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2.  Minimal residual disease detection with tumor-specific CD160 correlates with event-free survival in chronic lymphocytic leukemia 
Blood Cancer Journal  2015;5(1):e273-.
In chronic lymphocytic leukemia (CLL), the detection of minimal residual disease (MRD) correlates with outcome in the trial setting. However, MRD assessment does not guide routine clinical management and its assessment remains complex. We incorporated detection of the B cell, tumor-specific antigen CD160 to develop a single-tube, flow cytometry assay (CD160FCA) for CLL MRD to a threshold of 10−4 to 10−5. One hundred and eighty-seven patients treated for CLL were enrolled. Utilizing the CD160FCA methodology, there was a high level of comparison between blood and bone marrow (R=0.87, P<0.001). In a validation cohort, CD160FCA and the international standardised approach of the European Research Initiative on CLL group demonstrated high concordance (R=0.91, P<0.01). Patients in complete remission (CR) and CD160FCA negative had longer event-free survival (EFS) (63 vs 16 months, P<0.01) and prolonged time to next treatment (60 vs 15 months, P<0.001) vs MRD positive patients; with a median time to MRD positivity of 36 months. In multivariate analysis, CD160FCA MRD detection was independently predictive of EFS in patients in CR and even predicted EFS in the good-risk cytogenetic subgroup. CD160FCA offers a simple assay for MRD detection in CLL and gives prognostic information across different CLL risk groups.
PMCID: PMC4314455  PMID: 25615279
4.  Novel recurrent mutations in ethanolamine kinase 1 (ETNK1) gene in systemic mastocytosis with eosinophilia and chronic myelomonocytic leukemia 
Blood Cancer Journal  2015;5(1):e275-.
Although KITD816V occurs universally in adult systemic mastocytosis (SM), the clinical heterogeneity of SM suggests presence of additional phenotype-patterning mutations. Because up to 25% of SM patients have KITD816V-positive eosinophilia, we undertook whole-exome sequencing in a patient with aggressive SM with eosinophilia to identify novel genetic alterations. We conducted sequencing of purified eosinophils (clone/tumor sample), with T-lymphocytes as the matched control/non-tumor sample. In addition to KITD816V, we identified a somatic missense mutation in ethanolamine kinase 1 (ETNK1N244S) that was not present in 50 healthy controls. Targeted resequencing of 290 patients showed ETNK1 mutations to be distributed as follows: (i) SM (n=82; 6% mutated); (ii) chronic myelomonocytic leukemia (CMML; n=29; 14% mutated); (iii) idiopathic hypereosinophilia (n=137; <1% mutated); (iv) primary myelofibrosis (n=32; 0% mutated); and (v) others (n=10; 0% mutated). Of the 82 SM cases, 25 had significant eosinophilia; of these 20% carried ETNK1 mutations. The ten mutations (N244S=6, N244T=1, N244K=1, G245A=2) targeted two contiguous amino acids in the ETNK1 kinase domain, and are predicted to be functionally disruptive. In summary, we identified novel somatic missense ETNK1 mutations that were most frequent in SM with eosinophilia and CMML; this suggests a potential pathogenetic role for dysregulated cytidine diphosphate-ethanolamine pathway metabolites in these diseases.
PMCID: PMC4314457  PMID: 25615281
5.  Autophagy collaborates with ubiquitination to downregulate oncoprotein E2A/Pbx1 in B-cell acute lymphoblastic leukemia 
Yuan, N | Song, L | Lin, W | Cao, Y | Xu, F | Liu, S | Zhang, A | Wang, Z | Li, X | Fang, Y | Zhang, H | Zhao, W | Hu, S | Wang, J | Zhang, S
Blood Cancer Journal  2015;5(1):e274-.
