European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia.

The therapeutic landscape of chronic myeloid leukemia (CML) has profoundly changed over the past 7 years. Most patients with chronic phase (CP) now have a normal life expectancy. Another goal is achieving a stable deep molecular response (DMR) and discontinuing medication for treatment-free remission (TFR). The European LeukemiaNet convened an expert panel to critically evaluate and update the evidence to achieve these goals since its previous recommendations. First-line treatment is a tyrosine kinase inhibitor (TKI; imatinib brand or generic, dasatinib, nilotinib, and bosutinib are available first-line). Generic imatinib is the cost-effective initial treatment in CP. Various contraindications and side-effects of all TKIs should be considered. Patient risk status at diagnosis should be assessed with the new EUTOS long-term survival (ELTS)-score. Monitoring of response should be done by quantitative polymerase chain reaction whenever possible. A change of treatment is recommended when intolerance cannot be ameliorated or when molecular milestones are not reached. Greater than 10% BCR-ABL1 at 3 months indicates treatment failure when confirmed. Allogeneic transplantation continues to be a therapeutic option particularly for advanced phase CML. TKI treatment should be withheld during pregnancy. Treatment discontinuation may be considered in patients with durable DMR with the goal of achieving TFR.

Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy for the prediction of subsequent cardiotoxicity.

OBJECTIVES: The aim of this study was to assess whether global longitudinal strain (GLS) measured early during treatment with anthracycline (at a cumulative dose of 150mg/m2) can predict subsequent alterations in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Eighty-six patients suffering from Hodgkin's disease, non-Hodgkin's lymphoma or acute leukemia and receiving anthracyclines were prospectively included. They underwent complete echocardiography on four separate occasions: baseline (V1); after reaching a cumulative dose of 150mg/m2 (V2); end of treatment (V3); one year follow-up (V4). Six patients developed cardiotoxicity defined by a decrease in LVEF by more than 10 percentage points to a value of at least less than 53% at V4. Both GLS measured at V1 and at V2 were significantly lower in the cardiotoxicity group compared with the control group (P=0.042 and P=0.01, respectively). Compared to GLS at V1, GLS obtained at V2 provided implemental predictive information and appeared to be the strongest predictor of cardiotoxicity (area under the receiver operating characteristic curve, 0.823). At a threshold of -17.45% for GLS measured at V2, the sensitivity and specificity of detecting cardiotoxicity were 67% (95%CI: [33-100%]) and 97% (95%CI: [94-100%]) respectively. CONCLUSION: GLS>-17.45%, obtained after 150mg/m2 of anthracycline therapy, is a significant predictor of future anthracycline-induced cardiotoxicity. This study should encourage physicians to perform echocardiography earlier during treatment with anthracyclines.

[What size of surgical margins for carcinoma of the eyelid?]. / Quelles marges d'exérèse pour les carcinomes de paupières ?

Traditional surgical treatment of non-melanoma skin cancer includes excision with adjacent surgical margins, such "safety" margins theoretically leading to lower recurrence rates. Thus, some authors favor a clinical excision margin of 4mm for basal cell carcinoma and 6mm for squamous cell carcinoma. However, such "safety" margins cannot be applied in all cases of eyelids tumors for anatomic and functional reasons, because such recommendations may lead to severe ocular complications, even loss of the globe. Thus, in order to mitigate these issues in oculoplastic surgery, excision with reduced margins is proposed, either with frozen sections or with traditional pathologic analysis and secondary reconstructive surgery several days later. The purpose of this article is to demonstrate that it is possible to reduce surgical margins while respecting "safety" from tumor recurrence, in order to preserve ocular integrity. The most appealing technique is frozen section of the margins, corresponding to "slow-Mohs" micrographic surgery.

A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.

Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations.

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy.

Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications. Using a collection of 55 leukemia patients treated with TKI therapy (chronic myeloid leukemia, n=47; acute lymphoblastic leukemia, n=8), we found that dasatinib, a second-generation broad-spectrum TKI, induced a rapid, dose-dependent and substantial mobilization of non-leukemic lymphocytes and monocytes in blood peaking 1-2 h after an oral intake and the blood counts closely mirrored drug plasma concentration. A preferential mobilization was observed for natural killer (NK), NK T, B and γδ+ T cells. Mobilization was coupled with a more effective transmigration of leukocytes through an endothelial cell layer and improved cytotoxicity of NK cells. Platelet numbers decreased markedly after the drug intake in a proportion of patients. Similar effects on blood cell dynamics and function were not observed with any other TKI (imatinib, nilotinib and bosutinib). Thus, dasatinib induces a unique, rapid mobilization and activation of cytotoxic, extravasation-competent lymphocytes, which may not only enhance antileukemia immune responses but can also be causally related to the side-effect profile of the drug (pleural effusions, thrombocytopenia).

First-line imatinib mesylate in patients with newly diagnosed accelerated phase-chronic myeloid leukemia.

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.

False positive galactomannan Platelia due to piperacillin-tazobactam.

INTRODUCTION: Invasive aspergillosis is a serious disease, the lethality of which is important among hematology patients. Early diagnosis is crucial for treatment options and the prognosis. Detection of the antigen galactomannan is the most frequently used microbiological tools. But galactomannan detection may be falsely positive, and this false positivity has been associated with piperacillin-tazobactam treatment, the main antibiotic combination used in clinical hematology. OBJECTIVE: The purpose of our study, carried out from January 2009 to December 2010 at the Versailles hospital on in-patients with hematological disorders, was to evaluate the association between false galactomannan positivity and administration of piperacillin-tazobactam, and to study a possible variability of products issued by three manufacturers. PATIENTS AND METHOD: We noted that 207 patients were included (n=207), accounting for 69 false positive and 138 true negative results. The intrinsic galactomannan values in the study were sensitivity 100%, specificity 68%, positive and negative predictive values respectively 16%, 100%, and a likelihood positive and negative test at respectively 3.12, and 0. RESULTS: The statistical analysis did not determine any association between false positivity in galactomannan and piperacillin-tazobactam issued by two manufacturers (P=0.87 and P=0.94). But, there was a significant association between false galactomannan positivity and piperacillin-tazobactam issued by the third manufacturer (P=0.02). Four of the 25 batches issued by this manufacturer were tested and negative "in vitro" for galactomannan. DISCUSSION: This study results suggest that the association between false galactomannan positivity and piperacillin-tazobactam is not longer systematic, but can still prevail depending on the manufacturers. It also confirmed the positive contribution of testing piperacillin-tazobactam batches "in vitro" before using the antibiotic.

Dasatinib-associated major molecular responses in patients with chronic myeloid leukemia in chronic phase following imatinib failure: response dynamics and predictive value.

Dasatinib is a highly potent BCR-ABL inhibitor that has shown durable efficacy in patients with chronic phase (CP) chronic myeloid leukemia (CML) after resistance, suboptimal response, or intolerance to prior imatinib. In patients with CML, BCR-ABL transcript measurement is the most sensitive method for assessing minimal residual disease. Here, molecular responses were analyzed in 1067 patients with CML-CP treated with dasatinib during phase II/III trials. After 3, 6, 12, and 24 months of follow-up, a major molecular response (MMR) was achieved by 12, 22, 35, and 40% of patients, respectively. The 24-month MMR rate was 34% in patients with resistance or suboptimal response to imatinib (n=829) and 63% in imatinib-intolerant patients (n=238). Among patients who had achieved a complete cytogenetic response (CCyR), 72% also achieved MMR. Responses with dasatinib 100 mg once daily were similar to other doses. In landmark analyses, 24-month progression-free survival was higher in patients who had achieved MMR or CCyR at 12 months than in those without MMR or CCyR at 12 months. MMR at 12 months was associated with a longer duration of CCyR. Overall, this analysis shows that dasatinib treatment results in high MMR rates in patients with CML-CP after imatinib failure.

