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Mario Ojeda-Uribe,1 Valérie Rimelen,2 Cathérine Marzullo3 1Department of Hematology and Cellular Therapy Unit, Groupe Hospitalier Region Mulhouse-Sud-Alsace (GHRMSA), Mulhouse 68070, France; 2Laboratory of Molecular Biology CHRU Strasbourg, Strasbourg 67200, France; 3Laboratory of Immunology, Groupe Hospitalier Region Mulhouse-Sud-Alsace (GHRMSA), Mulhouse 68070, FranceCorrespondence: Mario Ojeda-UribeDepartment of Hematology and Cellular Therapy Unit, Groupe Hospitalier Region Mulhouse-Sud-Alsace (GHRMSA), 20 Avenue du Dr Laennec, Mulhouse Cedex 68070, FranceTel +33389647755Fax +33389647747Email ojeda-uribem@ghrmsa.frAbstract: Acquired von Willebrand syndrome (AVWS) in the setting of Waldenström macroglobulinemia (WM) is a challenging condition. No real standard of care is recommended for these patients, although the therapeutic strategy should include a rapid approach to the emergency bleeding events and to the underlying malignant lymphoid disorder. We report here our experience treating three elderly patients with these concomitant hematologic entities. The use of a bortezomib-based chemotherapy regimen showed a good profile of tolerance and efficacy even in a long-term follow-up period. These patients were treated for several years before switching their therapy to idelalisib, a targeted oral therapy that inhibits phosphatidylinositol 3-kinase isoform-delta (PI3KD), which is part of the signaling pathway downstream B-cell receptor. This approach was well tolerated and efficacious, although some adverse effects were observed, particularly at hepatic levels, but were all reversible. The same profile of tolerance/efficacy was observed in one very old patient who received idelalisib as a first-line therapy. We think that bortezomib-based therapy could be considered in refractory patients with AVWS associated with WM.Keywords: waldenström macroglobulinemia, acquired von Willebrand syndrome, bortezomib, idelalisib, proteasome inhibitors, von Willebrand factor

.1713 1-year OS in allografted patients (%)445621R/R AML Quizartinib monotherapy N = 57Previous exposure to midostaurin N = 27No previous exposure to midostaurin N = 30pAge (years)0 /> Median in allografted patients (months)7NR6.40 />AML status at quizartinib initiation, n (%)0. [Extracted from the article]

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.Leukemia (2006) 20, 400–403. doi:10.1038/sj.leu.2404115; published online 26 January 2006 [ABSTRACT FROM AUTHOR]

Background We and others have shown a critical role for CD34 + CD38 - cells in hematopoietic recovery after autologous stem cell transplantation (ASCT), in particular for platelet reconstitution. Thus a routine assessment of CD34 + CD38 - cells in freezing-thawing procedures for autografting could represent an important tool for predicting poor engraftment. Methods To compare the impact of cryopreservation on CD34 + CD38 + and CD34 + CD38 - hematopoietic stem cell subsets, 193 autograft products collected in 84 patients with malignancies were assessed before controlled-rate cryopreservation in 10% DMSO and after thawing for autografting. Results Cell counts after thawing were significantly different from the pre-freezing counts for total CD34 + ( P <0.0001) and CD34 + CD38 + ( P <0.0001) cells, but not for CD34 + CD38 - cells ( P =0.252). Median losses for CD34 + , CD34 + CD38 + and CD34 + CD38 - cells were, respectively, 11.8%, 11.4% and 0.0%. The magnitude of fresh/post-thawing percentage cell variation was significantly different when comparing between the CD34 + CD38 + and CD34 + CD38 - cell subsets ( P <0.001). Moreover, CD34 + CD38 - cells exhibited recovery values ≥100% in 85/160 graft products, compared with 51/193 in CD34 + CD38 + cells ( P <0.0001). Also, recovery values ≥90% were significantly better in the CD34 + CD38 - (98/160 grafts) than in the CD34 + CD38 + subsets (89/193 grafts) ( P <0.01). Discussion In this work we have demonstrated that CD34 + cells that do not express the CD38 Ag show a significantly better resistance to cryopreservation. This could represent another example of the particular ability of less committed progenitor cells to overcome environmental injuries. Moreover, we consider routine assessment of CD34 + CD38 - cells before freezing as clinically relevant, but post-thawing controls may be avoided because of their good resistance to freezing. [ABSTRACT FROM AUTHOR]

