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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Childhood Leukaemia
Acute Lymphocytic Leukemia: (ALL)
Acute Myeloid Leukemia: (AML)
Chronic Lymphocytic Leukemia: (CLL)
Chronic Myeloid Leukemia: (CML)
Hairy Cell Leukemia

Information Patients and the Public (13 links)

Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Barretto NN, Karahalios DS, You D, Hemenway CS
An AF9/ENL-targted peptide with therapeutic potential in mixed lineage leukemias.
J Exp Ther Oncol. 2014; 10(4):293-300 [PubMed] Related Publications
Misregulation of transcription elongation is proposed to underlie the pathobiology of MLL leukemia. AF4, AF9, and ENL, common MLL fusion partners, are found in complex with positive transcription elongation factor b (P-TEFb). AF9 and its homolog ENL directly interact with AF4 within these complexes. Previously, we designed a peptide that mimics the AF9 binding domain of AF4 and reported that MLL leukemia cell lines are inhibited by it. Extending these studies, we have modified the peptide design in order to avoid recognition by proteases. The peptide is as effective as its predecessor in vitro and enhances survival in mice bearing MLL leukemia cell lines.

Related: MLLT2 gene

Halim TA, Nabeel N
Two consecutive twin and a singleton pregnancy in a patient with chronic myeloid leukemia.
J Exp Ther Oncol. 2014; 10(4):259-61 [PubMed] Related Publications
Consecutive multiple pregnancies with Chronic myeloid leukemia is a rare event and little is known about its prevalence and management with or without chemotherapy. We present a case of three consecutive pregnancies in a woman with CML, two of which were multiple pregnancies.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology Breast cancer in pregnancy

Nabhan C, Rosen ST
Chronic lymphocytic leukemia: a clinical review.
JAMA. 2014; 312(21):2265-76 [PubMed] Related Publications
IMPORTANCE: The most common leukemia is chronic lymphocytic leukemia (CLL). Every year, there are 15 000 new diagnoses and 5000 CLL deaths in the United States. Although therapeutic choices were once limited, treatment of this disease has vastly improved in the last decade.
OBJECTIVE: Evidence-based review of the diagnosis, staging, and treatment of CLL.
EVIDENCE REVIEW: PubMed, Cochrane Library, Scopus, and Google Scholar databases were searched through August 28, 2014. English-language peer-reviewed articles published between 2000-2014 were found using the keywords chronic lymphocytic leukemia, upfront therapy, upfront therapies, upfront therapeutic, upfront therapeutics, upfront treatment, front-line treatment, first-line treatment, front-line treatments, first-line treatments, front-line therapy, front-line therapies, randomized, randomized studies, randomized study, clinical trial, clinical trials, phase 3, and phase 3 clinical trial. Abstracts and presentations at scientific meetings were excluded. A total of 277 articles were retrieved, of which 24 met our predefined selection criteria; treatment recommendations were based on subsequent analysis of these 24 articles.
FINDINGS: The Rai and Binet systems for staging CLL were established in 1975 and 1977, respectively. However, they do not account for new disease categories such as monoclonal B-cell lymphocytosis (peripheral blood clonal lymphocytosis that does not meet other criteria for CLL). Two subsets of CLL are now recognized based on risk stratification involving molecular and cytogenetic analyses. Outcomes are improved by the addition of immunotherapy to combination chemotherapy for initial treatment in all subsets of treated patients. Overall response rates between 75% and 90% and complete responses between 22% and 45% are expected in the current era, with more than 80% of treated patients alive at 3 years. Overall, 5-year survival has increased to 66% from 60% (P < .001) in the past 10 years.
CONCLUSIONS AND RELEVANCE: Chemoimmunotherapy is the standard first-line option approach for CLL, the most common leukemia observed in adults. Treatment is initiated when the disease becomes symptomatic, and survival is high following treatment.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Goldshtein A, Berger M
Friend or foe: can activating mutations in NOTCH1 contribute to a favorable treatment outcome in patients with T-ALL?
Crit Rev Oncog. 2014; 19(5):399-404 [PubMed] Related Publications
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of thymocytes. Despite significant improvement in the treatment of T-ALL, approximately 20% of children and most adults succumb to resistant or relapsed disease. Transformation events occur during crucial steps of thymocyte development and have been related to the expression of certain oncogenes such as TAL2, TLX1, LYL1, LMO1, and NOTCH1. Mutations that lead to constitutive activation of NOTCH1 are most commonly found in human patients with T-ALL. Moreover, overexpression of the intracellular portion of NOTCH1 can lead to the initiation of T-ALL in mouse models. These findings suggest that NOTCH1 may promote tumorigenesis through the regulation of differentiation of leukemic cells, and, potentially, of leukemia-initiating cell identity and function. Multiple studies and clinical trials aimed at targeting NOTCH1 in T-ALL or using NOTCH1 mutations as a prognostic tool are currently underway. Recent studies unexpectedly found that activating mutations in NOTCH1 are correlated with better treatment outcome. Here we review these studies and discuss possible explanations for these findings.

