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Leukemia

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)

  • 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).

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.

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.

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.

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.

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).

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.

Fuchs EJ
Haplo graft engineering: sculpting to a T.
Blood. 2015; 125(15):2315-6 [PubMed] Related Publications
In this issue of Blood, Airoldi et al find that γδ T cells can provide critical antiviral and antileukemia effects after HLA-haploidentical hematopoietic transplants depleted of αβ T cells.

Siegal-Willott JL, Jensen N, Kimi D, et al.
Evaluation of captive gibbons (Hylobates spp., Nomascus spp., Symphalangus spp.) in North American Zoological Institutions for Gibbon Ape Leukemia Virus (GALV).
J Zoo Wildl Med. 2015; 46(1):27-33 [PubMed] Related Publications
This study evaluated 79 captive gibbons (Hylobates, Nomascus, and Symphalangus spp.) within 30 North American zoological institutions for evidence of exposure to and possible infection with gibbon ape leukemia virus (GALV). Enzyme-linked immunosorbent assays (ELISAs) on gibbon serum samples revealed the presence of antibodies against GALV antigens in 28% of animals, indicating previous exposure or possibly protective immunity to GALV. Virus detection in gibbon blood or serum using polymerase chain reaction (PCR) or co-culture of gibbon peripheral blood mononuclear cells with human cells was negative for all samples submitted. The majority (19/27, 70%) of animals with reported health conditions were clinically healthy at the time of sample collection. Historically accrued clinical data were used to assess association of diseases in gibbons antibody positive for GALV. The results suggest captive gibbons could mount an immune response to GALV and show no evidence of infection. There was no association with neoplastic conditions in seropositive animals. The potential role of gibbons as a reservoir for GALV and the role of GALV as an epizoonotic-zoonotic agent or as a contributor to gibbon ape morbidity and mortality are not substantiated by the study findings.

Pinilla-Ibarz J, Chavez JC
Life after ibrutinib? A new unmet need in CLL.
Blood. 2015; 125(13):2013-4 [PubMed] Related Publications
In this issue of Blood, Jain et al reported on the poor outcomes of patients with chronic lymphocytic leukemia (CLL) after the discontinuation of ibrutinib.

Conti RM, Padula WV, Larson RA
Changing the cost of care for chronic myeloid leukemia: the availability of generic imatinib in the USA and the EU.
Ann Hematol. 2015; 94 Suppl 2:S249-57 [PubMed] Related Publications
Imatinib is an oral tyrosine kinase inhibitor and considered to be the most successful targeted anti-cancer agent yet developed given its substantial efficacy in treating chronic myeloid leukemia (CML) and other malignant diseases. In the USA and the European Union (EU), Novartis' composition of matter patent on imatinib will expire in 2016. The potential impact on health system spending levels for CML after generic imatinib becomes available is the subject of significant interest among stakeholders. The extent of the potential savings largely depends on whether and to what extent prices decline and use stays the same or even increases. These are also empirical questions since the likely spending implications following generic imatinib's availability are predicated on multiple factors: physicians' willingness to prescribe generic imatinib, molecule characteristics, and health system priorities. This article discusses each of these issues in turn. We then review their implications for the development of country-specific cost-effectiveness models to predict the implications for cost and quality of care from generic imatinib.

Höglund M, Sandin F, Simonsson B
Epidemiology of chronic myeloid leukaemia: an update.
Ann Hematol. 2015; 94 Suppl 2:S241-7 [PubMed] Related Publications
National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10-12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research.

Hanfstein B, Müller MC, Hochhaus A
Response-related predictors of survival in CML.
Ann Hematol. 2015; 94 Suppl 2:S227-39 [PubMed] Related Publications
The assessment of response to tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) does not only reflect tumor burden at a given time but has been shown to be linked to long-term survival outcomes as well. Therefore, the quantification of molecular or cytogenetic response as early as 3 months on treatment allows a prognostic stratification of a patient's individual risk. With competing TKI regimens available, a timely switch of treatment can be considered if unfavorable outcome has to be expected due to early response failure. Numerous studies have demonstrated the association of long-term outcome with early response for first-line treatment with imatinib, with second-generation TKI and for second-line TKI treatment as well.