Background: The immune form of thrombotic thrombocytopenic purpura (iTTP) and the hemolytic and uremic syndrome (HUS) are two major forms of thrombotic microangiopathy (TMA). Their treatment has been recently greatly improved. In this new era, both the prevalence and predictors of cerebral lesions occurring during the acute phase of these severe conditions remain poorly known., Aim: The prevalence and predictors of cerebral lesions appearing during the acute phase of iTTP and Shiga toxin-producing Escherichia coli-HUS or atypical HUS were evaluated in a prospective multicenter study., Methods: Univariate analysis was performed to report the main differences between patients with iTTP and those with HUS or between patients with acute cerebral lesions and the others. Multivariable logistic regression analysis was used to identify the potential predictors of these lesions., Results: Among 73 TMA cases (mean age 46.9 ± 16 years (range 21-87 years) with iTTP (n = 57) or HUS (n = 16), one-third presented with acute ischemic cerebral lesions on magnetic resonance imagery (MRI); two individuals also had hemorrhagic lesions. One in ten patients had acute ischemic lesions without any neurological symptom. The neurological manifestations did not differ between iTTP and HUS. In multivariable analysis, three factors predicted the occurrence of acute ischemic lesions on cerebral MRI: (1) the presence of old infarcts on cerebral MRI, (2) the level of blood pulse pressure, (3) the diagnosis of iTTP., Conclusion: At the acute phase of iTTP or HUS, both symptomatic and covert ischemic lesions are detected in one third of cases on MRI. Diagnosis of iTTP and the presence of old infarcts on MRI are associated with the occurrence of such acute lesions as well as increased blood pulse pressure, that may represent a potential target to further improve the therapeutic management of these conditions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

This phase 3 study evaluated the efficacy and safety of the new hypomethylating agent guadecitabine (n = 408) vs a preselected treatment choice (TC; n = 407) of azacitidine, decitabine, or low-dose cytarabine in patients with acute myeloid leukemia unfit to receive intensive induction chemotherapy. Half of the patients (50%) had poor Eastern Cooperative Oncology Group Performance Status (2-3). The coprimary end points were complete remission (19% and 17% of patients for guadecitabine and TC, respectively [stratified P = .48]) and overall survival (median survival 7.1 and 8.5 months for guadecitabine and TC, respectively [hazard ratio, 0.97; 95% confidence interval, 0.83-1.14; stratified log-rank P = .73]). One- and 2-year survival estimates were 37% and 18% for guadecitabine and 36% and 14% for TC, respectively. A large proportion of patients (42%) received <4 cycles of treatment in both the arms. In a post hoc analysis of patients who received ≥4 treatment cycles, guadecitabine was associated with longer median survival vs TC (15.6 vs 13.0 months [hazard ratio, 0.78; 95% confidence interval, 0.64-0.96; log-rank P = .02]). There was no significant difference in the proportion of patients with grade ≥3 adverse events (AEs) between guadecitabine (92%) and TC (88%); however, grade ≥3 AEs of febrile neutropenia, neutropenia, and pneumonia were higher with guadecitabine. In conclusion, no significant difference was observed in the efficacy of guadecitabine and TC in the overall population. This trial was registered at www.clinicaltrials.gov as #NCT02348489., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The prevalence, prognostic role, and diagnostic value of blood pressure in immune-mediated thrombotic thrombocytopenic purpura (iTTP) and other thrombotic microangiopathies (TMAs) remain unclear., Methods: Using a national cohort of iTTP ( n  = 368), Shigatoxin-induced hemolytic uremic syndrome ( n  = 86), atypical hemolytic uremic syndrome ( n  = 84), and hypertension-related thrombotic microangiopathy ( n  = 25), we sought to compare the cohort's blood pressure profile to assess its impact on prognosis and diagnostic performances., Results: Patients with iTTP had lower blood pressure than patients with other TMAs, systolic (130 [interquartile range (IQR) 118-143] vs 161 [IQR 142-180] mmHg) and diastolic (76 [IQR 69-83] vs 92 [IQR 79-105] mmHg, both p  < 0.001). The best threshold for iTTP diagnosis corresponded to a systolic blood pressure <150 mmHg. iTTP patients presenting with hypertension had a significantly poorer survival (hazard ratio 1.80, 95% confidence interval 1.07-3.04), and this effect remained significant after multivariable adjustment (hazard ratio = 1.14, 95% confidence interval 1.00-1.30). Addition of a blood pressure criterion modestly improved the French clinical score to predict a severe A disintegrin and metalloprotease with thrombospondin type 1 deficiency in patients with an intermediate score (i.e., either platelet count <30 × 10 9 /L or serum creatinine <200 µM)., Conclusions: Elevated blood pressure at admission affects the prognosis of iTTP patients and may help discriminate them from other TMA patients. Particular attention should be paid to blood pressure and its management in these patients., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

