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Childhood Leukaemia
Acute Lymphocytic Leukemia: (ALL)
Acute Myeloid Leukemia: (AML)
Chronic Lymphocytic Leukemia: (CLL)
Chronic Myeloid Leukemia: (CML)
Hairy Cell Leukemia

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  • PubMed search for publications about Leukaemia - Limit search to: [Reviews]

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    MeSH term: Leukemia
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Latest Research Publications

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

Bryan LJ, Gordon LI
Releasing the Brake on the Immune System: The PD-1 Strategy for Hematologic Malignancies.
Oncology (Williston Park). 2015; 29(6):431-9 [PubMed] Related Publications
Manipulation of the immune system as a viable cancer treatment strategy has re-emerged. The programmed death 1 (PD-1) pathway is an important, physiologic immune checkpoint necessary to limit autoimmune processes but co-opted by tumors to suppress the antitumor response and allow tumor escape. Blockade of the PD-1 pathway through the use of PD-1 or PD ligand 1(PD-L1) antibodies releases this brake on the immune response. The anti-PD-1 antibodies have produced encouraging results across a broad range of malignancies. Many hematologic malignancies have usurped the PD-1 pathway. Recent investigations have explored the use of anti-PD-1 therapy in hematologic malignancies, with encouraging results. Incorporation of PD-1 blockade into the treatment algorithms for hematologic malignancies is currently being pursued in multiple active clinical trials. Here we review the data on anti-PD-1 monoclonal antibodies to date and discuss ongoing and future clinical trials.

Marinescu C, Vlădăreanu AM, Mihai F
Acute Lymphocytic Leukemia in Adults. Pathologic Features and Prognosis.
Rom J Intern Med. 2015 Jan-Mar; 53(1):31-6 [PubMed] Related Publications
Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells. Among adults it is a relatively rare neoplasm with a curability rate around 30% at 5 years. Currently, the diagnosis and classification of ALL is a multistep procedure that relies on the simultaneous application of multiple techniques that include: cytomorphology, immunophenotype and cytogenetic assays. Some of them have important clinical implications for both diagnosis and predicting response to specific treatment regimens, while the role of others is still to be defined. Over the years, several prognostic factors have been identified and today a risk stratification at diagnosis and during the follow-up is based on the characteristics of the leukemic cells.

De La Harpe Golden P, Egan C, Leader M, et al.
Hodgkin lymphoma in a patient with chronic lymphocytic leukaemia--a rare presentation of Richter's transformation.
Ir Med J. 2015; 108(4):120-1 [PubMed] Related Publications
Richter's transformation of chronic lymphocytic leukaemia (CLL) to high-grade B-cell Non-Hodgkin lymphoma occurs in < 5% of CLL cases. Transformation of CLL to Hodgkin Lymphoma is a much rarer event and here we describe a patient who developed Richter's transformation into a Hodgkin Lymphoma presenting as rapidly progressive hepatosplenomegaly.

He R, Wiktor AE, Hanson CA, et al.
Conventional karyotyping and fluorescence in situ hybridization: an effective utilization strategy in diagnostic adult acute myeloid leukemia.
Am J Clin Pathol. 2015; 143(6):873-8 [PubMed] Related Publications
OBJECTIVES: Cytogenetics defines disease entities and predicts prognosis in acute myeloid leukemia (AML). Conventional karyotyping provides a comprehensive view of the genome, while fluorescence in situ hybridization (FISH) detects targeted abnormalities. The aim of this study was to compare the utility of karyotyping and FISH in adult AML.
METHODS: We studied 250 adult AML cases with concurrent karyotyping and FISH testing. Karyotyping was considered adequate when 20 or more metaphases were analyzed.
RESULTS: In total, 220 cases had adequate karyotyping and were classified as normal karyotype/normal FISH (n = 92), normal karyotype/abnormal FISH (n = 4), abnormal karyotype/normal FISH (n = 8), and abnormal karyotype/abnormal FISH (n = 116). The overall karyotype/FISH concordance rate was 97.7% with five discordant cases identified, four from the normal karyotype/abnormal FISH group and one from the abnormal karyotype/abnormal FISH group. No karyotype/FISH discordance was seen in the abnormal karyotype/normal FISH group for the FISH probes evaluated. FISH lent prognostic information in one (0.5%) of 220 cases with normal karyotype/abnormal FISH: CBFB-MYH11 fusion, indicating favorable prognosis.
CONCLUSIONS: In adult AML, FISH rarely provides additional information when karyotyping is adequate. We therefore propose an evidence-based, cost-effective algorithmic approach for routine conventional karyotype and FISH testing in adult AML workup.