Cross NC, Hochhaus A, Müller MC
Molecular monitoring of chronic myeloid leukemia: principles and interlaboratory standardization.
Ann Hematol. 2015; 94 Suppl 2:S219-25 [PubMed] Related Publications
Serial quantification of BCR-ABL1 messenger RNA (mRNA) is an important therapeutic indicator for patients with chronic myeloid leukemia, but historically, there has been substantial variation in results reported by different laboratories. To help improve the comparability of results, an international scale (IS) for BCR-ABL1 was proposed which is being implemented by testing laboratories worldwide. This is being achieved most commonly by the derivation of laboratory-specific conversion factors, but increasingly by the use of kits or reagents that are calibrated to the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL1 mRNA. Recent attention has focused on the need to define and validate levels of deeper molecular response (MR) within the context of the IS. While there has been substantial progress in the alignment of results, BCR-ABL1 measurement is technically challenging and standardization is an ongoing process.

Pfirrmann M, Lauseker M, Hoffmann VS, Hasford J
Prognostic scores for patients with chronic myeloid leukemia under particular consideration of competing causes of death.
Ann Hematol. 2015; 94 Suppl 2:S209-18 [PubMed] Related Publications
Nowadays in many fields of medicine, prognostic scores are used to predict the outcome for individual patients. In chronic myeloid leukemia (CML), the Sokal, the Euro, and the EUTOS score are established prognostic scores which were addressed by the CML management recommendations of the European LeukemiaNet. This review provides a general definition of prognostic scores and explains their meaning. Main differences between the Sokal, the Euro, and the EUTOS score are highlighted. Due to the therapeutic success of tyrosine kinase inhibitors, the proportion of patients with causes of death unrelated to CML is growing. To assess the potential of a drug to prevent dying of CML, causes of death unrelated to CML need to be considered as competing risks. Supported by data of patients randomized to imatinib-based treatments within the German CML study IV, this review also explores the prognostic performance of the established scores if the primary event is death due to CML only and explains the implicit statistical particularities when treating other causes of death as competing risks. In the presence of competing risks, the application of both the cause-specific hazard model and the subdistribution hazard model is recommended when investigating the influence of prognostic factors on the event of interest. Another purpose of this work is to foster the ability of hematologists to interpret the outcome of a cause-specific hazard and a subdistribution hazard model and to understand the differences between them.

Talpaz M, Mercer J, Hehlmann R
The interferon-alpha revival in CML.
Ann Hematol. 2015; 94 Suppl 2:S195-207 [PubMed] Related Publications
Interferon-alpha (IFNα) was once the standard of frontline treatment for chronic myeloid leukemia (CML). Its pleiotropic mechanism of action in CML includes immune activation and specific targeting of CML stem cells. Early studies of IFNα in CML demonstrated that patients in chronic phase could attain extremely stable remissions, which correlated with long-term survival. Some patients even sustained their remission after discontinuing therapy, but the mechanism underlying this phenomenon is not well understood. Today, BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, induce remarkable responses in CML patients and have become the mainstay of CML therapy. Although TKIs target the pathogenic BCR-ABL protein in CML, they cannot fully eradicate CML stem cells. Some of the clinical trials testing IFNα plus imatinib combination therapy suggest that addition of IFNα increases the speed and rate of responses with imatinib therapy. However, the undesirable side effects of IFNα can make this therapy difficult to deliver, and the optimal therapeutic window for using IFNα in combination therapy is unknown. Further studies are needed to clarify the best niche for IFNα use in CML.

Mahon FX
Discontinuation of tyrosine kinase therapy in CML.
Ann Hematol. 2015; 94 Suppl 2:S187-93 [PubMed] Related Publications
Over the past decade, a broad array of drugs designed to selectively inhibit protein tyrosine kinases (tyrosine kinase inhibitors or TKIs) have emerged as novel therapies for cancer patients. Chronic myeloid leukemia (CML) is one of the best examples of successful targeted therapy with a TKI. The overall survival of CML patients who respond to treatment is close to that of the healthy population. The response in many patients is so profound that it is possible to consider stopping their treatment and with time, the number of patients in this group has increased to the point where the issue of treatment cessation has become of utmost importance. This has led to the development of a new concept in the evaluation of CML entitled treatment-free remission. It will be the criterion to evaluate the success of future clinical trials, especially if we want to improve the management of the disease to the point where we can claim to have cured CML.

