessarily high rates of illness and/or fatality. Prophylactic measures are widely available for patients at risk of TLS, and are considered highly effective. The present article discusses the various manifestations of TLS, its risk factors and management options to prevent TLS from occurring.
PMCID: PMC3544586  PMID: 23237230
Acute renal failure; Allopurinol; Adverse events; Hematologic malignancies; Management; Prophylactic therapy; Solid tumors; Tumor lysis syndrome (TLS); Rasburicase; Uric acid
5.  Prognostic Significance of FDG-PET in Relapsed or Refractory Classical Hodgkin Lymphoma Treated with Standard Salvage Chemotherapy and Autologous Stem Cell Transplantation 
Positron emission tomography using [18F]fluorodeoxyglucose (FDG-PET) has emerged as the standard response assessment tool in front-line therapy for classical Hodgkin lymphoma (cHL). The ability of FDG-PET to predict outcomes in patients with relapsed cHL treated with modern standard salvage chemotherapy and autologous stem cell transplantation (ASCT) remains uncertain. Forty-six patients with relapsed/refractory cHL treated from 2001–2007 with standard salvage/ASCT therapy had FDG-PET available for blinded review. The results of pre-ASCT FDG-PET interpreted by the international harmonization project (IHP) criteria were compared to published prognostic models for prediction of event free survival (EFS) and overall survival (OS). Overall, 3 year EFS was 62% and OS was 78% with a median follow-up of 38 months. Pre-ASCT FDG-PET response significantly predicted 3 year EFS in FDG-PET negative (82%) versus FDG-PET positive (41%) patients (p=0.02). A trend was observed for 3 year OS comparing FDG-PET negative (91%) versus positive (64%) patients (p=0.08). Multivariate analysis demonstrated the independent prognostic significance of pre-ASCT FDG-PET for EFS with a HR of 3.2 (CI 1.1–9.0, p=0.03). Pre-ASCT FDG-PET scans predict EFS in patients with relapsed cHL patients treated with modern salvage/ASCT therapy, and warrant prospective evaluation.
PMCID: PMC3166401  PMID: 21601641
autologous stem cell transplantation; classical Hodgkin lymphoma; FDG-PET; prognosis
6.  Clonal Architecture of Secondary Acute Myeloid Leukemia 
The New England Journal of Medicine  2012;366(12):1090-1098.
The myelodysplastic syndromes are a group of hematologic disorders that often evolve into secondary acute myeloid leukemia (AML). The genetic changes that underlie progression from the myelodysplastic syndromes to secondary AML are not well understood.
We performed whole-genome sequencing of seven paired samples of skin and bone marrow in seven subjects with secondary AML to identify somatic mutations specific to secondary AML. We then genotyped a bone marrow sample obtained during the antecedent myelodysplastic-syndrome stage from each subject to determine the presence or absence of the specific somatic mutations. We identified recurrent mutations in coding genes and defined the clonal architecture of each pair of samples from the myelodysplastic-syndrome stage and the secondary-AML stage, using the allele burden of hundreds of mutations.
Approximately 85% of bone marrow cells were clonal in the myelodysplastic-syndrome and secondary-AML samples, regardless of the myeloblast count. The secondary-AML samples contained mutations in 11 recurrently mutated genes, including 4 genes that have not been previously implicated in the myelodysplastic syndromes or AML. In every case, progression to acute leukemia was defined by the persistence of an antecedent founding clone containing 182 to 660 somatic mutations and the outgrowth or emergence of at least one subclone, harboring dozens to hundreds of new mutations. All founding clones and subclones contained at least one mutation in a coding gene.
Nearly all the bone marrow cells in patients with myelodysplastic syndromes and secondary AML are clonally derived. Genetic evolution of secondary AML is a dynamic process shaped by multiple cycles of mutation acquisition and clonal selection. Recurrent gene mutations are found in both founding clones and daughter subclones. (Funded by the National Institutes of Health and others.)
PMCID: PMC3320218  PMID: 22417201
7.  Reduced Intensity Allogeneic Transplantation Provides High Event-Free And Overall Survival In Patients With Advanced Indolent B Cell Malignancies: CALGB 109901 
CALGB conducted a Phase II study to evaluate the safety and efficacy of a reduced-intensity conditioning regimen with allogeneic transplantation to treat patients with recurrent low grade B cell malignancies. Patients over age 18 with a diagnosis of relapsed, chemotherapy-sensitive disease underwent transplantation with a matched sibling donor and conditioning with cyclophosphamide (1 g/m2/d × 3) and fludarabine phosphate (25 mg/m2/d × 5). GVH prophylaxis included cyclosporine or tacrolimus plus low-dose methotrexate. Forty-four evaluable patients with a median age of 53 and median of two prior regimens were accrued. Sixteen patients had follicular NHL and 28 had histologies including 7 indolent B cell lymphomas, 4 mantle cell, 15 chronic lymphocytic leukemia, and 2 prolymphocytic leukemia pts. The six-month treatment-related mortality (TRM) was 2.4% and three-year TRM was 9%. Three-year event-free and overall survival were.75 and .81 for the follicular patients, .59 and .71 for the CLL/PLL patients, and .55 and .64 for the other histologies. The incidence of grade 2–4 acute graft vs host disease (GVHD) was 29% and extensive chronic GVHD was 18%. This report demonstrates that allogeneic sibling transplantation with a reduced intensity conditioning regimen is safe and efficacious for patients with advanced indolent B cell malignancies enrolled on a Cooperative Group study.