Related: NOTCH1 gene

Saito Y, Nakada D
The role of the Lkb1/AMPK pathway in hematopoietic stem cells and Leukemia.
Crit Rev Oncog. 2014; 19(5):383-97 [PubMed] Related Publications
The liver kinase B1 (Lkb1)/AMP-activated protein kinase (AMPK) pathway maintains metabolic homeostasis of cells by promoting catabolism and inhibiting anabolism. Activation of this pathway induces tumor suppressors, including p53, and leads to inhibition of the mammalian target of rapamycin pathway, which often is overactivated in multiple cancers. Thus, the Lkb1/AMPK pathway suppresses cancer by negatively regulating cell proliferation. However, recent studies of mouse hematopoietic stem cells (HSCs) revealed that Lkb1 is critical for maintaining HSCs, rather than limiting their proliferation. Furthermore, the role of AMPK in cancer cells has remained elusive. Outstanding questions concern the role of the Lkb1/AMPK pathway in regulating the metabolism and proliferation of cancer cells within a physiological setting. This review focuses on the function of the Lkb1/AMPK pathway in HSCs and leukemia and provides an overview of the therapeutic strategies aimed at targeting this pathway in cancer.

Related: STK11

Hendriks RW
Stress equips CLL cells to survive.
Blood. 2014; 124(20):3040-1 [PubMed] Related Publications
In this issue of Blood, Krysov et al demonstrate that B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) results in partial activation of the unfolded protein response (UPR).

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Mansour MR, Abraham BJ, Anders L, et al.
Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.
Science. 2014; 346(6215):1373-7 [PubMed] Related Publications
In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself. Additionally, most endogenous super-enhancers found in T-ALL cells are occupied by MYB and CBP, which suggests a general role for MYB in super-enhancer initiation. Thus, this study identifies a genetic mechanism responsible for the generation of oncogenic super-enhancers in malignant cells.

Related: TAL1 gene

Challagundla P, Medeiros LJ, Kanagal-Shamanna R, et al.
Differential expression of CD200 in B-cell neoplasms by flow cytometry can assist in diagnosis, subclassification, and bone marrow staging.
Am J Clin Pathol. 2014; 142(6):837-44 [PubMed] Related Publications
OBJECTIVES: To analyze CD200 expression by flow cytometry in a large series of B-cell neoplasms in a variety of tissue types in comparison with benign B-lineage cells.
METHODS: We measured CD200 expression levels in 505 peripheral blood (PB), bone marrow (BM), and lymphoid tissue biopsy specimens, including 364 cases positive for B-cell leukemias and lymphomas.
RESULTS: CD200 expression in chronic lymphocytic leukemia cases was as bright as or brighter than normal PB B cells in nearly all cases, while mantle cell lymphoma (MCL) cases were usually dim or negative. However, rare MCL cases (about 5%) were moderately bright for CD200. Marginal zone lymphomas varied by subtype, with nodal cases brighter, splenic cases dimmer, and extranodal cases heterogeneous for CD200 expression. Follicular lymphoma (FL) cells were brighter for CD200 in BM specimens than in lymph nodes. In some BM specimens, dim CD200 could distinguish FL cells from background hematogones. Large B-cell lymphomas of the non-germinal center type tended to be brighter for CD200 than those of the germinal center type, while Burkitt lymphomas were negative.
CONCLUSIONS: CD200 staining by flow cytometry can be useful in the differential diagnosis of B-cell neoplasms and in their detection in the BM.

