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Allogeneic hematopoietic stem cell transplantation has been and still the only curative treatment for chronic myeloid leukemia (CML), despite its complications and high mortality rates. It still keeps its place in the CML treatment arsenal even with the availability of first and second generations of tyrosine-kinase inhibitors. Patientswho fail to respond to the previously cited treatments combined or as single therapy will have to evaluate new promising treatments with either omacetaxine mepesuccinate or ponatinib. We present in this paper a review of different past and near future treatment options for CML. [ABSTRACT FROM AUTHOR]

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3–67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.Leukemia (2006) 20, 1061–1066. doi:10.1038/sj.leu.2404236; published online 27 April 2006 [ABSTRACT FROM AUTHOR]

Summary:In order to study efficacy, toxicity and the long-term results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation (HSCT) in 30 patients with a median delay of 107.5 months after transplant and 58 months after DLI. After DLI, 15 patients established full donor chimerism, three patients developed grade III and one grade IV acute GVHD. A total of 15 patients achieved a disease response. Among the 14 patients with chronic myeloid leukemia (CML), 11 are alive at the last follow-up: five are in complete molecular response (CMR) and two in complete cytogenetic response (CCR) with no other intervention after DLI, three in CMR after imatinib mesylate given after DLI and one in complete hematological response after imatinib mesylate and reduced-intensity conditioning allogeneic SCT performed after DLI. At the time of the last follow-up, 19 (63%) patients died and 11 (37%) remain alive. The 3-year probability of survival for the entire population, CML patients and non-CML patients, was 60, 93, 62%after transplantation, and 48, 80 and 48%after DLI, respectively. A multivariate analysis demonstrated a significantly worse survival rate after transplantation for female recipients, advanced disease and acute leukemia before transplantation.Bone Marrow Transplantation (2005) 35, 601-608. doi:10.1038/sj.bmt.1704807 Published online 31 January 2005 [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of a 34-year-old woman with myelodysplastic syndrome-secondary acute myeloid leukemia (AML) and underwent a treatment of extensive cutaneous graft-versus-host-disease (GVHD) through allogeneic hematopoietic stem cell transplantation (HSCT).

The article discusses the study of the impact of BCR-ABL P-loop mutations to patients with chronic myelogenous leukemia. A multivariate analysis is performed to patients resistant to imatinib including with and without mutations, poor prognosis features, clonal evolution and high peripheral basophil counts. Results indicated the importance of patient selection, impact of new agents and stem cell transplantation as well as the genetic background.

Resistance to cancer therapy is an enduring challenge and accurate and reliable preclinical models are lacking. We interrogated this unmet need using high grade serous ovarian cancer (HGSC) as a disease model. We created five in vitro and two in vivo platinum-resistant HGSC models and characterised the entire cell panel via whole genome sequencing, RNASeq and creation of intraperitoneal models. Mutational signature analysis indicated that platinum-resistant cell lines evolved from a pre-existing ancestral clone but a unifying mutational cause for drug resistance was not identified. However, cisplatin-resistant and carboplatin-resistant cells evolved recurrent changes in gene expression that significantly overlapped with independent samples obtained from multiple patients with relapsed HGSC. Gene Ontology Biological Pathways (GOBP) related to the tumour microenvironment, particularly the extracellular matrix, were repeatedly enriched in cisplatin-resistant cells, carboplatin-resistant cells and also in human resistant/refractory samples. The majority of significantly over-represented GOBP however, evolved uniquely in either cisplatin- or carboplatin-resistant cell lines resulting in diverse intraperitoneal behaviours that reflect different clinical manifestations of relapsed human HGSC. Our clinically relevant and usable models reveal a key role for non-genetic factors in the evolution of chemotherapy resistance. Biological pathways relevant to the extracellular matrix were repeatedly expressed by resistant cancer cells in multiple settings. This suggests that recurrent gene expression changes provide a fitness advantage during platinum therapy and also that cancer cell-intrinsic mechanisms influence the tumour microenvironment during the evolution of drug resistance. Candidate genes and pathways identified here could reveal therapeutic opportunities in platinum-resistant HGSC. • A new panel of platinum-resistant HGSC cell lines and in vivo models that are easy to use in standard laboratory conditions. • Resistant HGSC cell lines evolved from a pre-existing clone without a unifying mutational cause for drug resistance. • Recurrent changes in gene expression were shared by resistant HGSC cells and multiple patients with resistant HGSC. • Extracellular matrix-related genes and pathways were repeatedly expressed by resistant HGSC cell lines and human patients. • Resistant HGSC cell lines produced diverse intraperitoneal behaviours that reflect relapsed human HGSC. [ABSTRACT FROM AUTHOR]