B-cell acute lymphoblastic leukemia (B-ALL) accounts for the most cancer incidences in children. We present here that autophagy is downregulated in pediatric B-ALL, suggesting a possible link between autophagy failure and pediatric B-ALL leukemogenesis. With a pediatric t(1;19) B-ALL xenograft mouse model, we show here that activation of autophagy by preventive administration of rapamycin improved the survival of leukemia animals by partial restoration of hematopoietic stem/progenitor cells, whereas treatment of the animals with rapamycin caused leukemia bone marrow cell-cycle arrest. Activation of autophagy in vitro or in vivo by rapamycin or starvation downregulated oncogenic fusion protein E2A/Pbx1. Furthermore, E2A/Pbx1 was found to be colocalized with autophagy marker LC3 in autolysosomes and with ubiquitin in response to autophagy stimuli, whereas autophagy or ubiquitination inhibitor blocked these colocalizations. Together, our data suggest a collaborative action between autophagy and ubiquitination in the degradation of E2A/Pbx1, thereby revealing a novel strategy for targeted preventive or treatment therapy on the pediatric ALL.
PMCID: PMC4314458  PMID: 25615280
6.  Hypoxia promotes stem cell-like phenotype in multiple myeloma cells 
Blood Cancer Journal  2014;4(12):e262-.
PMCID: PMC4315888  PMID: 25479569
7.  Reduced TET2 function leads to T-cell lymphoma with follicular helper T-cell-like features in mice 
Blood Cancer Journal  2014;4(12):e264-.
TET2 (Ten Eleven Translocation 2) is a dioxygenase that converts methylcytosine (mC) to hydroxymethylcytosine (hmC). TET2 loss-of-function mutations are highly frequent in subtypes of T-cell lymphoma that harbor follicular helper T (Tfh)-cell-like features, such as angioimmunoblastic T-cell lymphoma (30–83%) or peripheral T-cell lymphoma, not otherwise specified (10–49%), as well as myeloid malignancies. Here, we show that middle-aged Tet2 knockdown (Tet2gt/gt) mice exhibit Tfh-like cell overproduction in the spleen compared with control mice. The Tet2 knockdown mice eventually develop T-cell lymphoma with Tfh-like features after a long latency (median 67 weeks). Transcriptome analysis revealed that these lymphoma cells had Tfh-like gene expression patterns when compared with splenic CD4-positive cells of wild-type mice. The lymphoma cells showed lower hmC densities around the transcription start site (TSS) and higher mC densities at the regions of the TSS, gene body and CpG islands. These epigenetic changes, seen in Tet2 insufficiency-triggered lymphoma, possibly contributed to predated outgrowth of Tfh-like cells and subsequent lymphomagenesis. The mouse model described here suggests that TET2 mutations play a major role in the development of T-cell lymphoma with Tfh-like features in humans.
PMCID: PMC4315889  PMID: 25501021
8.  Definition and management of ruxolitinib treatment failure in myelofibrosis 
Blood Cancer Journal  2014;4(12):e268-.
Ruxolitinib, a Janus kinase (JAK)-1 and JAK-2 inhibitor, is the first-in-class drug to be licensed in the United States for the treatment of high- and intermediate-risk myelofibrosis (MF). Several other JAK inhibitors are in development with some currently undergoing phase-3 clinical trial testing. None of the currently available JAK inhibitors are specific to mutant JAK2; their mechanism of action involves attenuation of JAK-STAT signaling with downregulation of proinflammatory cytokines, rather than selective suppression of the disease clone. Accordingly, while ruxolitinib and other JAK inhibitors are effective in controlling splenomegaly and alleviating constitutional symptoms, their benefit in terms of reversing bone marrow fibrosis or inducing complete or partial remissions appears to be limited. The experience to date with ruxolitinib shows that despite its salutary effects on quality of life, over half of the patients discontinue treatment within 2–3 years. In the current perspective, we examine the incidence and causes of ruxolitinib ‘treatment failure' in MF patients based on our personal experience as well as a review of the published literature. We also discuss the challenges in defining and classifying ruxolitinib failure, and within the context of several clinical scenarios, we provide recommendations for the post-ruxolitinib management of MF patients.
PMCID: PMC4315890  PMID: 25501025
9.  Decision analysis for donor selection in stem cell transplantation—HLA-8/8 allele-matched unrelated donor vs HLA-1 AG mismatched related donor 
Blood Cancer Journal  2014;4(12):e263-.