Weinberg OK, Seetharam M, Ren L, et al.
Mixed phenotype acute leukemia: A study of 61 cases using World Health Organization and European Group for the Immunological Classification of Leukaemias criteria.
Am J Clin Pathol. 2014; 142(6):803-8 [PubMed] Related Publications
OBJECTIVES: The 2008 World Health Organization (WHO) classification system grouped bilineal and biphenotypic acute leukemias together under a new heading of mixed phenotype acute leukemia (MPAL). The lineage-specific marker criteria have also changed for a diagnosis of MPAL. The goal of this study was to characterize clinical significance of this new group.
METHODS: Sixty-one patients diagnosed with MPAL using either European Group for the Immunological Classification of Leukaemias (EGIL) criteria or 2008 WHO criteria were included in this study.
RESULTS: Sixteen patients (26%) diagnosed with acute biphenotypic leukemia using EGIL criteria did not fulfill 2008 WHO criteria for MPAL. Cytogenetic data were available for 32 patients, and the most common abnormality was t(9;22) (five of 32 cases). Clinical outcome data suggested that younger patients with MPAL (≤21 years) had better overall survival (OS) in both the EGIL and WHO groups (EGIL, P = .0403; WHO, P = .0601). Compared with 177 patients with acute myeloid leukemia (AML), MPAL patients had better OS (P = .0003) and progression-free survival (P = .0001). However, no difference in OS between MPAL and 387 patients with acute lymphoblastic leukemia was present (P = .599).
CONCLUSIONS: As defined by the 2008 WHO classification, fewer patients are now classified as having MPAL than with the EGIL criteria. In this study, patients with MPAL have a better clinical outcome compared with patients with AML.

Duval C, Boucher S, Moulin JC, et al.
Fatal stimulation of acute myeloid leukemia blasts by pegfilgrastim.
Anticancer Res. 2014; 34(11):6747-8 [PubMed] Related Publications
UNLABELLED: We herein report the case of a male patient with acute myeloid leukemia with fatal outcome attributable to pharmacokinetics of pegfilgrastim.
CASE REPORT: An unexplained blast proliferation in a patient with acute myeloid leukemia following cytotoxic induction chemotherapy was investigated in depth. Myeloblast hyperstimulation was likely related to pegfilgrastim, the long half-life of which extended the duration of side-effects, resulting in massive and rapidly fatal leukemia cell proliferation.
CONCLUSION: Pegfilgrastim can cause unexpected deleterious effects in acute myeloid leukemia. We, thus, recommend administering drugs with a shorter half-life, such as filgrastim or lenograstim, to reduce infection incidence in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.

Related: Acute Myeloid Leukemia (AML)

Nagahara Y, Nagahara K
N-(2-amino-5-chlorobenzoyl)benzamidoxime derivatives inhibit human leukemia cell growth.
Anticancer Res. 2014; 34(11):6521-6 [PubMed] Related Publications
BACKGROUND/AIM: Amidoxime derivatives have been previously reported to have potent anti-microbial and anti-tumor activity. Little is known about the tumor cell growth-inhibition mechanism of amidoximes, especially benzamidoxime derivatives. Herein we determined the effects of N-(2-amino-5-chlorobenzoyl)benzamidoxime analogs on mammalian cancer cells.
MATERIALS AND METHODS: We synthesized four chloride-substituted benzamidoxime analogs from the original benzamidoxime to investigate their anticancer cell activity using the Jurkat T-cell lymphoma cell line and the human leukemia cell line HL-60RG.
RESULTS: All amidoxime derivatives inhibited Jurkat and HL-60RG cell viability dose-dependently. Benzamidoximes tended to damage HL-60RG cells to a greater extent compared to Jurkat cells. Benzamidoximes with chloride substitutes caused a strong decrease in cell growth, and this cell growth attenuation was transient at 5 μM (below the half-maximal inhibitory concentration, IC50) but long-lasting at 10 μM (greater than the IC50).
CONCLUSION: Benzamidoxime derivatives caused a transient cell-cycle delay at a low dose and cell death at a high dose.