Imatinib mesylate is the sole BCR-ABL tyrosine kinase inhibitor approved as first-line treatment of accelerated-phase (AP) chronic myeloid leukemia (CML). Indication was based on the STI571 0109 study, in which imatinib favorably compared to historical treatments in patients failing prior therapies. The relevance of these results to currently newly diagnosed AP-CML patients remains unknown. We evaluated the benefit of imatinib in 42 newly diagnosed AP-CML patients. In all, 16 patients had hematological acceleration without chromosomal abnormalities in addition to the Philadelphia chromosome (ACAs; HEM-AP), 16 solely had ACAs (ACA-AP) and 10 had hematological acceleration plus ACAs (HEM-AP+ACA). Major cytogenetic responses were achieved in 93.7% of HEM-AP patients, 75% of patients with ACA-AP (P=NS) and 40% of patients with HEM-AP+ACA (P=0.0053). The 24-month failure-free survival rate was 87.5% in HEM-AP patients, 43.8% in ACA-AP patients and 15% in HEM-AP+ACA patients (P=0.022). The 24-month estimate of progression-free survival was 100% in HEM-AP patients, 92.8% in ACA-AP patients and 58.3% in HEM-AP+ACA patients (P=0.0052). In conclusion, frontline imatinib allows favorable outcomes in HEM-AP and ACA-AP patients but appears insufficient for patients with HEM-AP+ACA. Broader-target and/or more potent BCR-ABL tyrosine kinase inhibitors alone or in combination may be considered in this setting. [ABSTRACT FROM AUTHOR]

To investigate whether haematopoietic stem cells in patients with sickle cell (SS) disease might be altered, we examined the number and cycling status of 5-week long-term culture-initiating cells (LTC-ICs) and in vitro multilineage colony-forming cells (CFCs) present in the blood of a large and clinically diverse group of SS patients. The concentrations of both of these cell types per ml of blood varied over a wide range in individual patients, but, on average, were significantly elevated above normal values (∼sevenfold and 15-fold respectively) and to an even greater extent than the lineage-restricted CFCs in the same samples. Wide variations in the concentration of circulating progenitors, particularly the LTC-ICs, were also seen over time (in concert with changes in the white blood cell count) in SS patients. [3H]-Thymidine suicide assays showed most of the CFCs and LTC-ICs in SS blood to be quiescent like their counterparts in normal blood. However, by comparison with historical data, the SS progenitors could be recruited into the cycle more quickly (i.e. within 2 vs. 3 d), thus showing the same kinetics of activation exhibited by ‘mobilized’ progenitors from patients given chemotherapy and exogenous growth factors. Taken together, these findings implicate previously documented increases in endogenous Steel factor, interleukin 3 and granulocyte–macrophage colony-stimulating factor levels in SS patients in the establishment of a chronically mobilized progenitor phenotype. [ABSTRACT FROM AUTHOR]

Neoplastic CD34+ cells from chronic myeloid leukemia (CML) patients proliferate in vitro in the absence of serum or defined growth factors due to an autocrine mechanism involving IL-3 and G-CSF (Jiang et al. Proc Natl Acad Sci USA 1999; 96: 12804). Detailed examination of the various cell types produced in such cultures has now demonstrated the rapid, factor-independent, generation of clonogenic progenitors for all lineages (granulocyte-macrophage, megakaryocyte and erythroid) with the additional appearance within 10 days of large numbers of mature granulocytes, macrophages, and megakaryocytes, as well as occasional erythroid cells. Inclusion of flt3-ligand, Steel factor, IL-3, IL-6, and G-CSF +/- erythropoietin (EPO) in the cultures enhanced only slightly the output of mature cells (except for the erythroid population which was much larger when EPO was added). Analogous subpopulations of normal CD34+ cells produced similar numbers and types of cells but, as expected, only when growth factors were added. Thus primitive CD34+ CML cells proliferating autonomously in vitro recapitulate the full spectrum of differentiation responses of normal CD34+ cells stimulated by IL-3 and G-CSF. These findings point to a role of autocrine IL-3 and G-CSF in the similar multi-lineage expansion of differentiating CD34+ CML cells that occurs in vivo. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented about Dasatinib-induced acute hepatitis.

A letter to the editor is presented in response to the article about the effect of homoharringtonine on chronic myeloid leukemia.