In this randomized phase 3 study, the FILO group tested whether the addition of 6 mg/m 2 of gemtuzumab ozogamycin (GO) to standard chemotherapy could improve outcome of younger patients with de novo acute myeloid leukemia (AML) and intermediate-risk cytogenetics. GO arm was prematurely closed after 254 inclusions because of toxicity. A similar complete remission rate was observed in both arms. Neither event-free survival nor overall survival were improved by GO in younger AML patients (<60 years) ineligible for allogeneic stem-cell transplantation. (P = .086; P = .149, respectively). Using unsupervised hierarchical clustering based on mutational analysis of seven genes (NPM1, FLT3-ITD, CEBPA, DNMT3A, IDH1, IDH2, and ASXL1), six clusters of patients with significant different outcome were identified. Five clusters were based on FLT3-ITD, NPM1, and CEBPA mutations as well as epigenetic modifiers (DNMT3A, IDH1/2, ASXL1), whereas the last cluster, representing 25% of patients, had no mutation and intermediate risk. One cluster isolated FLT3-ITD mutations with higher allelic ratio and a very poor outcome. The addition of GO had no impact in these molecular clusters. Although not conclusive for GO impact in AML patients <60 years, this study provides a molecular classification that distinguishes six AML clusters influencing prognosis in younger AML patients with intermediate-risk cytogenetic., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: The impact of conventional treatment for acute myeloid leukemia (AML) on the nutritional, cognitive, and functional status of elderly patients is seldom studied. This assessment was performed in the context of the LAMSA 2007 trial., Methods: The trial enrolled 424 patients with de novo AML. Among them, 316 benefited from geriatric assessment (GA) including nutritional, cognitive, and functional status and were scored according to Eastern Cooperative Oncology Group (ECOG) and sorror for the prediction of treatment toxicity, morbidity, and mortality. Patients were investigated at diagnosis for three times during follow-up., Results: This study showed that AML and its treatment have no impact on cognitive (P = .554) nor functional status (P = .842 for Activity of Daily Living and P = .087 for Instrumental Activities of Daily Living). The nutritional status improved over time (P = .041). None of these three parameters at baseline, associated or not with ECOG and sorror scores, impacted survivals or toxicities., Conclusions: The cognitive, functional, and nutritional status had no impact in this cohort of fit elderly AML patients without unfavorable cytogenetics. The GA tools used provided no additional information compared with ECOG and sorror scores, to predict toxicity, morbidity, or mortality due to intensive chemotherapy., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Therapeutic Plasma Exchange (TPE) is the primary therapy of immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP). Efficacy and safety data for TPE of iTTP have been assessed with Quarantine and Solvent-Detergent inactivated (SD) plasma. Here, amotosalen-UVA pathogen inactivated (AI) plasma, also in routine use, was evaluated in iTTP., Methods: We conducted a retrospective review of iTTP cases prospectively reported to the French national registry (2010-2013). Cases reviewed underwent TPE with ≥70% of either AI or SD plasma. The primary endpoint was time to platelet count recovery; secondary endpoints were related to follow-up (sustained remission, relapses, flare-ups and refractoriness)., Results: 30 Test patients were identified in the AI group which could be timely matched to 40 Control patients in the SD group. The groups were fairly comparable for clinical presentation. Major findings were: (i) iTTP patients were exposed to lower plasma volumes in the AI group than in the SD group; (ii) Recovery rates were comparable between the groups. Median time to platelet count recovery (>150 × 10 9 /L) trended to be shorter in the AI group though non significantly. Tolerance of AI vs SD plasma was of comparable frequency and severity in either group., Conclusion: TPE with Amotosalen-inactivated plasma demonstrated therapeutic efficacy and tolerability for iTTP patients. In view of the retrospective design, confirmation of these results is required in larger prospective studies., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Acute myeloid leukemia (AML) in elderly patients has a poor prognosis. In an attempt to improve outcome for these patients, the prospective open-label phase III LAM-SA 2007 (Adding Lomustine to Chemotherapy in Older Patients With Acute Myelogenous Leukemia (AML), and Allogeneic Transplantation for Patients From 60 to 65 Years Old) trial randomly assigned patients to a standard induction regimen with lomustine added or to a consolidation regimen with cytarabine and idarubicin., Patients and Methods: Adults age 60 years or older with previously untreated AML who were fit to receive intensive chemotherapy and who were without unfavorable cytogenetics received standard chemotherapy with lomustine (idarubicin, cytarabine, and lomustine [ICL]) or without (idarubicin and cytarabine [IC]). The primary objective of the study was overall survival (OS); secondary objectives were response rate, cumulative incidence of relapse (CIR), event-free survival (EFS), and safety., Results: From February 2008 to December 2011, 459 patients were enrolled. Comparing patients in the IC and ICL arms, complete response or complete response with incomplete recovery was achieved in 74.9% versus 84.7% ( P = .01). The proportional hazards assumption was rejected for OS ( P = .02), which led us to consider two separate time intervals: during and after induction. There was no significant difference between the two arms during induction, although induction deaths were 3.7% versus 7.7%, respectively ( P = .11). However, significantly better results were observed after induction with an improved 2-year OS of 56% in the ICL arm versus 48% in the IC arm ( P = .02). At 2 years, EFS was improved at 41% in the ICL arm versus 26% in the IC arm ( P = .01). The CIR at 2 years was 41.2% in the ICL arm versus 60.9% in the IC arm ( P = .003). Grade 3 and 4 toxicities, mostly hematologic, were significantly higher in the ICL arm ( P = .04), and fewer patients required a second treatment after ICL., Conclusion: Adding lomustine to standard chemotherapy significantly improved the outcome of elderly patients with AML.