Related: Apoptosis

Sakai C, Arai M, Tanaka S, et al.
Effects of arsenic compounds on growth, cell-cycle distribution and apoptosis of tretinoin-resistant human promyelocytic leukemia cells.
Anticancer Res. 2014; 34(11):6489-94 [PubMed] Related Publications
BACKGROUND/AIM: The effects of inorganic and organic arsenicals on proliferation, cell-cycle distribution, and apoptosis of all-transretinoic acid (ATRA)-resistant human promyelocytic leukemia HL-60 (HL-60-R2) cells were herein investigated.
MATERIALS AND METHODS: Cell proliferation was examined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell-cycle distribution and apoptotic cells were analyzed by flow cytometry.
RESULTS: The 50% inhibitory concentrations (IC50 values) for As2O3 against proliferation of HL-60 and HL-60-R2 cells were 12.2 and 7.2 μM, while those for arsenate were >200 and 62.1 μM, respectively. In contrast, organic methylarsinic acid, dimethylarsonic acid, trimethylarsine oxide, and tetramethylarsonium did not exert any inhibitory effects even at 200 μM. As2O3 and arsenate increased the proportion of apoptotic cells dose-dependently at a concentration range of 5-200 μM. As2O3 did not activate caspase 3/7 in HL-60 and HL-60-R2 cells.
CONCLUSION: As2O3 and arsenate inhibit cell proliferation, affect cell-cycle distribution, and induce apoptosis of ATRA-resistant HL-60-R2 cells. The apoptosis-inducing mechanism appears not to be mediated through caspase3/7.

Related: Apoptosis CASP3

Tohda S
NOTCH signaling roles in acute myeloid leukemia cell growth and interaction with other stemness-related signals.
Anticancer Res. 2014; 34(11):6259-64 [PubMed] Related Publications
NOTCH activation plays oncogenic roles in acute T-lymphoblastic leukaemia (T-ALL). However, whether NOTCH is oncogenic or tumor-suppressive in acute myeloid leukaemia (AML) is still controversial. Herein, the roles of NOTCH in AML are reviewed. AML cells express NOTCH and NOTCH ligands; however, cell-autonomous activation is not observed. Activating NOTCH1 mutations are rare in AML, unlike in T-ALL. NOTCH ligand stimulation generally suppresses the in vitro growth of AML cells but promotes transient growth of some samples. Conversely, knockdown of NOTCH1 and NOTCH2 does not affect the growth of AML cells, whereas it suppresses the growth of T-ALL cells. These findings suggest that NOTCH is dispensable or suppressive for AML cell growth. However, the effects of NOTCH differ depending on cell conditions, and various stemness-related signals modify these effects; hence, forced NOTCH activation in vitro may not exhibit effects in bone marrow. Thus, further understanding is required for the development of AML therapies targeting NOTCH signalling.

Related: Acute Myeloid Leukemia (AML) Signal Transduction

McGill CM, Alba-Rodriguez EJ, Li S, et al.
Extracts of Devil's club (Oplopanax horridus) exert therapeutic efficacy in experimental models of acute myeloid leukemia.
Phytother Res. 2014; 28(9):1308-14 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a group of hematological malignancies defined by expanded clonal populations of immature progenitors (blasts) of myeloid phenotype in blood and bone marrow. Given a typical poor prognostic outlook, there is great need for novel agents with anti-AML activity. Devil’s club (Oplopanax horridus) is one of the most significant medicinal plants used among the indigenous people of Southeast Alaska and the coastal Pacific Northwest, with different linguistic groups utilizing various parts of the plant to treat many different conditions including cancer. Studies identifying medically relevant components in Devil’s club are limited. For this research study, samples were extracted in 70% ethanol before in vitro analysis, to assess effects on AML cell line viability as well as to study regulation of tyrosine phosphorylation and cysteine oxidation. The root extract displayed better in vitro anti-AML efficacy in addition to a noted anti-tyrosine kinase activity independent of an antioxidant effect. In vivo therapeutic studies using an immunocompetent murine model of AML further demonstrated that Devil’s club root extract improved the murine survival while decreasing immunosuppressive regulatory T cells and improving CD8+ T-cell functionality. This study defines for the first time an anti-AML efficacy for extracts of Devil’s club.

Related: Acute Myeloid Leukemia (AML) Signal Transduction

Gonçalves E, Martelli DR, Coletta RD, et al.
Risk of leukemia in first degree relatives of patients with nonsyndromic cleft lip and palate.
Braz Oral Res. 2014 Jan-Feb; 28(1):1-3 [PubMed] Related Publications
The aim of this study was to determine the frequency of leukemia in parents of patients with nonsyndromic cleft lip and/or cleft palate (NSCL/P). This case-control study evaluated first-degree family members of 358 patients with NSCL/P and 1,432 subjects without craniofacial alterations or syndromes. Statistical analysis was carried out using Fisher's test. From the 358 subjects with NSCL/P, 3 first-degree parents had history of leukemia, while 2 out of 1,432 subjects from the unaffected group had a family history of leukemia. The frequency of positive family history of leukemia was not significantly increased in first-degree relatives of patients with NSCL/P.