Risk of relapse during the unrelated donor coordination period biases comparisons between allogeneic hematopoietic stem cell transplantation from an HLA 8 of 8 allele-matched unrelated donor (8/8 MUD) and that from a related donor with an HLA-1 antigen mismatch in the graft-versus-host (GVH) direction (RD/1AGMM-GVH). To reduce this bias, we performed a decision analysis focusing on acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The primary outcome measure was 5-year survival probability with or without quality-of-life (QOL) adjustment. A baseline analysis showed that the decision to perform MUD transplantation was superior to that to perform RD/1AGMM-GVH transplantation for patients with AML or ALL. However, in the ALL cohort, the direction of superiority was reversed when the interval between CR1 and 8/8 MUD transplantation was >5.5 months (without QOL adjustment) or >6 months (after QOL adjustment) or when overall survival of RD/1AGMM-GVH transplantation improved by 1.3% without QOL adjustment and 2.1% after QOL adjustment. In conclusion, 8/8 MUD should be prioritized in transplantation for AML and ALL in CR1. However, the MUD coordination period and improvements in RD/1AGMM-GVH transplantation might change the donor selection priority in transplantation for ALL in CR1.
PMCID: PMC4315891  PMID: 25479570
12.  Concurrent IMRT and weekly cisplatin followed by GDP chemotherapy in newly diagnosed, stage IE to IIE, nasal, extranodal NK/T-Cell lymphoma 
Blood Cancer Journal  2014;4(12):e267-.
On the basis of the benefits of frontline radiation in early-stage, extranodal natural killer (NK)/T-cell lymphoma (ENKTL), we conducted the trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of gemcitabine, dexamethasone and cisplatin (GDP). Thirty-two patients with newly diagnosed, stage IE to IIE, nasal ENKTL received CCRT (that is, all patients received intensity-modulated radiotherapy 56 Gy and cisplatin 30 mg/m2 weekly, 3–5 weeks). Three cycles of GDP (gemcitabine 1000 mg/m2 intravenously (i.v.) on days 1 and 8, dexamethasone 40 mg orally on days 1–4 and cisplatin 75 mg/m2 i.v. on day 1 (GDP), every 21 days as an outpatient were scheduled after CCRT. All patients completed CCRT, which resulted in 100% response that included 24 complete responses (CRs) and eight partial responses. The CR rate after CCRT was 75.0% (that is, 24 of 32 responses). Twenty-eight of the 32 patients completed the planned three cycles of GDP, whereas four patients did not because they withdrew (n=1) or because they had an infection (n=3). The overall response rate and the CR rate were 90.6% (that is, 29 of 32 responses) and 84.4% (that is, 27 of 32 responses), respectively. Only two patient experienced grade 3 toxicity during CCRT (nausea), whereas 13 of the 30 patients experienced grade 4 neutropenia. The estimated 3-year overall survival and progression-free rates were 87.50% and 84.38%, respectively. In conclusion, CCRT followed by GDP chemotherapy can be a feasible and effective treatment strategy for stage IE to IIE nasal ENKTL.
PMCID: PMC4315894  PMID: 25501024
13.  Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells 
Blood Cancer Journal  2014;4(12):e269-.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34+ cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.
PMCID: PMC4315895  PMID: 25501026
14.  Inter- and intratumoral heterogeneity of BCL2 correlates with IgH expression and prognosis in follicular lymphoma 
Blood Cancer Journal  2014;4(10):e249-.