The extreme Kuiper Belt binary 2001 QW322.

The study of binary Kuiper Belt objects helps to probe the dynamic conditions present during planet formation in the solar system. We report on the mutual-orbit determination of 2001 QW322, a Kuiper Belt binary with a very large separation whose properties challenge binary-formation and -evolution theories. Six years of tracking indicate that the binary's mutual-orbit period is approximately 25 to 30 years, that the orbit pole is retrograde and inclined 50 degrees to 62 degrees from the ecliptic plane, and, most surprisingly, that the mutual orbital eccentricity is <0.4. The semimajor axis of 105,000 to 135,000 kilometers is 10 times that of other near-equal-mass binaries. Because this weakly bound binary is prone to orbital disruption by interlopers, its lifetime in its present state is probably less than 1 billion years.

Hyperdiploid karyotypes in acute myeloid leukemia define a novel entity: a study of 38 patients from the Groupe Francophone de Cytogenetique Hematologique (GFCH).

A series of 38 patients with acute myeloblastic leukemia (AML) with 49 or more chromosomes and without structural abnormalities was selected within the Groupe Francophone de Cytogénétique Hématologique (GFCH) to better define their characteristics. The median age of the patients was 65 years, and all FAB subtypes were represented. Although all chromosomes were gained, some seems to prevail: chromosome 8 (68%), 21 (47%), 19 (37%), and 13 and 14 (34% each). Since MLL rearrangement leads patients in a group with an unfavorable prognosis, search for cryptic rearrangements of MLL was performed in 34 patients and showed abnormalities in 5 (15%). When we applied the most frequent definition of complex karyotypes (three or more abnormalities), all patients with high hyperdiploid AML fall in the unfavorable category. Among the 18 patients without MLL rearrangement receiving an induction therapy, 16 (89%) reached CR and 6 (33%) were still alive after a 31-month median follow-up (14-61 months). Although this study was retrospective, these results suggest that high hyperdiploid AML without chromosome rearrangement seems to be a subgroup of uncommon AML (less than 1%), and may be better classified in the intermediate prognostic group.

[Salivary nitrates. New perspectives concerning the physiological function of saliva]. / Les nitrates salivaires. Nouvellesperspectives concernant les fonctions physiologiques de la salive.

For many years, nitrate ions have been thought to be "toxic agents", but scientific reality seems very different. The source of nitrate ions is double: exogenous and endogenous, and the metabolism of nitrates is partly salivary. The strong concentration of nitrate ions in saliva has many beneficial physiological effects. Salivary nitrate has anti-infectious effects on the oral cavity and all along the digestive tract. They give cardiovascular protection, are instrumental in the adaptive relaxation of the stomach by acting on smooth stomach muscles and have a protective action on the gastric mucosa.

[Ureteral obstruction from endometriosis: a case report and review of the literature]. / Obstruction urétérale d'origine endométriosique: à propos d'un cas et revue de la littérature.

Endometriosis frequently affects women with genital activity and exceptionally involves the urinary tract, and the ureter in particular. From a case report of a female consulting for renal colic pain related to an intrinsic-type pelvic ureteral endometriosis, we report the difficulty in diagnosing this pseudotumoral obstruction and finding therapeutic options with a review of the literature. Ureteral endometriosis is marked by non-specific symptoms liable to delay preoperative diagnosis with a risk of deterioration of renal function due to the obstruction. Regarding the therapeutic approach, the surgical treatment associated or not with GNRH agonists seems best.

A phase I dose-finding and pharmacokinetic study of subcutaneous semisynthetic homoharringtonine (ssHHT) in patients with advanced acute myeloid leukaemia.