Akyay A, Olcay L, Sezer N, Atay Sönmez Ç
Muscle strength, motor performance, cardiac and muscle biomarkers in detection of muscle side effects during and after acute lymphoblastic leukemia treatment in children.
J Pediatr Hematol Oncol. 2014; 36(8):594-8 [PubMed] Related Publications
Muscle side effects have not been frequently assessed in childhood acute lymphoblastic leukemia (ALL) patients. Our objective was to determine the early and late muscle side effects during childhood ALL treatment. To this end, we examined the early muscle side effects in 15 newly diagnosed "therapy patients" (group I), and the late side effects in 18 ALL survivors "off therapy patients" (group II). Muscle side effects were assessed by measuring hand grip strength (HGS), the "timed up and go" (TUG) test, creatine phosphokinase, myoglobin, plasma electrolytes, cardiac troponin I before and after induction chemotherapy in group I. The same parameters and cranial radiotherapy dose were examined in group II at a single timepoint. Cumulative doses of chemotherapy were calculated, and echocardiograms were obtained for each group. As a result, we found that the HGS and TUG measures of group I at the end of induction were poorer than measures of the first admission, control subjects, and group II. Low HGS measures had been normalized over time, but the TUG measures remained poor. Overt rhabdomyolysis and pyomyositis were not detected in any of the patients. These results suggested that muscle side effect monitoring might be helpful in the follow-up of children with ALL.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Bansode YV, Admane V, Goroshi M, Katria P
Plasma cell leukaemia a rare cause of disproportionate anaemia in a patient presenting as CKD.
J Assoc Physicians India. 2014; 62(3):271-3 [PubMed] Related Publications
The anaemia in patient of chronic kidney disease is commonly related to secondary erythropoietin deficiency. When the severity of anaemia is disproportionate and associated with other haematological abnormalities like thrombocytopenia, then primary haematological disorder and secondary renal involvement must be considered. Renal involvement is common in haematologic disorder like Multiple Myeloma. The diagnosis of haematological disorder may be missed. This is a case of chronic kidney disease with disproportionate severe anaemia with bleeding diasthesis which ultimately turned out to be plasma cell leukaemia.

Nagler A
HLA-DP1 matching: are we there yet?
Blood. 2014; 124(16):2476-7 [PubMed] Related Publications
In this issue of Blood, Pidala et al report that nonpermissive DPB1 allele mismatch is associated with increased transplant-related mortality (TRM) and should be avoided to secure optimal unrelated donor hematopoietic stem cell transplantations (HSCTs).

Yoshida N, Karube K, Utsunomiya A, et al.
Molecular characterization of chronic-type adult T-cell leukemia/lymphoma.
Cancer Res. 2014; 74(21):6129-38 [PubMed] Related Publications
Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL.

Estey EH
Acute myeloid leukemia: 2014 update on risk-stratification and management.
Am J Hematol. 2014; 89(11):1063-81 [PubMed] Related Publications
OVERVIEW: Evidence suggests that even patients aged 70 or above benefit from specific AML therapy. The fundamental decision in AML then becomes whether to recommend standard or investigational treatment. This decision must rest on the likely outcome of standard treatment. Hence we review factors that predict treatment related mortality and resistance to therapy, the latter the principal cause of failure even in patients aged 70 or above. We emphasize the limitations of prediction of resistance based only on pre-treatment factors and stress the need to incorporate post-treatment factors, for example indicators of minimal residual disease. We review various newer therapeutic options and considerations that underlie the decision to recommend allogeneic hematopoietic cell transplant.

Related: Monoclonal Antibodies Acute Myeloid Leukemia (AML)

Maude SL, Frey N, Shaw PA, et al.
Chimeric antigen receptor T cells for sustained remissions in leukemia.
N Engl J Med. 2014; 371(16):1507-17 [PubMed] Article available free on PMC after 16/04/2015 Related Publications
BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.
METHODS: We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.
RESULTS: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.
CONCLUSIONS: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