This article presents a letter to the editor about three additional cases of chronic myeloid leukemia patients with an e802 BCR-ABL fusion transcripts treated with imatinib.

Objectives To study the management of chronic disseminated candidiasis (CDC) in patients presenting with acute leukemia. Patients and methods Single-center retrospective study of acute leukemia patients (2006–2015) to investigate three aspects of CDC: its impact on the time interval between diagnosis and hematopoietic stem cell transplantation, when required (non-parametric Wilcoxon-Mann-Whitney test); its impact on overall survival (Cox proportional hazard regression model); antifungal therapeutic strategies implemented. Results A total of 639 patients presenting with acute leukemia were included; 144 were transplanted and 29 developed CDC. CDC did not significantly increase the time interval between diagnosis and transplantation, nor did it impact the overall survival of recipients. An improved overall survival was observed in non-transplanted acute leukemia patients presenting with CDC. Conclusion CDC should not postpone transplantation if antifungal treatment is optimized. [ABSTRACT FROM AUTHOR]

Actinomycosis is a rare chronic and multifaceted disease caused by Actinomyces species frequently mimicking malignancy or other chronic granulomatous lung diseases. We report 4 original presentations of actinomycosis arising under supposed penicillin prophylaxis in allogeneic stem cell transplantation recipients. [ABSTRACT FROM AUTHOR]

Toxoplasmosis (TXP) is a life-threatening complication of allogeneic haematopoietic stem cell transplantation (AHSCT). Little is known about the risk factors and there is no consensus on prophylactic measures. To investigate the risk factors, we conducted a single-centre, retrospective matched case–control study among adults who underwent AHSCT from January 2006 to March 2015 in our hospital. TXP cases were identified from the prospectively maintained hospital's database. The 1:2 control population consisted of the two patients who received an AHSCT immediately before and after each case with similar donor relationship (related, unrelated) but who did not develop TXP. Risk factors were identified by conditional logistic regression. Clinical features and outcome of TXP were examined. Twenty-three (3.9%) cases of TXP (20 diseases, three infections) were identified among 588 AHSCT recipients. Twenty (87%) cases had a positive pre-transplant Toxoplasma gondii serology. In comparison with 46 matched control patients, risk factors were the absence of effective anti- Toxoplasma prophylaxis (odds ratio (OR) 11.95; 95% CI 3.04–46.88; p <0.001), high-grade (III–IV) acute graft-versus-host-disease (OR 3.1; 95% CI 1.04–9.23; p 0.042) and receipt of the tumour necrosis factor-α blocker etanercept (OR 12.02; 95% CI 1.33–108.6; p 0.027). Mortality attributable to TXP was 43.5% ( n = 10). Non-relapse mortality rates during the study period of cases and controls were 69.6% ( n = 16) and 17.4% ( n = 8), respectively. Lung involvement was the dominant clinical feature ( n = 14). Two cases were associated with graft failure, one preceded by haemophagocytic syndrome. Given TXP-related morbidity and attributable mortality, anti- Toxoplasma prophylaxis is essential for optimized management of seropositive AHSCT recipients. [ABSTRACT FROM AUTHOR]

The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response. [ABSTRACT FROM AUTHOR]