Most follicular lymphomas (FLs) are genetically defined by the t(14;18)(q32;q21) translocation that juxtaposes the BCL2 gene to the immunoglobulin heavy chain (IgH) 3' regulatory regions (IgH-3'RRs). Despite this recurrent translocation, FL cases are heterogeneous in terms of intratumoral clonal diversity for acquired mutations and variations in the tumor microenvironment. Here we describe an additional mechanism that contributes to inter- and intratumoral heterogeneity in FLs. By applying a novel single-molecule RNA fluorescence-based in situ hybridization (FISH) technique to detect mRNA molecules of BCL2 and IgH in single cells, we found marked heterogeneity in the number of BCL2 mRNA transcripts within individual lymphoma cells. Moreover, BCL2 mRNA molecules correlated with IgH mRNA molecules in individual cells both in t(14;18) lymphoma cell lines and in patient samples. Consistently, a strong correlation between BCL2 and IgH protein levels was found in a series of 205 primary FL cases by flow cytometry and immunohistochemistry. Inter- and intratumoral heterogeneity of BCL2 expression determined resistance to drugs commonly used in FL treatment and affected overall survival of FL patients. These data demonstrate that BCL2 and IgH expressions are heterogeneous and coregulated in t(14;18)-translocated cells, and determine the response to therapy in FL patients.
PMCID: PMC4220646  PMID: 25303368
15.  Comparative analysis of minimal residual disease detection by multiparameter flow cytometry and enhanced ASO RQ-PCR in multiple myeloma 
Blood Cancer Journal  2014;4(10):e250-.
Multiparameter flow cytometry (MFC) and allele-specific oligonucleotide real-time quantitative PCR (ASO RQ-PCR) are the two most sensitive methods to detect minimal residual disease (MRD) in multiple myeloma (MM). We compared these methods in 129 paired post-therapy samples from 22 unselected, consecutive MM patients in complete/near complete remission. Appropriate immunophenotypic and ASO RQ-PCR-MRD targets could be detected and MRD analyses constructed for all patients. The high PCR coverage could be achieved by gradual widening of the primer sets used for clonality detection. In addition, for 13 (55%) of the patients, reverse orientation of the ASO primer and individual design of the TaqMan probe improved the sensitivity and specificity of ASO RQ-PCR analysis. A significant nonlinear correlation prevailed between MFC-MRD and PCR-MRD when both were positive. Discordance between the methods was found in 32 (35%) paired samples, which were negative by MFC-MRD, but positive by ASO RQ-PCR. The findings suggest that with the described technique, ASO RQ-PCR can be constructed for all patients with MM. ASO RQ-PCR is slightly more sensitive in MRD detection than 6−10-color flow cytometry. Owing to technical demands ASO RQ-PCR could be reserved for patients in immunophenotypic remission, especially in efficacy comparisons between different drugs and treatment modalities.
PMCID: PMC4220647  PMID: 25303369
16.  Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma 
Blood Cancer Journal  2014;4(10):eXX-.
Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r2=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4+ T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.
PMCID: PMC4220648  PMID: 25303370
17.  Phase 1 dose-escalation study of IV ixazomib, an investigational proteasome inhibitor, in patients with relapsed/refractory lymphoma 
Blood Cancer Journal  2014;4(10):e251-.
Ixazomib is an investigational proteasome inhibitor that has shown preclinical activity in lymphoma models. This phase 1 study assessed the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics and preliminary activity of intravenous (IV) ixazomib in relapsed/refractory lymphoma patients who had received ⩾2 prior therapies. Thirty patients with a range of histologies received ixazomib 0.125−3.11 mg/m2 on days 1, 8 and 15 of 28-day cycles. Patients received a median of two cycles (range 1−36). MTD was determined to be 2.34 mg/m2. Most common drug-related adverse events (AEs) included fatigue (43%), diarrhea (33%), nausea, vomiting and thrombocytopenia (each 27%). Drug-related grade ⩾3 AEs included neutropenia (20%), thrombocytopenia (13%) and diarrhea (10%). Drug-related peripheral neuropathy occurred in four (13%) patients; no grade ⩾3 events were reported. Plasma exposure increased dose proportionally from 0.5−3.11 mg/m2; terminal half-life was 4−12 days after multiple dosing. Of 26 evaluable patients, five achieved responses: 4/11 follicular lymphoma patients (one complete and three partial responses) and 1/4 peripheral T-cell lymphoma patients (partial response). Sustained responses were observed with ⩾32 cycles of treatment in two heavily pretreated follicular lymphoma patients. Results suggest weekly IV ixazomib is generally well tolerated and may be clinically active in relapsed/refractory lymphoma.