To determine the maximum-tolerated dose (MTD), dose-limiting toxicities and pharmacokinetic of semisynthetic homoharringtonine (ssHHT), given as a twice daily subcutaneous (s.c.) injections for 9 days, in patients with advanced acute leukaemia, 18 patients with advanced acute myeloid leukaemia were included in this sequential Bayesian phase I dose-finding trial. A starting dose of 0.5 mg m(-2) day(-1) was explored with subsequent dose escalations of 1, 3, 5 and 6 mg m(-2) day(-1). Myelosuppression was constant. The MTD was estimated as the dose level of 5 mg m(-2) day(-1) for 9 consecutive days by s.c. route. Dose-limiting toxicities were hyperglycaemia with hyperosmolar coma at 3 mg m(-2), and (i) one anasarque and haematemesis, (ii) one life-threatening pulmonary aspergillosis, (iii) one skin rash and (iv) one scalp pain at dose level of 5 mg m(-2) day(-1). The mean half-life of ssHHT was 11.01+/-3.4 h, the volume of distribution at steady state was 2+/-1.4 l kg(-1) and the plasma clearance was 11.6+/-10.4 l h(-1). Eleven of the 12 patients with circulating leukaemic cells had blood blast clearance, two achieved complete remission and one with blast crisis of CMML returned in chronic phase. The recommended daily dose of ssHHT on the 9-day schedule is 5 mg m(-2) day(-1).

Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).

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.

Telomerase targeting by retinoids in cells from patients with myeloid leukemias of various subtypes, not only APL.

Numerous strategies have been proposed to specifically inhibit telomerase (human telomerase reverse transcriptase (hTERT)) but to date only a few are clinically relevant in anticancer therapy. Recently, we have shown that long-term treatment with all-trans retinoic acid (ATRA), a compound clinically approved for differentiation therapy of acute promyelocytic leukemia (APL), represses hTERT in differentiation-resistant APL cell lines leading to telomere shortening and death. This signaling requires the co-activation of the retinoic acid receptor alpha (RARalpha) and the retinoic X receptor (RXR). In contrast to differentiation-therapy, which is only successful in this subtype of leukemia, the telomerase-targeted pathway could also be of use in non-APL. Here, we demonstrate that repression of hTERT occurs in fresh blasts cells from patients with myeloid leukemias of various subtypes exposed ex vivo to ATRA or synthetic retinoids. These results support the idea that, by hTERT targeting, retinoids can induce telomere shortening and cell death and their integration in therapy protocols for myeloid leukemias refractory to maturation should be considered.

High-dose imatinib mesylate combined with vincristine and dexamethasone (DIV regimen) as induction therapy in patients with resistant Philadelphia-positive acute lymphoblastic leukemia and lymphoid blast crisis of chronic myeloid leukemia.

Imatinib combined with high-dose chemotherapy is now becoming the gold standard for treatment of Philadelphia chromosome-positive acute leukemias. However, in all studies imatinib dosage was tapered to 400-600 mg per day. We decided to initiate a clinical trial to evaluate an opposite strategy based on high-dose imatinib (800 mg per day) combined with a less intensive chemotherapeutic regimen (vincristine and dexamethasone), which we called the DIV induction regimen. Thirty-one patients (18 relapsing or refractory Ph+ acute lymphoblastic leukemias and 13 lymphoid blast crisis chronic myelogenous leukemias) were enrolled. Complete remission (CR) was obtained in 28 out of 30 assessable patients. The median bcr-abl/abl ratio after the induction course was 0.1%. Median time to neutrophil recovery was 21 days. Fungus infections were observed in six patients out of 31 and possibly related to dexamethasone. Neuropathy due to vincristine was noted in 14 cases. Nine out of 19 patients under 55 years received allogenic stem cell transplantation after a median time of 78 days post-CR. Patients older than 55 years experienced a 90% CR rate without additional toxicities, suggesting the DIV regimen may also be proposed as a front line therapy in older patients.