Welner RS, Amabile G, Bararia D, et al.
Treatment of chronic myelogenous leukemia by blocking cytokine alterations found in normal stem and progenitor cells.
Cancer Cell. 2015; 27(5):671-81 [PubMed] Article available free on PMC after 11/05/2016 Related Publications
Leukemic cells disrupt normal patterns of blood cell formation, but little is understood about the mechanism. We investigated whether leukemic cells alter functions of normal hematopoietic stem and progenitor cells. Exposure to chronic myelogenous leukemia (CML) caused normal mouse hematopoietic progenitor cells to divide more readily, altered their differentiation, and reduced their reconstitution and self-renewal potential. Interestingly, the normal bystander cells acquired gene expression patterns resembling their malignant counterparts. Therefore, much of the leukemia signature is mediated by extrinsic factors. Indeed, IL-6 was responsible for most of these changes. Compatible results were obtained when human CML were cultured with normal human hematopoietic progenitor cells. Furthermore, neutralization of IL-6 prevented these changes and treated the disease.

Méndez-Ferrer S, García-Fernández M, de Castillejo CL
Convert and conquer: the strategy of chronic myelogenous leukemic cells.
Cancer Cell. 2015; 27(5):611-3 [PubMed] Related Publications
Emerging evidence is contributing to explain how leukemias disrupt normal blood cell production. In this issue of Cancer Cell, Welner and colleagues show that, during the development of chronic myeloid leukemia, mutated cells transform normal hematopoietic progenitors into "leukemic like" cells through IL-6 secretion, proposing a new cellular target.

Antony-Debré I, Steidl U
Functionally relevant RNA helicase mutations in familial and sporadic myeloid malignancies.
Cancer Cell. 2015; 27(5):609-11 [PubMed] Related Publications
In this issue of Cancer Cell, Polprasert and colleagues identified recurrent mutations in the DEAD/H-box RNA helicase gene DDX41 in familial and acquired cases of myelodsyplasia and acute myeloid leukemia. These mutations induce defects in RNA splicing and represent a new class of mutations in myeloid malignancies.

Wendtner CM, Fischer K
Targeted drugs in concert with chemo: opposites attract.
Blood. 2015; 125(19):2878-9 [PubMed] Related Publications
In this issue of Blood, Brown and colleagues show an impressive additional value when combining a tyrosine kinase inhibitor, that is, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, with classic chemoimmunotherapy in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma

Aburn G, Gott M
Educatin given to parents of children newly diagnosed with acute lymphoblastic leukemia: the parent's perspective.
Pediatr Nurs. 2014 Sep-Oct; 40(5):243-8, 256 [PubMed] Related Publications
Over the last 30 years, diagnosis and treatment of childhood cancers have improved significantly due to medical research and advancements in technology. Increasingly, parents are taking on the role of providing "nursing" care for their children, including managing emergency situations as well as everyday treatment needs. This study investigated the perceptions and experiences of parents caring for newly diagnosed children with acute lymphoblastic leukemia (ALL) in relation to education given prior to the first discharge from hospital. Using a grounded theory approach, 12 parents of children with ALL from a tertiary pediatric hematology and oncology setting in New Zealand were interviewed using a semi-structured interview technique. Key findings of relevance to clinical practice include the importance of recognizing the emotional strain parents experience following diagnosis and the resultant impact upon how education is understood. Findings may also be applicable to other complex child health areas where education is provided, both in a local and international context. Understanding the family perspective is crucial to enabling clinicians to provide appropriate and informative education to children with ALL and their families.