Gratwohl A, Baldomero H, Passweg J
The role of hematopoietic stem cell transplantation in chronic myeloid leukemia.
Ann Hematol. 2015; 94 Suppl 2:S177-86 [PubMed] Related Publications
Allogeneic hematopoietic stem cell transplantation (HSCT) is currently recommended as 2nd or 3rd line therapy for patients with chronic myeloid leukemia (CML) in first chronic phase or as salvage for patients with very advanced disease. As a consequence, numbers of HSCT in chronic phase have dropped significantly since the introduction of tyrosine kinase inhibitors (TKI), numbers of transplants in advanced disease to a lesser extent. These current recommendations consider primarily disease risk, defined as failure of TKI therapy; they might need to be adapted. We propose a more balanced appraisal of HSCT for individual patients which should include disease risk, transplant risk, and macroeconomic aspects. HSCT should be integrated into the treatment algorithms from diagnosis and be considered very early at first TKI failure for patients with high disease but low transplant risk. For patients with very advanced disease and high transplant risk in contrast, HSCT might only be recommended in a restricted research setting.

Palani R, Milojkovic D, Apperley JF
Managing pregnancy in chronic myeloid leukaemia.
Ann Hematol. 2015; 94 Suppl 2:S167-76 [PubMed] Related Publications
Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the potential detrimental effect of TKIs on fertility and gonadal function. The recommendation given to patients planning pregnancy differs according to their disease response to TKI therapy, which is the most important prognostic factor in CML.

Saußele S, Silver RT
Management of chronic myeloid leukemia in blast crisis.
Ann Hematol. 2015; 94 Suppl 2:S159-65 [PubMed] Related Publications
Due to the high efficacy of BCR-ABL tyrosine kinase inhibition (TKI) in chronic phase (CP) chronic myeloid leukemia (CML), the frequency of blast crisis (BC) is greatly reduced compared to the pre-TKI era. However, TKI treatment of BC has only marginally improved the number of favorable responses, including remissions, which for the most part have only been transitory. Occasionally, they provide a therapeutic window to perform an allogeneic stem cell transplantation (allo-SCT). The challenge remains to improve management of BC with the limited options available. We review and summarize articles pertaining to the treatment of BC CML published after 2002. Additionally, we will discuss whether there is a need for a new definition of BC and/or treatment failure.

Rea D
Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia.
Ann Hematol. 2015; 94 Suppl 2:S149-58 [PubMed] Related Publications
Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new-generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient-related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed.

Baccarani M, Castagnetti F, Gugliotta G, Rosti G
A review of the European LeukemiaNet recommendations for the management of CML.
Ann Hematol. 2015; 94 Suppl 2:S141-7 [PubMed] Related Publications
Several guidelines and recommendations on the management of chronic myeloid leukemia (CML) have been prepared by several scientific societies. The European LeukemiaNet (ELN) appointed a panel of experts who submitted their recommendations to peer-reviewed scientific journals in 2006, 2009, and 2013. Here, we make a critical review of the last, 2013, ELN recommendations, concerning the use of the five available tyrosine kinase inhibitors (TKIs), the evaluation of cytogenetic and molecular response, and the strategy of treatment. Three TKIs (imatinib, nilotinib, dasatinib) are recommended first-line. Bosutinib and ponatinib are available second-line; ponatinib is particularly indicated in case of the T315I mutation. Achieving an optimal response, not only for survival but also for a deeper, stable, treatment-free remission, requires a BCR-ABL transcripts level ≤ 10 % at 3 months, ≤ 1 % at 6 months, ≤ 0.1 % at 1 year, and ≤ 0.01 % later on. Molecular monitoring must include mutational analysis in every case of failure. A successful treatment of accelerated and blastic phase requires TKIs, and in many cases also allogeneic stem cell transplantation.