Objectives: Anthracyclines and cytarabine are cornerstones for intensive chemotherapy in acute myeloid leukemia (AML). The goals of this study were to comprehensively assess deviations from theoretical doses and the impact of body-surface area (BSA) on patients' characteristics, physicians' strategy, dose adjustment, and clinical outcome., Methods: The GOELAMS 2001 phase III trial included 823 AML patients below 60 years of age. In the course of treatment, anthropomorphic parameters and chemotherapy doses were prospectively registered., Results: Very high BSA (≥2.15 m 2 ) was the factor most significantly associated with the physician's decision to reduce chemotherapy doses during induction and postremission therapy. Despite similar AML characteristics and therapeutic strategies, the very high BSA group exhibited a significantly worse survival (5-years OS of 27%) compared to the low (BSA≤1.5 m 2 ), intermediate (1.5 m 2 2 ), or high (2 m 2 2 ) BSA groups (46%, 47%, 56%, respectively) (P=.009). In the very high BSA group, dose capping was associated with worse overall survival, although not significantly (P=.09)., Conclusion: The presence of a very high BSA is the main reason prompting physicians to reduce chemotherapy doses in adult AML. Furthermore, these patients display a poor outcome and could benefit from full doses calculated on actual BSA., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (<10%) acquired ADAMTS13 deficiency-associated TTP from our National database that included 423 patients, who had an initial misdiagnosis (20% of all TTP). Main diagnostic errors were attributed to autoimmune thrombocytopenia, associated (51%) or not (37%) with autoimmune hemolytic anemia. At admission, misdiagnosed patients were more frequently females (P = .034) with a history of autoimmune disorder (P = .017) and had organ involvement in 67% of cases; they had more frequently antinuclear antibodies (P = .035), a low/undetectable schistocyte count (P = .001), a less profound anemia (P = .008), and a positive direct antiglobulin test (DAT) (P = .008). In multivariate analysis, female gender (P = .022), hemoglobin level (P = .028), a positive DAT (P = .004), and a low schistocytes count on diagnosis (P < .001) were retained as risk factors of misdiagnosis. Platelet count recovery was significantly longer in the misdiagnosed group (P = .041) without consequence on mortality, exacerbation and relapse. However, patients in the misdiagnosed group had a less severe disease than those in the accurately diagnosed group, as evidenced by less organ involvement at TTP diagnosis (P = .006). TTP is frequently misdiagnosed with autoimmune cytopenias. A low schistocyte count and a positive DAT should not systematically rule out TTP, especially when associated with organ failure., (© 2017 Wiley Periodicals, Inc.)