Siddiqi T, Rosen ST
Novel biologic agents for non-Hodgkin lymphoma and chronic lymphocytic leukemia-part 2: adoptive cellular immunotherapy, small-molecule inhibitors, and immunomodulation.
Oncology (Williston Park). 2015; 29(4):299-308 [PubMed] Related Publications
Globally, the incidence of non-Hodgkin lymphoma is increasing. Aggressive non-Hodgkin lymphomas like diffuse large B-cell lymphoma are treated with curative intent in the frontline setting, but indolent diseases like chronic lymphocytic leukemia/small lymphocytic lymphoma are not considered to be curable in general. Additionally, relapsed/refractory non-Hodgkin lymphomas have a poor overall outcome, with treatment response durations often decreasing with each relapse. Novel therapies are sought to improve outcomes in this patient population. In a two-part review, we describe the promising new biologic therapies that have emerged over the last 5 years, some approved by the US Food and Drug Administration and others undergoing active investigation. In Part 1, we discussed monoclonal antibodies. Here, in Part 2, we discuss adoptive cellular immunotherapies, small-molecule inhibitors, and immunomodulatory agents. We also mention other novel therapies on the horizon.

Polprasert C, Schulze I, Sekeres MA, et al.
Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms.
Cancer Cell. 2015; 27(5):658-70 [PubMed] Related Publications
Most cases of adult myeloid neoplasms are routinely assumed to be sporadic. Here, we describe an adult familial acute myeloid leukemia (AML) syndrome caused by germline mutations in the DEAD/H-box helicase gene DDX41. DDX41 was also found to be affected by somatic mutations in sporadic cases of myeloid neoplasms as well as in a biallelic fashion in 50% of patients with germline DDX41 mutations. Moreover, corresponding deletions on 5q35.3 present in 6% of cases led to haploinsufficient DDX41 expression. DDX41 lesions caused altered pre-mRNA splicing and RNA processing. DDX41 is exemplary of other RNA helicase genes also affected by somatic mutations, suggesting that they constitute a family of tumor suppressor genes.

Rahman HS, Rasedee A, Chartrand MS, et al.
Zerumbone induces G2/M cell cycle arrest and apoptosis via mitochondrial pathway in Jurkat cell line.
Nat Prod Commun. 2014; 9(9):1237-42 [PubMed] Related Publications
This investigation determined the anticancer properties of zerumbone (ZER) on the human T-cell (Jurkat) line using the MTT assay, microscopic evaluations, flow cytometric analyses, and caspase activity estimations. The results showed that ZER is selectively cytotoxic to Jurkat cells in a dose and time-dependent manner with IC50 of 11.9 ± 0.2, 8.6 ± 0.5 and 5.4 ± 0.4 μg/mL at 24, 48 and 72 hours of treatment, respectively. ZER did not produce an adverse effect on normal human peripheral blood mononuclear cells (PBMC). ZER is not as cytotoxic as doxorubicin, which imposed an inhibitory effect on Jurkat cells with IC50 of 2.1 ± 0.2, 1.8 ± 0.15, 1.5 ± 0.07 μg/mL after 24, 48 and 72 hours treatment, respectively. ZER significantly (P < 0.05) arrested Jurkat cells at the G2/M phase of the cell cycle. The antiproliferative effect of ZER on Jurkat cells was through the apoptotic intrinsic pathway via the activation of caspase-3 and -9. The results showed that ZER can be further developed into a safe chemotherapeutic compound for the treatment of cancers, especially leukemia.