PMCID: PMC3134602  PMID: 21296675
8.  Clonal evolution in relapsed acute myeloid leukemia revealed by whole genome sequencing 
Nature  2012;481(7382):506-510.
Most patients with acute myeloid leukemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level1,2. To determine the mutational spectrum associated with relapse, we sequenced the primary tumor and relapse genomes from 8 AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to precisely define clonality and clonal evolution patterns at relapse. Besides discovering novel, recurrently mutated genes (e.g. WAC, SMC3, DIS3, DDX41, and DAXX) in AML, we found two major clonal evolution patterns during AML relapse: 1) the founding clone in the primary tumor gained mutations and evolved into the relapse clone, or 2) a subclone of the founding clone survived initial therapy, gained additional mutations, and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific vs. primary tumor mutations in all 8 cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped in part by the chemotherapy that the patients receive to establish and maintain remissions.
PMCID: PMC3267864  PMID: 22237025
Nature Genetics  2011;44(1):53-57.
Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole genome sequencing to perform an unbiased comprehensive screen to discover all the somatic mutations in a sAML sample and genotyped these loci in the matched MDS sample. Here we show that a missense mutation affecting the serine at codon 34 (S34) in U2AF1 was recurrently mutated in 13/150 (8.7%) de novo MDS patients, with suggestive evidence of an associated increased risk of progression to sAML. U2AF1 is a U2 auxiliary factor protein that recognizes the AG splice acceptor dinucleotide at the 3′ end of introns and mutations are located in highly conserved zinc fingers in U2AF11,2. Mutant U2AF1 promotes enhanced splicing and exon skipping in reporter assays in vitro. This novel, recurrent mutation in U2AF1 implicates altered pre-mRNA splicing as a potential mechanism for MDS pathogenesis.
PMCID: PMC3247063  PMID: 22158538
10.  Recurrent DNMT3A Mutations in Patients with Myelodysplastic Syndromes 
Alterations in DNA methylation have been implicated in the pathogenesis of myelodysplastic syndromes (MDS), although the underlying mechanism remains largely unknown. Methylation of CpG dinucleotides is mediated by DNA methyltransferases, including DNMT1, DNMT3A, and DNMT3B. DNMT3A mutations have recently been reported in patients with de novo acute myeloid leukemia (AML), providing a rationale for examining the status of DNMT3A in MDS samples. Here, we report the frequency of DNMT3A mutations in patients with de novo MDS, and their association with secondary AML. We sequenced all coding exons of DNMT3A using DNA from bone marrow and paired normal cells from 150 patients with MDS and identified 13 heterozygous mutations with predicted translational consequences in 12/150 patients (8.0%). Amino acid R882, located in the methyltransferase domain of DNMT3A, was the most common mutation site, accounting for 4/13 mutations. DNMT3A mutations were expressed in the majority of cells in all tested mutant samples regardless of blast counts, suggesting that DNMT3A mutations occur early in the course of MDS. Patients with DNMT3A mutations had worse overall survival compared to patients without DNMT3A mutations (p=0.005) and more rapid progression to AML (p=0.007), suggesting that DNMT3A mutation status may have prognostic value in de novo MDS.
PMCID: PMC3202965  PMID: 21415852
myelodysplastic syndrome; DNMT3A; mutation
11.  Use of whole genome sequencing to diagnose a cryptic fusion oncogene 
Whole genome sequencing (WGS) is becoming increasingly available for research purposes, but it has not yet been routinely used for clinical diagnosis.
To determine whether whole genome sequencing can identify cryptic, actionable mutations in a clinically relevant time frame.
Design, Setting, and Patient
We were referred a difficult diagnostic case of acute promyelocytic leukemia with no pathogenic X-RARA fusion identified by routine metaphase cytogenetics or interphase FISH. The patient was enrolled in an IRB approved protocol, with consent specifically tailored to the implications of whole genome sequencing. The protocol employs a ‘movable firewall,’ which maintains patient anonymity within the entire research team, but allows the research team to communicate medically relevant information to the treating physician.