We investigated noninvasive procedures by hybrid imaging to assess the sites of active or inactive hematopoiesis in patients with primary myelofibrosis (PMF). To this end, we used two radionuclides, technetium 99m ((99m) Tc) and indium 111-chloride ((111) In-Cl3 ), coupled with single-photon emission tomography/computed tomography (SPECT/CT). We studied five patients with PMF and one with secondary myelofibrosis (MF). The classical pattern of lower fixation of both tracers at the axial skeleton where the myelofibrotic process occurs and the reactivation of sites of active hematopoiesis at the distal skeleton were confirmed. Coupling both radionuclides to SPECT/CT imaging allowed for more precise visualization of the sites of extramedullary hematopoiesis as those observed in the spleen and liver. Splenic high uptake of (111) In-Cl3 coupled with SPECT/CT represents a pathognomonic feature of PMF. We conclude that, the hybrid imaging procedures that we studied might constitute an alternative noninvasive method for the screening of the whole-body marrow and, by this way, to assess the impact of targeted therapies in PMF patients in whom it is well known that the distribution of the hematopoietic active areas is disturbed. Hybrid imaging could also be useful for diagnostic purposes in cases of early PMF or in suspected cases of myelofibrosis secondary to polycythemia vera or essential thrombocythemia., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Short intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial., Methods: In this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 μmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882., Results: Between Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events., Interpretation: Addition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma., Funding: Gustave Roussy Cancer Campus, Roche, Chugai, Sanofi., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Drug-mediated thrombotic microangiopathy may cause life-threatening medical emergencies. Novel targeted therapies have dramatically changed the prognosis of a number of oncological diseases. Tyrosine kinase inhibitors of the Breakpoint Cluster Region-Abelson (BCR-ABL) oncoprotein are used in patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Imatinib mesylate, which was the first anti-BCR-ABL tyrosine kinase inhibitor, has demonstrated a high tolerance profile and efficacy in these patients for many years. Good results have also been observed in patients with gastrointestinal stromal tumors. In this study, we describe two patients with Philadelphia chromosome-positive hematological malignancies who presented with secondary thrombotic microangiopathy that was most likely linked to the use of imatinib. Other potential causes of thrombotic microangiopathy were discarded, and the predisposing role of some comorbidities and potential short or long-term drug-drug interactions was assessed. The clinical and biological data were more indicative of atypical secondary hemolytic uremic syndrome in one of the cases and of secondary thrombotic microangiopathy with renal and cardiac impairment in the other, which is also categorized as secondary hemolytic uremic syndrome. The outcome was favorable after imatinib discontinuation and the treatment of severe cardiac and renal failures., (© The Author(s) 2015.)

Purpose: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia., Findings: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively., Conclusions: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782)., (© 2015 Wiley Periodicals, Inc.)

Background: Refractory or relapsed large B-cells lymphoma are usually treated with a high dose chemotherapy regimen followed by an autolougous stem cells transplantation. BEAM (carmustine, etoposide, cytarabine, melphalan) or more recently Z-BEAM (ibritumomab tiuxetan and BEAM) are commonly used regimens, but recently carmustine availability became difficult. The purpose of this study was to evaluate the feasibility and the safety of replacing carmustine by bendamustine in a new Z-BeEAM regimen (ibritumomab tiuxetan, bendamustine, etoposide, cytarabine, melphalan) prior to autologous stem cell transplantation., Findings: This study was a retrospective analyze of six patients, with a median age of 60, treated by Z-BeEAM before autologous stem cell transplantation. We did not put in evidence any additional toxicities compared to conventional induction chemotherapy. The main toxicities were mucositis (3 grade III among 6 patients), gastrointestinal (2 grade III vomiting and 2 grade III diarrhea) and neutropenia (6 grade IV). Engraftment was successfully achieved for all patients. At the time of analysis of this study all patients were alive and in complete response based on the PET-CT evaluation., Conclusions: BeEAM plus ibritumomab tiuxetan combined regimen before autologous stem cell transplantation is feasible and safe in aggressive relapsing large B-cell lymphoma.

Background: Infectious events have been reported as major environmental triggers of thrombotic thrombocytopenic purpura (TTP). We detail here the potential association between infections and TTP., Study Design and Methods: We recruited randomly and prospectively a cohort of 280 consecutive TTP patients during a 9-year period. Features of infection were systematically recorded., Results: Features consistent with an infectious event were observed in 114 patients (41%) at time of TTP diagnosis. Infectious agents were documented in 34 cases and were mainly Gram-negative bacilli. At time of diagnosis infected patients more frequently had fever (p < 0.001). Infections at diagnosis did not impact prognosis and outcome. Thirty-six percent of patients experienced an infectious event during hospitalization, which resulted in more exacerbation of TTP (p = 0.02). Infections were not overrepresented during treatment in patients who received steroids and/or rituximab. Further genetic analysis of toll-like receptor (TLR)-9 functionally relevant polymorphisms revealed that TLR-9 +2848 G and TLR-9 +1174 A genotypes were more frequent in TTP patients than in controls (p = 0.04 and p = 0.026, respectively) and more particularly in patients negative for the Class II human leukocyte antigen system susceptibility allele DRB1*11 (p = 0.001 and p = 0.002, respectively). Haplotypes estimation showed that 1174A-2848G haplotype was significantly more frequent in TTP (p = 0.004), suggesting a primary role for this haplotype variation in conferring a predisposition for acquired TTP., Conclusion: Infections should be considered as an aggravating factor during the course of TTP. Particular polymorphisms in TLR-9 gene may represent risk factors for TTP., (© 2013 American Association of Blood Banks.)