Tedeschi PM, Kathari YK, Johnson-Farley N, Bertino JR
Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination.
Cancer Chemother Pharmacol. 2015; 75(6):1247-52 [PubMed] Article available free on PMC after 11/05/2016 Related Publications
PURPOSE: To investigate the effectiveness of a combination of 6-thioguanine (6-TG) and pralatrexate (PDX) in methylthioadenosine phosphorylase (MTAP)-deficient T-cell acute lymphoblastic leukemia (T-cell ALL).
METHODS: CCRF-CEM (MTAP(-/-)) and Molt4 (MTAP(+/+)) T-cell ALL cell lines were treated with 6-TG or PDX and evaluated for efficacy 72 h later. NOD/SCID gamma mice bearing CEM or Molt4 xenografts were treated with 6-TG and PDX alone or in combination to evaluate antitumor effects.
RESULTS: CEM cells were more sensitive to 6-TG and PDX in vitro than Molt4. In vivo, CEM cells were very sensitive to PDX and 6-TG, whereas Molt4 cells were highly resistant to 6-TG. A well-tolerated combination of PDX and 6-TG achieved significant tumor regression in CEM xenografts.
CONCLUSIONS: The loss of MTAP expression may be therapeutically exploited in T-cell ALL. The combination of 6-TG and PDX, with the inclusion of leucovorin rescue, allows for a safe and effective regimen in MTAP-deficient T-cell ALL.

Entrena A, Varas A, Vázquez M, et al.
Mesenchymal stem cells derived from low risk acute lymphoblastic leukemia patients promote NK cell antitumor activity.
Cancer Lett. 2015; 363(2):156-65 [PubMed] Related Publications
Mesenchymal stem cells (MSCs) are key components of the bone marrow microenvironment which contribute to the maintenance of the hematopoietic stem cell niche and exert immunoregulatory functions in innate and adaptive immunity. We analyze the immunobiology of MSCs derived from acute lymphoblastic leukemia (ALL) patients and their impact on NK cell function. In contrast to the inhibitory effects on the immune response exerted by MSCs from healthy donors (Healthy-MSCs), we demonstrate that MSCs derived from low/intermediate risk ALL patients at diagnosis (ALL-MSCs) promote an efficient NK cell response including cytokine production, phenotypic activation and most importantly, cytotoxicity. Longitudinal studies indicate that these immunostimulatory effects of ALL-MSCs are progressively attenuated. Healthy-MSCs adopt ALL-MSC-like immunomodulatory features when exposed to leukemia cells, acquiring the ability to stimulate NK cell antitumor function. The mechanisms underlying to these functional changes of ALL-MSCs include reduced production of soluble inhibitory factors, differential expression of costimulatory and coinhibitory molecules, increased expression of specific TLRs and Notch pathway activation. Collectively our findings indicate that, in response to leukemia cells, ALL-MSCs could mediate a host beneficial immunomodulatory effect by stimulating the antitumor innate immune response.

Kang X, Lu Z, Cui C, et al.
The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development.
Nat Cell Biol. 2015; 17(5):665-77 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
Conventional strategies are not particularly successful in the treatment of leukaemia, and identification of signalling pathways crucial to the activity of leukaemia stem cells will provide targets for the development of new therapies. Here we report that certain receptors containing the immunoreceptor tyrosine-based inhibition motif (ITIM) are crucial for the development of acute myeloid leukaemia (AML). Inhibition of expression of the ITIM-containing receptor LAIR1 does not affect normal haematopoiesis but abolishes leukaemia development. LAIR1 induces activation of SHP-1, which acts as a phosphatase-independent signalling adaptor to recruit CAMK1 for activation of downstream CREB in AML cells. The LAIR1-SHP-1-CAMK1-CREB pathway sustains the survival and self-renewal of AML stem cells. Intervention in the signalling initiated by ITIM-containing receptors such as LAIR1 may result in successful treatment of AML.