PMCID: PMC4220649  PMID: 25325301
18.  Markedly improved outcomes and acceptable toxicity in adolescents and young adults with acute lymphoblastic leukemia following treatment with a pediatric protocol: a phase II study by the Japan Adult Leukemia Study Group 
Blood Cancer Journal  2014;4(10):e252-.
The superiority of the pediatric protocol for adolescents with acute lymphoblastic leukemia (ALL) has already been demonstrated, however, its efficacy in young adults remains unclear. The ALL202-U protocol was conducted to examine the efficacy and feasibility of a pediatric protocol in adolescents and young adults (AYAs) with BCR–ABL-negative ALL. Patients aged 15–24 years (n=139) were treated with the same protocol used for pediatric B-ALL. The primary objective of this study was to assess the disease-free survival (DFS) rate and its secondary aims were to assess toxicity, the complete remission (CR) rate and the overall survival (OS) rate. The CR rate was 94%. The 5-year DFS and OS rates were 67% (95% confidence interval (CI) 58–75%) and 73% (95% CI 64–80%), respectively. Severe adverse events were observed at a frequency that was similar to or lower than that in children treated with the same protocol. Only insufficient maintenance therapy significantly worsened the DFS (hazard ratio 5.60, P<0.001). These results indicate that this protocol may be a feasible and highly effective treatment for AYA with BCR–ABL-negative ALL.
PMCID: PMC4220650  PMID: 25325302
20.  Plerixafor is superior to conventional chemotherapy for first-line stem cell mobilisation, and is effective even in heavily pretreated patients 
Blood Cancer Journal  2014;4(10):e255-.
This study (PHANTASTIC) compares first-line plerixafor with granulocyte colony-stimulating factor (G-CSF) in 98 myeloma and lymphoma patients with 151 historic controls mobilised by conventional chemotherapy+G-CSF. Eleven patients developed mild transient symptoms possibly related to plerixafor. No serious adverse events were seen. Seventy (71%) plerixafor-mobilised patients achieved both ⩾4 × 106 CD34+ cells/kg in ⩽2 aphereses and no neutropenia (<1.0 × 109/l). This is significantly >48 (32%) of 151 historical chemotherapy+G-CSF-mobilised control patients achieving this end point (P<0.001). Ninety-six (98%) plerixafor-mobilised patients achieved ⩾2 × 106 CD34+ cells/kg within one harvest round compared with 114 (75%) of controls (P=0.001). Engraftment times and 12-month outcome were comparable in both groups. Prior treatment was summarised by two scoring systems. Controls mobilising either >2.0 or >4.0 × 106 CD34+ cells/kg have significantly lower scores than mobilisation failures (P=0.002), but this relationship was not seen for plerixafor-mobilised patients. Plerixafor is a more effective and less toxic mobilising agent than conventional chemotherapy (especially in heavily pretreated patients), with comparable subsequent outcome, and merits consideration as the first-line standard of care for stem cell mobilisation.
PMCID: PMC4220652  PMID: 25360901
23.  Variable risk of second primary malignancy in multiple myeloma patients of different ethnic subgroups 
Blood Cancer Journal  2014;4(9):e243-.
Second primary malignancies (SPMs) among multiple myeloma (MM) patients have been reported with an estimated incidence varying from 1 to 15%. We have previously reported that significant disparity exists in MM survival across patients of different ethnicities. We undertook a Surveillance Epidemiology and End Results-based analysis to describe the incidence of SPMs among MM patients of different ethnicities, to explore the variable impact that SPMs might have on MM outcomes of patients across racial subgroups. We found that the risk of developing SPMs among MM patients is variable depending on the patient's ethnic background. This warrants further exploration of the impact of SPMs on outcomes of MM patients across different racial subgroups, especially in the form of prospective data collection and analyses.
PMCID: PMC4183772  PMID: 25192415

Results 1-25 (260)