La leucémie chronique à éosinophiles associéeau transcrit FIP1L1-PDGFRA (LCE F/P) est un syndrome hyperéosinophilique(SHE) clonal qui présente une grande sensibilité àl'Imatinib Mesylate (IM) et dont l'incidence n'est pas connue. Les séries publiées à ce jour sont de petite taille, avec un suivi limité et bien que les caractéristiques cliniques ainsi que la possibilité d'arrêt de l'IM soient connues, aucun facteur prédictif de rechute n'a été mis en évidence. Étude française, multicentrique, rétrospective en partenariat avec le groupe des biologistes moléculaires des hémopathies malignes incluant l'ensemble des patients ayant eu une recherche de F/P positive entre 2003 et 2019. Les patients avec une hémopathie aiguë ou des données cliniques manquantes ont été exclus. Un modèle de régression logistique a été utilisé pour identifier des facteurs de risque de rechute. Parmi les 197 transcrits F/P positifs, 151 patients ont été inclus (97 % d'hommes, âge moyen 49 ans). L'incidence de la LCE F/P était estimée à 0,18 cas par an par million d'habitants. Comme précédemment décrit, les organes les plus fréquemment atteints étaient la rate (44 %), la peau (32 %), le poumon (30 %), le coeur (19 %) et le Système Nerveux Central (10 %). Par ailleurs, des atteintes vasculaires (thrombose, occlusion artérielle, vascularite), articulaire et rénale ont également été décrites. Le pic d'éosinophilie moyen était de 10,3 (± 6) G/l et les taux de vitamine B12, de tryptase et d'IgE totales étaient élevés dans 74/79 (94 %), 45/57 (79 %) et 12/86 (14 %) des cas tandis qu'une élévation franche de la CRP (i.e. > 40 mg/l) n'était retrouvée que chez 5 patients. Trente et un (20 %) patients ont été traités par corticoïdes sans aucune rémission complète tandis que tous les patients traités par IM (n = 148) ont eu une réponse hématologique et moléculaire (n = 84 tests) complète. Parmi les 46 patients ayant arrêté l'IM, 20 (47 %) ont présenté une rechute. En analyse multivariée, le délai d'introduction du traitement (HR continu : 1,02 [1,00–1,03] ; p = 0,01) et la durée du traitement (HR continu : 0,97 [0,95–0,99] ; p = 0,01) était des facteurs associés à la rechute. La durée de suivi moyenne était de 80 (± 56) mois avec une survie globale à 1, 5 et 10 ans de 99 %, 95 % et 84 % respectivement. Cette étude avec un large effectif confirme la prédominance masculine de cette pathologie ainsi que la fréquence des atteintes respiratoire, cardiaque, cutanée et splénique. Après arrêt de l'IM une courte durée de traitement préalable et un délais prolongé d'introduction de l'IM étaient associés à la rechute. [ABSTRACT FROM AUTHOR]

BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo-HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at \[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches. [ABSTRACT FROM AUTHOR]

Background: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL).Methods: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months.Results: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.Conclusions: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .). [ABSTRACT FROM AUTHOR]

The article discusses results of a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia. Information on ponatinib is presented. The authors found no single BCR-ABL mutation conferring resistance to ponatinib. The authors conclude that ponatinib has anti-laukemic activity categories of disease stage and mutation status.

Several retrospective studies have described the clinical manifestation of peripheral artery occlusive disease (PAOD) in patients receiving nilotinib. We thus prospectively screened for PAOD in patients with chronic phase chronic myeloid leukemia (CP CML) being treated with tyrosine kinase inhibitors (TKI), including imatinib and nilotinib. One hundred and fifty-nine consecutive patients were evaluated for clinical and biochemical risk factors for cardiovascular disease. Non-invasive assessment for PAOD included determination of the ankle-brachial index (ABI) and duplex ultrasonography. A second cohort consisted of patients with clinically manifest PAOD recruited from additional collaborating centers. Pathological ABI were significantly more frequent in patients on first-line nilotinib (7 of 27; 26%) and in patients on second-line nilotinib (10 of 28; 35.7%) as compared with patients on first-line imatinib (3 of 48; 6.3%). Clinically manifest PAOD was identified in five patients, all with current or previous nilotinib exposure only. Relative risk for PAOD determined by a pathological ABI in first-line nilotinib-treated patients as compared with first-line imatinib-treated patients was 10.3. PAOD is more frequently observed in patients receiving nilotinib as compared with imatinib. Owing to the severe nature of clinically manifest PAOD, longitudinal non-invasive monitoring and careful assessment of risk factors is warranted. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is characterized by the impaired osteogenic differentiation of human mesenchymal stromal cells (hMSCs). Canonical Wnt signaling is critical for the regulation of bone formation, however, recent evidence suggests that the non-canonical Wnt agonist Wnt5a stimulates human osteoblastogenesis through its co-receptor Ror2. The effects of MM cells on non-canonical Wnt signaling and the effect of the activation of this pathway on MM-induced osteoblast exhaustion are not known and were investigated in this study. We found that the osteogenic differentiation of bone marrow hMSCs toward osteoprogenitor cells (PreOB) significantly increased Ror2 expression, and that MM cells inhibit Ror2 expression by PreOB in co-culture by inhibiting the non-canonical Wnt5a signaling. The activation of the non-canonical Wnt pathway in hMSCs by means of Wnt5a treatment and the overexpression of Wnt5 or Ror2 by lentiviral vectors increased the osteogenic differentiation of hMSCs and blunted the inhibitory effect of MM in co-culture. Consistently, Wnt5a inhibition by specific small interfering RNA reduced the hMSC expression of osteogenic markers. Our findings demonstrate that the Wnt5a/Ror2 pathway is involved in the pathophysiology of MM-induced bone disease and that the activation of the non-canonical Wnt5a/Ror2 pathway in hMSCs increases osteogenic differentiation and may counterbalance the inhibitory effect of MM cells. [ABSTRACT FROM AUTHOR]