Hallek M
Chronic lymphocytic leukemia: 2015 Update on diagnosis, risk stratification, and treatment.
Am J Hematol. 2015; 90(5):446-60 [PubMed] Related Publications
DISEASE OVERVIEW: Chronic lymphocytic leukemia (CLL) is the commonest leukemia in western countries. The disease typically occurs in elderly patients and has a highly variable clinical course. Leukemic transformation is initiated by specific genomic alterations that impair apoptosis of clonal B-cells.
DIAGNOSIS: The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes, which identify a clonal B-cell population carrying the CD5 antigen as well as B-cell markers.
PROGNOSIS: Two prognostic staging systems exist, the Rai and Binet staging systems, which are established by physical examination and blood counts. Various biological and genetic markers also have prognostic value. Deletions of the short arm of chromosome 17 (del(17p)) predict resistance to available chemotherapies. Comprehensive prognostic scores are currently being developed.
THERAPY: Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For physical fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, the initial treatment may be repeated, if the treatment-free interval exceeds two to three years. If the disease relapses earlier, therapy should be changed using alternative agents such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. An allogeneic SCT may be considered in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies. Future challenges: Several new agents (e.g., ibrutinib, idelalisib, obinutuzumab) hold the potential to improve the outcome of patients with CLL. However, their optimal use (in terms of combination, sequence, and duration) is unknown. Therefore, CLL patients should be treated in clinical trials whenever possible.

Usumoto Y, Sameshima N, Tsuji A, et al.
Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.
Fukuoka Igaku Zasshi. 2014; 105(12):234-40 [PubMed] Related Publications
We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives.

Konuma T, Kato S, Ishii H, et al.
Long-term outcomes of granulocyte colony-stimulating factor-combined conditioning in allogeneic hematopoietic stem cell transplantation from HLA-identical family donors for myeloid malignancies.
Leuk Res. 2015; 39(6):625-31 [PubMed] Related Publications
Dormant leukemia cells, which might escape the cytotoxic effect of conditioning before hematopoietic stem cell transplantation (HSCT), could be induced to enter the cell cycle by granulocyte colony-stimulating factor (G-CSF) and become more susceptible to the cell-cycle-specific agent cytarabine arabinoside (Ara-C). Based on this effect, we have utilized G-CSF-combined high-dose Ara-C in myeloablative conditioning for allogeneic bone marrow or peripheral blood stem cell transplantation from HLA-identical family donors since 1988. We report on the long-term outcomes of allogeneic HSCT using a conditioning regimen of 12Gy total body irradiation and G-CSF-combined high-dose Ara-C in 89 adult patients with acute myeloid leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome. With a median follow-up of 135 months, the probability of overall survival and cumulative incidence of relapse at 5 years were 67.8% and 19.4%, respectively. In multivariate analysis, disease status at HSCT was associated with survival and relapse. These data demonstrate that G-CSF-combined myeloablative conditioning could be safely and effectively used for patients with myeloid malignancies.

Forconi F
Three years of ibrutinib in CLL.
Blood. 2015; 125(16):2455-6 [PubMed] Related Publications
In this issue of Blood, Byrd et al provide an important update on the prolonged efficacy and the limited and reducing toxicity of the single-agent Bruton tyrosine kinase inhibitor ibrutinib in chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma patients who are followed for a median time of 3 years from start of treatment.

Litzow MR
Finally moving forward in adult ALL.
Blood. 2015; 125(16):2453-4 [PubMed] Related Publications
In this issue of Blood, Dhédin et al from the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) show that young to middle-aged adults who receive a pediatric-intensive chemotherapy regimen for treatment of Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-neg ALL) do not appear to require an allogeneic stem cell transplant (alloSCT) if they achieve a good response on minimal residual disease (MRD) testing after induction therapy. Patients who are not good MRD responders however, achieve better outcomes with alloSCT than their counterparts who do not receive alloSCT.