Related: Cytokines Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Hsi AC, Robirds DH, Luo J, et al.
T-cell prolymphocytic leukemia frequently shows cutaneous involvement and is associated with gains of MYC, loss of ATM, and TCL1A rearrangement.
Am J Surg Pathol. 2014; 38(11):1468-83 [PubMed] Related Publications
T-cell prolymphocytic leukemia (T-PLL) is a rare aggressive mature T-cell leukemia with frequent cutaneous presentation, which has not been well characterized. Among the 25 T-PLLs diagnosed between 1990 and 2013 at our institution, 32% (8/25) showed cutaneous manifestations, presenting as rash, purpura, papules, and ulcers. The skin biopsies showed leukemia cutis with perivascular and periadnexal irregular, small to medium-sized lymphoid infiltrates without epidermotropism. The lymphoid infiltrates were composed of mature CD4+ T cells expressing other T-cell antigens, and a subset (48%) showed dual CD4+/CD8+ coexpression. Higher median absolute peripheral blood lymphocyte count (43.0 vs. 13.0 k/mm; P=0.031) and elevated lactate dehydrogenase levels (P=0.00018) at the time of diagnosis were significantly associated with T-PLLs with skin involvement compared with those without. The extent of bone marrow involvement (P=0.849) and overall survival (P=0.144) was similar in the 2 groups. Fluorescence in situ hybridization or karyotype revealed frequent gains of MYC (67%; n=9), loss of ATM (64%; n=11), and TCL1A rearrangement or inversion 14q (75%; n=12). Gains of TCL1A was also seen (78%; n=9), including in some cases that had concurrent TCL1A rearrangement, whereas TP53 loss was less common (30%; n=10). No correlation was seen between the immunophenotype and morphology versus the presence or absence of skin involvement. These data suggest that cutaneous involvement by T-PLL is relatively common and often associated with significant peripheral blood involvement. The frequent MYC, ATM, and TCL1A alterations identified support that these genes are integral to the pathogenesis of T-PLL.

Related: FISH Skin Cancer MYC gene TCL1A gene ATM

Szwed M, Jozwiak Z
Genotoxic effect of doxorubicin-transferrin conjugate on human leukemia cells.
Mutat Res Genet Toxicol Environ Mutagen. 2014; 771:53-63 [PubMed] Related Publications
Doxorubicin (DOX) is an effective anthracycline antibiotic against a wide spectrum of tumors and hematological malignancies. It mainly interacts with DNA, but can also generate reactive oxygen species (ROS), which damage cell components. Unfortunately, numerous side effects, such as severe cardiotoxicity and bone-marrow suppression, limit its use. To reduce this obstacle and improve its pharmacokinetics, we conjugated DOX to transferrin (TRF), a human plasma protein. In our study, we compared the effect of DOX and the doxorubicin-transferrin conjugate (DOX-TRF) on human leukemic lymphoblasts (CCRF-CEM), and on normal peripheral blood mononuclear cells (PBMC). In parallel, experiments were carried out on two human chronic myeloid leukemia (CML) cell lines derived from K562 cells, of which one was sensitive and the other resistant to doxorubicin (K562/DOX). By use of the alkaline comet assay, the effect of the agents on the induction of DNA damage in normal human cells and human leukemia cells was determined. Oxidative and alkylating DNA damage were assayed by a slightly modified comet assay that included the use of the DNA-repair enzymes endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (Fpg). To investigate whether DNA breaks are the result of apoptosis, we examined the induction of DNA fragmentation visualized as oligosomal ladders after simple agarose electrophoresis under neutral conditions. Modifications of the genome induced by the different drugs were analyzed following assessment of the cell-cycle phase. The DOX-TRF conjugate caused more DNA damage than the free drug, the degree of DNA fragmentation being dependent on the duration of treatment and the cell type analyzed. With neutral agarose electrophoresis we showed that the test compounds caused the formation of a characteristic DNA-ladder pattern. Furthermore, the DOX-TRF conjugate generated a higher percentage of apoptotic cells in the subG1 fraction and blocked more cells in the G2/M phase of the cell cycle than did free DOX. In summary, both agents induced DNA damage in cancer cells, but the DOX-TRF conjugate generated more genotoxic effects and apoptosis than the unconjugated drug.