Invasive aspergillosis (IA) during induction chemotherapy of acute myeloid leukemia (AML) could worsen the prognosis. Our objective was to study how the development of IA during AML interferes with the therapeutic strategy and to evaluate its impact on the short- and long-term survival. Newly diagnosed AML patients between the years 2004 and 2007 were retrospectively analyzed. The outcome was death of the patient. A Cox proportional hazards model with the diagnosis of IA and post-induction response evaluation as the main exposure was fitted. Overall, 262 patients were analyzed and 58 IA were observed. The 2-year survival of patients having had remission of AML was 54% and, for patients with failure of chemotherapy, it was 5% ( p < 0.001). The 2-year survival of patients having had IA was 14%, and without IA, it was 32% ( p = 0.01). Multivariate analysis showed that IA was associated with a higher risk of death in case of remission compared to no IA (hazard ratio [HR] = 1.66 [1.05-2.65], p = 0.031) and also in case of failure (HR = 6.43, p < 0.001). IA was associated with an increased risk of death for patients if they were either in remission or in failure after induction chemotherapy. [ABSTRACT FROM AUTHOR]

Abstract: High-dose chemotherapy with stem cells support has largely improved in terms of hematopoietic stem and progenitor cells harvest procedures as well as in those, which target or manipulate the cellular composition of autologous graft. Optimal preparative regimens and supportive care had lead to better use of autologous transplantation procedure. For other patients assigned to hematopoietic transplantation, availability of allogeneic donors appears to be an interesting alternative source of hematopoietic stem cells. Since three decades, hematopoietic growth factors development has allowed mobilization optimization and collection of peripheral hematopoietic stem cells leading to reduced days of hospitalization and less blood products requirements, being more cost-effective for patients in autologous transplantation settings and for stem cell collection facilities in allogeneic ones. New perspectives include, besides ex vivo manipulation of graft, development of mobilizing drugs in order to perform transplantation even in poor mobilizers patients. An important goal is achieved with the description of genetic polymorphisms related to optimal mobilization of stem cells. New approach using more promising and selective agents called chemokines, such as plerixafor the main leader among these agents are now available and appear complementary for alternative approach using cytokines alone (G-CSF, GM-CSF, SCF). The aim of this review is to assess the evolution of theses biotechnologies and their role in different steps of autologous transplantation and allogeneic stem cells collection. [Copyright &y& Elsevier]

A letter to the editor is presented in response to the article "Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1," by A. Tefferi in the 2010 issue.

A letter to the editor is presented discussing the use of imatinib in chronic phase-chronic myelogenous leukaemia patients.

A letter to the editor is presented which is about sensitivity of hematopoietic (HPs) and mesenchymal (MPs) progenitors to fludarabine with regard to HP mobilization and impaired bone marrow niche.

High-dose cyclophosphamide (HDC) has been shown to be an effective regimen for collecting PBPC in multiple myeloma (MM) patients, but the optimal dose to be used remains controversial. Two historical cohorts of MM patients who received G- or GM-CSF and HDC at the dose of either 7 g/m2 (HDC7, n = 74) or 4 g/m (HDC4, n = 42) were compared. As patients in the HDC4 group were more likely to have received G-CSF than GM-CSF (P < 10-3) and fewer previous alkylating agents (P = 0.004), multivariate logistic regression analysis was performed. In the HDC4 group, patients had a shorter median duration of neutropenia (P < 10-4), fewer RBC (P < 10-3) and platelet transfusions (P < 10-3) with fewer patients with platelets <20 × 109/l (P = 0.004). Moreover, fewer febrile episodes (P < 10-3) and less need of intravenous antibiotics (P < 10-3) were found in the HDC4 group. No statistical difference was observed with regard to CD34+ cell collection efficiency. Thus, the use of HDC at the dose of 4 g/m2 for the collection of PBPC in MM patients decreases hematological and extrahematological toxicity with an equivalent CD34+ cell collection efficiency. Bone Marrow Transplantation (2001) 27, 837–842. [ABSTRACT FROM AUTHOR]