Lazenby M, Hills R, Burnett AK, Zabkiewicz J
The HSP90 inhibitor ganetespib: A potential effective agent for Acute Myeloid Leukemia in combination with cytarabine.
Leuk Res. 2015; 39(6):617-24 [PubMed] Article available free on PMC after 01/11/2015 Related Publications
HSP90 is a multi-client chaperone involved in regulating a large array of cellular processes and is commonly overexpressed in many different cancer types including hematological malignancies. Inhibition of HSP90 holds promise for targeting multiple molecular abnormalities and is therefore an attractive target for heterogeneous malignancies such as Acute Myeloid Leukemia (AML). Ganetespib is a highly potent second generation HSP90 inhibitor which we show is significantly more effective against primary AML blasts at nanomolar concentrations when compared with cytarabine (p<0.001). Dose dependant cytotoxicity was observed with an apoptotic response coordinate with the loss of pro-survival signaling through the client protein AKT. Combination treatment of primary blasts with ganetespib and cytarabine showed good synergistic interaction (combination index (CI): 0.47) across a range of drug effects with associated reduction in HSP70 feedback and AKT signaling levels. In summary, we show ganetespib to have high activity in primary AMLs as a monotherapy and a synergistic relationship with cytarabine when combined. The combination of cytotoxic cell death, suppression of cytoprotective/drug resistance mechanisms such as AKT and reduced clinical toxicity compared to other HSP90 inhibitors provide strong rationale for the clinical assessment of ganetespib in AML.

Hillmen P, Robak T, Janssens A, et al.
Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial.
Lancet. 2015; 385(9980):1873-83 [PubMed] Related Publications
BACKGROUND: Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options.
METHODS: We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189.
FINDINGS: We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were more common in the chlorambucil plus ofatumumab group (109 [50%] patients; vs 98 [43%] given chlorambucil alone), with neutropenia being the most common event (56 [26%] vs 32 [14%]). Grade 3 or greater infections had similar frequency in both groups. Grade 3 or greater infusion-related adverse events were reported in 22 (10%) patients given chlorambucil plus ofatumumab. Five (2%) patients died during treatment in each group.
INTERPRETATION: Addition of ofatumumab to chlorambucil led to clinically important improvements with a manageable side-effect profile in treatment-naive patients with chronic lymphocytic leukaemia who were elderly or had comorbidities. Chlorambucil plus ofatumumab is therefore an important treatment option for these patients who cannot tolerate more intensive therapy.
FUNDING: GlaxoSmithKline, Genmab A/S.

Tang W, Fan X, Wang L, Hu J
Busulfan and fludarabine conditioning regimen given at hematological nadir of cytoreduction fludarabine, cytarabine, and idarubicin chemotherapy in patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation: a single arm pilot consort study.
Medicine (Baltimore). 2015; 94(15):e706 [PubMed] Related Publications
To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol is accepted as being warranted for further study. Based on the above data, our phase II study demonstrated that the sequential FLAG-IDA cytoreduction chemotherapy followed by Flu-BU conditioning regimen given at the hematological nadir was feasible and has sufficient activity to warrant further investigation prospectively with a larger patient sample (clinicaltrials.gov identifier: NCT01496547).

Kumar KR, Chen W, Koduru PR, Luu HS
Myeloid and lymphoid neoplasm with abnormalities of FGFR1 presenting with trilineage blasts and RUNX1 rearrangement: a case report and review of literature.
Am J Clin Pathol. 2015; 143(5):738-48 [PubMed] Related Publications
OBJECTIVES: Myeloid and lymphoid neoplasms with abnormalities of fibroblast growth factor receptor 1 gene (FGFR1) are a rare and aggressive disease group that harbors translocations of FGFR1 with at least 14 recognized partner genes. We report a case of a patient with a novel t(17;21)(p13;q22) with RUNX1 rearrangement and trilineage blasts.
METHODS: A 29-year-old man with relapsed T-lymphoblastic lymphoma in the cervical nodes showed a myeloproliferative neoplasm in his bone marrow with three separate populations of immunophenotypically aberrant myeloid, T-lymphoid, and B-lymphoid blasts by flow cytometry. Cytogenetic and fluorescent in situ hybridization studies showed unique dual translocations of t(8;13)(p11.2;q12) and t(17;21)(p13;q22) with RUNX1 rearrangement.
RESULTS: The patient was initiated on a mitoxantrone, etoposide, and cytarabine chemotherapy regimen and died of complications of disease 1 month later.
CONCLUSIONS: To our knowledge, this is the first reported case of a myeloid and lymphoid neoplasm with abnormalities of FGFR1 with t(17;21)(p13;q22) and trilineage blasts.