Related: Doxorubicin Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Al Ustwani O, Griffiths EA, Wang ES, Wetzler M
Omacetaxine mepesuccinate in chronic myeloid leukemia.
Expert Opin Pharmacother. 2014; 15(16):2397-405 [PubMed] Related Publications
INTRODUCTION: Homoharringtonine (HHT) and other alkaloid esters were originally isolated from the Cephalotaxus evergreen tree and have been used in traditional Chinese medicine since the 1970s to treat a variety of malignancies. Although HHT was investigated for the treatment of chronic myeloid leukemia (CML) in the 1990s with good results, the advent of BCR-ABL1 tyrosine kinase inhibitors (TKIs) at that time rapidly established a new standard of care for CML. Omacetaxine mepesuccinate is a semisynthetic derivative of HHT with known clinical activity in relapsed or refractory CML following TKI therapy.
AREAS COVERED: In this review, we summarize the biologic effects of HHT and its derivative, omacetaxine, in CML. Additionally, we analyze the concepts learned from the early trials using these drugs. Data from clinical trials resulting in drug approval are also reviewed.
EXPERT OPINION: Omacetaxine has a clear role in the CML armamentarium for patients in chronic and accelerated phase who have failed or were intolerant to two or more TKIs.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Paganin M, Fabbri G, Conter V, et al.
Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia.
J Clin Oncol. 2014; 32(31):3553-8 [PubMed] Related Publications
PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Monitoring minimal residual disease (MRD) by using real-time quantitative polymerase chain reaction (RQ-PCR) provides information for patient stratification and individual risk-directed treatment. Cooperative studies have documented that measurement of blast clearance from the bone marrow during and after induction therapy identifies patient populations with different risk of relapse. We explored the possible contribution of measurements of MRD during the course of treatment.
PATIENTS AND METHODS: We used RQ-PCR to detect MRD in 110 unselected patients treated in Italy in the International Collaborative Treatment Protocol for Children and Adolescents With Acute Lymphoblastic Leukemia (AIEOP-BFM ALL 2000). The trial took place in AIEOP centers during postinduction chemotherapy. Results were categorized as negative, low positive (below the quantitative range [< 5 × 10(-4)]), or high positive (≥ 5 × 10(-4)). Patients with at least one low-positive or high-positive result were assigned to the corresponding subgroup.
RESULTS: Patients who tested high positive, low positive, or negative had significantly different cumulative incidences of leukemia relapse: 83.3%, 34.8%, and 8.6%, respectively (P < .001). Two thirds of positive cases were identified within 4 months after induction-consolidation therapy, suggesting that this time frame may be most suitable for cost-effective MRD monitoring, particularly in patients who did not clear their disease at the end of consolidation.
CONCLUSION: These findings provide further insights into the dynamic of MRD and the ongoing effort to define molecular relapse in childhood ALL.

Related: Methotrexate Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology

Bosman MC, Schepers H, Jaques J, et al.
The TAK1-NF-κB axis as therapeutic target for AML.
Blood. 2014; 124(20):3130-40 [PubMed] Related Publications
Development and maintenance of leukemia can be partially attributed to alterations in (anti)-apoptotic gene expression. Genome-wide transcriptome analyses revealed that 89 apoptosis-associated genes were differentially expressed between patient acute myeloid leukemia (AML) CD34(+) cells and normal bone marrow (NBM) CD34(+) cells. Among these, transforming growth factor-β activated kinase 1 (TAK1) was strongly upregulated in AML CD34(+) cells. Genetic downmodulation or pharmacologic inhibition of TAK1 activity strongly impaired primary AML cell survival and cobblestone formation in stromal cocultures. TAK1 inhibition was mainly due to blockade of the nuclear factor κB (NF-κB) pathway, as TAK1 inhibition resulted in reduced levels of P-IκBα and p65 activity. Overexpression of a constitutive active variant of NF-κB partially rescued TAK1-depleted cells from apoptosis. Importantly, NBM CD34(+) cells were less sensitive to TAK1 inhibition compared with AML CD34(+) cells. Knockdown of TAK1 also severely impaired leukemia development in vivo and prolonged overall survival in a humanized xenograft mouse model. In conclusion, our results indicate that TAK1 is frequently overexpressed in AML CD34(+) cells, and that TAK1 inhibition efficiently targets leukemic stem/progenitor cells in an NF-κB-dependent manner.

Related: Apoptosis Acute Myeloid Leukemia (AML) Signal Transduction

Tam CS, O'Brien S, Plunkett W, et al.
Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab).
Blood. 2014; 124(20):3059-64 [PubMed] Article available free on PMC after 16/04/2015 Related Publications
Although fludarabine, cyclophosphamide, and rituximab (FCR) together are established as a standard first-line treatment of younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or who have relapsed after, receiving frontline FCR treatment. To define optimal salvage strategy and identify patients unsuitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled in a phase 2 study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months after disease progression. The duration of first remission (REM1) was a key determinant of survival after disease progression and first salvage. Patients with a short REM1 (<3 years) had a short survival period, irrespective of salvage therapy received; these patients have high unmet medical needs and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care.