In order to determine whether doses of cyclosporine and methylprednisolone used for prophylaxis and therapy of acute graft-versus-host disease (GVHD) have any influence on relapse and survival following allogeneic bone marrow transplantation (BMT), we studied 176 adult patients with hematologic malignancies, who underwent a first allogeneic transplant from an HLA-identical sibling donor. Two methods of management of acute GVHD used in two different centers were compared: group I included 62 patients who had ‘standard’ management of GVHD including prophylaxis with 1–3 mg/kg/day of cyclosporine and treatment with 2 mg/kg/day of methylprednisolone when acute GVHD developed; group II included 114 patients who received ‘intensive’ management of GVHD including prophylaxis with 5 mg/kg/day of cyclosporine and treatment with high-dose methylprednisolone (8–20 mg/kg/day for 3 days) at the onset of GVHD. The overall incidence of GVHD was the same in both groups. However, acute GVHD was more severe in group I than in group II (P < 0.0001), with consequently less resolution of gvhd after treatment in group i (61%) than in group ii (80%) (P = 0.06). Overall survival and disease-free survival (DFS) did not differ between the two groups. However, actuarial risk of disease relapse was significantly higher in group II than in group I (36% vs 17%, P = 0.02). In a multivariate analysis taking into account known factors influencing GVHD and relapse, only type of GVHD management and age were significantly predictive for the occurrence of GVHD, while only type of GVHD management and pathology other than chronic myeloid leukemia (CML) were predictive for relapse. This study demonstrates that intensity of GVHD prophylaxis and therapy can influence the graft-versus-leukemia effect by decreasing severity of GVHD but at the price of increasing relapse rate post transplant. [ABSTRACT FROM AUTHOR]

The EMA86 study showed efficacy of intensive sequential chemotherapy with mitoxantrone, 12 mg/m2 day on days 1-3, etoposide, 200 mg/m2/day as a continuous infusion on days 8-10 and cytarabine (araC), 500 mg/m2/day as continuous infusion on days 1-3 and 8-10 (EMA regimen) in previously treated patients with AML. The goal of the EMA91 study was to determine whether administration of GM-CSF between the two sequences of EMA chemotherapy and during the second sequence could increase therapeutic efficacy by potentially increasing leukemic cell recruitment into the S phase of cell cycle before the second sequence. One hundred and ninety-two patients aged less than 65 years with previously treated AML received GM-CSF, 5 microg/kg/day or placebo from day 4 to day 8 of EMA chemotherapy. One hundred and twenty were refractory and 72 were in first relapse after a complete remission (CR) of more than 6 months duration. CR rates after one course of chemotherapy were 65% in the GM-CSF group (refractory: 51%; first relapse: 89%), not significantly different from the 59% CR rate (refractory: 46%; first relapse: 81%) in the placebo group. Median time to recovery of neutrophils was 38 and 37 days and median time to last platelet transfusion 32 and 32 days respectively in the GM-CSF and placebo groups. WHO grade > or = 3 non-hematologic toxicities were mainly sepsis (45% and 51%, respectively) and mucositis (34% and 31%) and did not differ between the two groups. Toxic death rate was 5% and 8%, respectively, in the GM-CSF and placebo groups. Patients achieving CR were scheduled to receive six courses of maintenance with reduced-dose EMA. Time to progression tended to be longer in the GM-CSF group (median 154 vs 115 days, progression-free rate at 18 months 33% vs 19%, P = 0.08), particularly in refractory patients (P = 0.06). However, at the current follow-up, this did not translate into a significantly longer disease-free survival and survival. Cell cycle studies showed increased recruitment of cells in the S phase between day 4 and day 8 in the GM-CSF group compared to placebo (P = 0.006). However, this did not significantly relate to prognosis in this cohort of patients. GM-CSF might marginally increase efficacy of sequential chemotherapy without increasing its toxicity in the absence of any detected relationship between this effect and observed leukemic cell recruitment into the cell cycle. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented discussing a pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response.

Presents a letter to the editor about an aged woman who developed secondary Philadelphia chromosome following nonmyeoablative peripheral blood stem cell transplantation for myelodysplastic syndrome.

Presents a letter to the editor in response to the article "Coexistence of AML1/RUNX1 and BCR-ABL Point Mutations in an Imatinib-Resistant Form of CML," published in previous issue.

Presents a letter to the editor addressing the identification of the rare e6a2 BCR-ABL fusion gene during the disease progression of chronic myelomonocytic leukemia.

A correction to the article "Preferential sensitivity of hematopoietic (HPs) and mesenchymal (MPs) progenitors to fludarabine suggests impaired bone marrow niche and HP mobilization" that was published in a previous issue is presented.