Shaver AC, Greig BW, Mosse CA, Seegmiller AC
B-ALL minimal residual disease flow cytometry: an application of a novel method for optimization of a single-tube model.
Am J Clin Pathol. 2015; 143(5):716-24 [PubMed] Related Publications
OBJECTIVES: Optimizing a clinical flow cytometry panel can be a subjective process dependent on experience. We develop a quantitative method to make this process more rigorous and apply it to B lymphoblastic leukemia/lymphoma (B-ALL) minimal residual disease (MRD) testing.
METHODS: We retrospectively analyzed our existing three-tube, seven-color B-ALL MRD panel and used our novel method to develop an optimized one-tube, eight-color panel, which was tested prospectively.
RESULTS: The optimized one-tube, eight-color panel resulted in greater efficiency of time and resources with no loss in diagnostic power.
CONCLUSIONS: Constructing a flow cytometry panel using a rigorous, objective, quantitative method permits optimization and avoids problems of interdependence and redundancy in a large, multiantigen panel.

Greaves M
When one mutation is all it takes.
Cancer Cell. 2015; 27(4):433-4 [PubMed] Related Publications
In a recent issue of Nature Genetics, Andersson and colleagues report that MLL fusion alone may be sufficient to spawn an aggressive leukemia in infants. Some other pediatric cancers may share a similar, single, "big-hit" origin, possibly reflecting a critical developmental window of stem cell vulnerability.

Malkan UY, Gunes G, Isik A, et al.
Rebound Thrombocytosis following Induction Chemotherapy is an Independent Predictor of a Good Prognosis in Acute Myeloid Leukemia Patients Attaining First Complete Remission.
Acta Haematol. 2015; 134(1):32-7 [PubMed] Related Publications
There are very few data about the relationship between acute myeloid leukemia (AML) prognosis and bone marrow recovery kinetics following chemotherapy. In this study, we aimed to assess the prognostic importance and clinical associations of neutrophil and platelet recovery rates and rebound thrombocytosis (RT) or neutrophilia (RN) in the postchemotherapy period for newly diagnosed AML patients. De novo AML patients diagnosed between October 2002 and December 2013 were evaluated retrospectively. One hundred patients were suitable for inclusion. Cox regression analysis using need for reinduction chemotherapy as a stratification parameter revealed RT as the only parameter predictive of OS, with borderline statistical significance (p = 0.06, OR = 7; 95% CI 0.92-53), and it was the only parameter predictive of DFS (p = 0.024, OR = 10; 95% CI 1.3-75). In order to understand whether RT or RN was related to a better marrow capacity or late consolidation, we considered neutrophil recovery time and platelet recovery time and nadir-first consolidation durations in all patients in the cohort. Both the marrow recovery duration and the time between marrow aplasia and first consolidation were shorter in RT and RN patients. To our knowledge, this is the first study to report a correlation between RT/RN and prognosis in AML.