Related: Cyclophosphamide Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Rituximab (Mabthera) Fludarabine

Tasaki T, Yamauchi T, Matsuda Y, et al.
The response to induction therapy is crucial for the treatment outcomes of elderly patients with acute myeloid leukemia: single-institution experience.
Anticancer Res. 2014; 34(10):5631-6 [PubMed] Related Publications
BACKGROUND/AIM: The prognosis of acute myeloid leukemia (AML) in elderly patients remains poor due to their poor general condition and the intrinsic chemotherapy-resistant nature of their leukemia cells. The present retrospective study evaluated the clinical background as well as the response to treatment, of an unselected group of elderly patients with AML who were admitted to our Institution over a period of six years.
PATIENTS AND METHODS: Patients aged 65 years or older with AML admitted to our Institution between January 2005 and May 2011 were evaluated retrospectively.
RESULTS: Forty-six patients were admitted to our Institution, among whom 41 received remission induction chemotherapy. Twenty-four patients received intensive chemotherapy, while 13 received low-dose cytarabine-based chemotherapy. Other modalities were used in four patients. Complete remission was obtained in 20 patients (48.8%). The complete remission rate (50.0%) tended to be higher in patients receiving intensive chemotherapy than in those receiving low-dose cytarabine-based regimens (30.7%; p=0.25). The median survival time for the whole patient group was 12 months and the 2-year overall survival was 18%. The median survival times for patients with complete remission and for non-responding patients were 14 months and 7 months, respectively. The 2-year overall survival in patients with complete remission was 32%, while that of non-responding patients was 6% (p=0.0025, log-rank test).
CONCLUSION: The present study suggests the necessity of achieving complete remission for obtaining better survival for elderly patients with AML.

Related: Acute Myeloid Leukemia (AML)

Yamauchi T, Uzui K, Nishi R, et al.
Gemtuzumab ozogamicin and olaparib exert synergistic cytotoxicity in CD33-positive HL-60 myeloid leukemia cells.
Anticancer Res. 2014; 34(10):5487-94 [PubMed] Related Publications
BACKGROUND/AIM: Gemtuzumab ozogamicin (GO) consists of the cluster of differentiation 33 (CD33) antibody linked to calicheamicin. The binding of GO to the CD33 antigen on leukemic cells results in internalization and subsequent release of calicheamicin, thereby inducing DNA strand breaks. We hypothesized that the poly (ADP-ribose) polymerase inhibitor olaparib might inhibit DNA repair initiated by GO-induced DNA strand breaks, thereby increasing cytotoxicity.
MATERIALS AND METHODS: The human myeloid leukemia cell line HL-60 and a GO-resistant variant (HL/GO20) were used.
RESULTS: The 50% growth-inhibitory concentrations (IC50) were 24 ng/ml for HL-60 cells and 550 ng/ml for GO-resistant variant HL/GO20 cells. HL/GO20 cells were also refractory to GO-induced apoptosis. CD33 positivity was reduced in HL/GO20 cells. Olaparib-alone did not inhibit the cell growth and did not induce apoptosis in either HL-60 cells or HL/GO20 cells at concentrations of up to 10 μM. When cells were treated with different concentrations of GO in the presence of 10 μM olaparib, the IC50 of GO for HL-60 cells was 13 ng/ml. The combination index was 0.86, indicating synergistic cytotoxicity of GO and olaparib in combination. Such a combination was ineffective for HL/GO20 cells.
CONCLUSION: GO and olaparib exerted synergistic cytotoxicity in CD33-positive myeloid leukemia cells in vitro.

Related: Apoptosis Gemtuzumab (Mylotarg)

Kunami N, Katsuya H, Nogami R, et al.
Promise of combining a Bcl-2 family inhibitor with bortezomib or SAHA for adult T-cell leukemia/lymphoma.
Anticancer Res. 2014; 34(10):5287-94 [PubMed] Related Publications
BACKGROUND: Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor.
MATERIALS AND METHODS: The potential of combining the Bcl-2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-XL, and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T-lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated.
RESULTS: ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1-Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti-apoptotic molecule that confers drug resistance on ATL cells.
CONCLUSION: The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL.

Related: Apoptosis PMAIP1 Bortezomib

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