Hochhaus A, Ernst T, Eigendorff E, La Rosée P
Causes of resistance and treatment choices of second- and third-line treatment in chronic myelogenous leukemia patients.
Ann Hematol. 2015; 94 Suppl 2:S133-40 [PubMed] Related Publications
For patients with chronic myelogenous leukemia who fail first-line therapy, several factors should be considered for the decision of the next treatment option. Second-generation tyrosine kinase inhibitors (TKIs) dasatinib, nilotinib, and bosutinib offer improved potency and a high likelihood of success for these patients. Overall, efficacy data are comparable for these agents, and so physicians should consider the BCR-ABL1 mutation profile and the patient's history to make a decision on the best choice. Only a few BCR-ABL1 mutations seem to be less responsive to any of the three drugs, and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient's disease history. The third-generation TKI ponatinib is available after dasatinib or nilotinib failure or for patients with T315I mutations. However, optimal dose of ponatinib is still under investigation. Overall, it is recommended to select a drug that minimizes the likelihood of worsening the patient's past side effects or comorbid conditions. In any case, chance and risk of allogeneic stem cell transplantation should be compared with the long-term outcome of TKI therapy in patients eligible for this procedure.

Fava C, Rege-Cambrin G, Saglio G
The choice of first-line chronic myelogenous leukemia treatment.
Ann Hematol. 2015; 94 Suppl 2:S123-31 [PubMed] Free Access to Full Article Related Publications
Imatinib has represented a revolution in the treatment of chronic myeloid leukemia (CML), inducing an overall survival never seen with previous therapies. However, with the commonly used dosage of 400 mg, one third of the treated patients does not reach the criteria associated with an optimal outcome and could potentially benefit from a different treatment strategy. Several trials exploring modified imatinib-based treatments or second-generation tyrosine-kinase as front-line therapy have been performed. In some studies, high-dose (800 mg per day) or dose-adapted imatinib or imatinib plus interferon was reported to be able to induce better cytogenetic and molecular responses compared with standard-dose imatinib, although no improvements in progression-free survival (PFS) or overall survival (OS) have been so far reported. At the moment, these approaches are still considered investigational. On the other side, on the basis of their capacity to induce very fast and deep molecular responses, including major molecular responses (MMRs) and the newly defined very deep molecular responses MR⁴ and MR(4.5), and to prevent at least part of the early progressions to AP/BC that still occur during the first 2-3 years from diagnosis, dasatinib and nilotinib have been approved and registered by FDA and EMA as the first-line therapy for CML patients, opening the possibility to use different therapeutic strategies for newly diagnosed CML patients and a consequent intense debate among hematologists.

Chereda B, Melo JV
Natural course and biology of CML.
Ann Hematol. 2015; 94 Suppl 2:S107-21 [PubMed] Related Publications
Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and 'indolent' symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease.

Smirnova OA
Myeloid leukemia risk assessment and dynamics of the granulocytopoietic system in acutely and continuously irradiated humans: modeling approach.
Health Phys. 2015; 108(5):492-502 [PubMed] Related Publications
A dynamic modeling approach to the risk assessment of radiogenic myeloid leukemia is proposed. A basic tool of this approach is a biologically motivated mathematical model of the granulocytopoietic system, which is capable of predicting the dynamics of blood granulocytes and bone marrow granulocytopoietic cells in acutely and chronically irradiated humans. The performed modeling studies revealed that the dose dependence of the scaled maximal concentration of bone marrow granulocytopoietic cells with radiation-induced changes, which make a cell premalignant, and the dose dependence of the scaled integral of the concentration of these cells over the period of the response of the granulocytopoietic system to acute irradiation conform to the dose dependence of excess relative risk for myeloid leukemia among atomic bomb survivors in a wide range of doses and in a range of comparatively low doses, respectively. Additionally, the dose dependence of the scaled integral of the concentration of these cells over the period of the response of the granulocytopoietic system to continuous irradiation with the dose rate and durations, which were used in brachytherapy, conforms to the dose dependence of excess relative risk for leukemia among the respective groups of exposed patients. These modeling findings demonstrate the potential to use the proposed modeling approach for predicting the excess relative risk for myeloid leukemia among humans exposed to various radiation regimes. Obviously, this is especially important in the assessment of the risks for radiogenic myeloid leukemia among people residing in contaminated areas after an accident or explosion of a radiological device, among astronauts on long-term space missions, as well as among patients treated with radiotherapy.

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