Main Outcome Measure
Clinical relevance of whole genome sequencing and time to communicate validated results to the treating physician.
Massively parallel paired-end sequencing allowed us to identify a cytogenetically cryptic event: 77 kilobases from chromosome 15 was inserted en bloc into the second intron of the RARA gene on chromosome 17, resulting in a classic bcr3 PML-RARA fusion gene. RT-PCR subsequently validated the expression of the fusion transcript. Novel FISH probes identified two additional cases of t(15;17)-negative acute promyelocytic leukemia that had cytogenetically invisible insertions. Whole genome sequencing and validation were completed in seven weeks, and changed the treatment plan for the patient.
Whole genome sequencing can identify cytogenetically invisible oncogenes in a clinically relevant timeframe.
PMCID: PMC3156695  PMID: 21505136
12.  DNA sequencing of a cytogenetically normal acute myeloid leukemia genome 
Nature  2008;456(7218):66-72.
Lay Summary
Acute myeloid leukemia is a highly malignant hematopoietic tumor that affects about 13,000 adults yearly in the United States. The treatment of this disease has changed little in the past two decades, since most of the genetic events that initiate the disease remain undiscovered. Whole genome sequencing is now possible at a reasonable cost and timeframe to utilize this approach for unbiased discovery of tumor-specific somatic mutations that alter the protein-coding genes. Here we show the results obtained by sequencing a typical acute myeloid leukemia genome and its matched normal counterpart, obtained from the patient’s skin. We discovered 10 genes with acquired mutations; two were previously described mutations thought to contribute to tumor progression, and 8 were novel mutations present in virtually all tumor cells at presentation and relapse, whose function is not yet known. Our study establishes whole genome sequencing as an unbiased method for discovering initiating mutations in cancer genomes, and for identifying novel genes that may respond to targeted therapies.
We used massively parallel sequencing technology to sequence the genomic DNA of tumor and normal skin cells obtained from a patient with a typical presentation of FAB M1 Acute Myeloid Leukemia (AML) with normal cytogenetics. 32.7-fold ‘haploid’ coverage (98 billion bases) was obtained for the tumor genome, and 13.9-fold coverage (41.8 billion bases) was obtained for the normal sample. Of 2,647,695 well-supported Single Nucleotide Variants (SNVs) found in the tumor genome, 2,588,486 (97.7%) also were detected in the patient’s skin genome, limiting the number of variants that required further study. For the purposes of this initial study, we restricted our downstream analysis to the coding sequences of annotated genes: we found only eight heterozygous, non-synonymous somatic SNVs in the entire genome. All were novel, including mutations in protocadherin/cadherin family members (CDH24 and PCLKC), G-protein coupled receptors (GPR123 and EBI2), a protein phosphatase (PTPRT), a potential guanine nucleotide exchange factor (KNDC1), a peptide/drug transporter (SLC15A1), and a glutamate receptor gene (GRINL1B). We also detected previously described, recurrent somatic insertions in the FLT3 and NPM1 genes. Based on deep readcount data, we determined that all of these mutations (except FLT3) were present in nearly all tumor cells at presentation, and again at relapse 11 months later, suggesting that the patient had a single dominant clone containing all of the mutations. These results demonstrate the power of whole genome sequencing to discover novel cancer-associated mutations.
PMCID: PMC2603574  PMID: 18987736
13.  Cellular immune therapy for refractory cancers: novel therapeutic strategies 
Experimental hematology  2005;33(12):1427-1435.
Allogeneic stem cell transplantation is curative for certain cancers, but the high doses of chemotherapy and radiotherapy may lead to toxicity. This review summarizes the field of cellular immune therapy using very-low–dose conditioning for refractory cancers.
In our initial study, we treated 25 patients with refractory cancers with 100 cGy total body irradiation followed by allogeneic, nonmobilized peripheral blood cells. Eighteen patients received sibling and seven patients received unrelated cord blood stem cells.
None of the 13 patients with solid tumors achieved donor chimerism or had a sustained response. Twelve patients with hematologic malignancies were treated, 1 received a cord blood transplant and 11 received sibling donor cells. Nine of these 11 patients achieved donor chimerism, ranging from 5% to 100%. Four patients had sustained complete remission of their cancers. The patients who received cord blood transplants did not respond. Development of chimerism correlated with total previous myelotoxic chemotherapy (p < 0.001). We review additional studies in this area, including data in the haploidentical and unrelated donor setting. The data presented comprises studies performed at the four institutions represented by the authors, and a review of other pertinent studies in this area.
Cellular immune therapy is an emerging application of transplantation therapy, which may be appropriate for refractory cancers. New studies in solid tumors, and with alternative donors, will expand the application of this new and promising treatment.
PMCID: PMC1986765  PMID: 16338484

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