Sung HJ, Lee SR, Choi IK, et al.
Imatinib Mesylate Dose Adjustment Based on Body Surface Area for CML Chronic Phase Patients Intolerant to Standard Dosage.
Acta Haematol. 2015; 134(1):59-68 [PubMed] Related Publications
AIM: Chronic myelogenous leukemia (CML) chronic phase (CP) patients cannot tolerate a standard dose (400 mg/day) of imatinib mesylate (IM), sometimes needing a reduced dose. This study aimed to find convenient clinical indexes, rather than plasma trough levels of IM, to define the appropriate IM dosage.
METHODS: Seventy CML CP patients who experienced an IM dose reduction, or a temporary cessation, were enrolled from 2002 to 2010. The IM treatment was resumed and maintained at either ≥400 mg in 25 patients (35.7%; group ≥400 mg) or at ≤300 mg in 45 patients (64.3%; group ≤300 mg). The various clinical characteristics of these patients were evaluated. The plasma trough level of IM was monitored in 20 patients from group ≤300 mg.
RESULTS: Via multivariate analysis, the IM dosage divided by the body surface area (BSA) was an important index, presupposing a complete cytogenetic response at 12 months (CCyR12). Patients with IM/BSA >206.7 mg/m2 showed a higher probability of CCyR12 than others. The IM/BSA (221.7 mg/m2) in group ≤300 mg was higher than in group ≥400 mg (207.6 mg/m2). The sustained response and survival rate of group ≤300 mg was comparable to that of group ≥400 mg. The plasma trough level of IM was significantly correlated with the IM/BSA.
CONCLUSION: Our study suggests that IM dose adjustments, based on IM/BSA, could improve the clinical outcomes in CML CP patients.

Lozano-Santos C, Amigo-Jiménez I, Nova-Gurumeta S, et al.
Arsenic trioxide synergistically potentiates the cytotoxic effect of fludarabine in chronic lymphocytic leukemia cells by further inactivating the Akt and ERK signaling pathways.
Biochem Biophys Res Commun. 2015; 461(2):243-8 [PubMed] Related Publications
CLL remains an incurable disease, making it crucial to continue searching for new therapies efficient in all CLL cases. We have studied the effect of combining arsenic trioxide (ATO) with fludarabine, a frontline drug in CLL. We have found a synergistic interaction between 1 μM ATO and 5 μM fludarabine that significantly enhanced the cytotoxic effect of the individual drugs. Importantly, ATO sensitized fludarabine-resistant cells to the action of this drug. The mechanism behind this effect included the downregulation of phospho-Akt, phospho-ERK, and the Mcl-1/Bim and Bcl-2/Bax ratios. The combination of ATO and fludarabine partially overcame the survival effect induced by co-culturing CLL cells with stromal cells. Therefore, low concentrations of ATO combined with fludarabine may be an efficient therapeutic strategy in CLL patients.

Stenehjem JS, Kjærheim K, Bråtveit M, et al.
Benzene exposure and risk of lymphohaematopoietic cancers in 25 000 offshore oil industry workers.
Br J Cancer. 2015; 112(9):1603-12 [PubMed] Article available free on PMC after 28/04/2016 Related Publications
BACKGROUND: The aim of this work was to examine the risk of lymphohaematopoietic (LH) cancer according to benzene exposure among offshore workers.
METHODS: Cancer registry data were used to identify 112 cancer cases diagnosed during 1999-2011 in a cohort of 24 917 Norwegian men reporting offshore work between 1965 and 1999. Analyses were conducted according to a stratified case-cohort design with a reference subcohort of 1661 workers. Cox regression was used to estimate hazard ratios with 95% confidence intervals, adjusted for other benzene exposure and smoking.
RESULTS: Most workers were exposed to benzene for <15 years. The upper range values of average intensity and cumulative exposure were estimated to 0.040 p.p.m. and 0.948 p.p.m.-years, respectively. Risks were consistently elevated among exposed workers for all LH cancers combined and for most subgroups, although case numbers were small and yielded imprecise risk estimates. There was evidence of dose-related risk patterns according to cumulative exposure for acute myeloid leukaemia (AML), multiple myeloma (MM) (P trends 0.052 and 0.024, respectively), and suggestively so for chronic lymphocytic leukaemia (CLL) according to average intensity (P trend 0.094).
CONCLUSIONS: Our results support an association between cumulative and intensity metrics of low-level benzene exposure and risk for AML, MM, and suggestively for CLL.

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