The use of biological therapies for treating autoimmune diseases is increasing. These therapies are sometimes administered to pregnant women as part of a planned therapeutic regimen or to women with unexpected or unplanned pregnancies. The safety of biological therapies in this setting is a major issue. Here, we describe three young pregnant patients with autoimmune disorders: two patients with rheumatoid arthritis and one with idiopathic thrombotic thrombocytopenic purpura. These patients were exposed to rituximab (anti-CD20 monoclonal antibody) or abatacept (fusion protein CTLA4Ig) during the first trimester of their pregnancies. No significant adverse effects or complications were observed during the pregnancies, and all three patients delivered healthy newborns. In the rituximab cases, this result might be explained in part by the very low transplacental maternofetal transfer of rituximab during the first trimester of pregnancy. Despite these favorable outcomes, the use of these two biological agents must follow international recommendations. Their use is not currently allowed during pregnancy except in cases where the potential benefit to the mother justifies the potential risk to the fetus. In the case of exposure to the single agent rituximab during the first trimester, current data suggest that the low risk to the fetus may be outweighed by the potential benefit to the mother.

Therapy-related acute myeloid leukemia (t-AML) is a clinical syndrome occurring as a complication after cytotoxic and/or radiation therapy. The incidence of t-AML after acute promyelocytic leukemia (APL), all-transretinoic acid (ATRA), and anthracycline-based therapy is rather low. However, because of the high remission rates and long-term overall survival achieved with current APL treatments, late complications related to antileukemic therapy should be taken into account, giving priority to efficacy agents with the lowest potential of leukemogenesis, despite individual genetic susceptibilities that are not well known. Here, we report two cases of t-AML observed in two young women who achieved a rapid, complete molecular remission (CMR) of APL and who were still in CMR when t-AML was diagnosed. These t-AMLs shared some clinical and biological features such as poor-risk cytogenetics and a rapidly progressing, unfavorable outcome. Retrospective RT-PCR WT1 expression from the onset of APL to t-AML diagnosis did not prove to be a good marker for t-AML development., (© 2012 John Wiley & Sons A/S.)

The LAM2001 phase 3 trial, involving 832 patients with acute myeloid leukemia (AML; median: 46 years) proposed HLA-identical sibling allograft HSCT for all patients with an identified donor. The trial compared reduced-intensity conditioning (RIC) for patients older than 50 years of age (N = 47) and myeloablative conditioning for younger patients (N = 117). BM HSCT was performed in the younger patients, while the older ones received a consolidation course, followed by peripheral blood allo-HSCT using RIC. The incidence of grade II-IV acute GVHD, was 51.9% (95% confidence interval [CI]: 42.1-61.8) and 11.3% (1.6-21.2) after myeloablative or RIC, respectively (P < .0001) and that of chronic GVHD 45.8% (95% CI: 34.8-56.7) and 41.7% (24.7-58.6; NS). Cumulative incidence of nonrelapse mortality at 108 months was 15.8% (95% CI: 9.8-23.2) for myeloablative, and 6.5% (0.2-16.2) for RIC (NS). CI of relapse at 108 months was 21.7% (95% CI: 13.9-28.6) and 28.6% (16.5-43.4; NS). Overall survival at 108 months was 63.4% (95% CI: 54.6-72.2) and 65.8% (52.2-72.2), respectively, after myeloablative or RIC (NS). RIC peripheral blood stem cell allo-HSCT is prospectively feasible for patients between the ages of 51 and 60 years without excess of relapse or nonrelapse mortality, and compares favorably with myeloablative marrow allo-HSCT proposed to younger patients.

The prognosis of acute myeloid leukemia (AML) is very poor in elderly patients, especially in those classically defined as having unfavorable cytogenetics. The recent monosomal karyotype (MK) entity, defined as 2 or more autosomal monosomies or combination of 1 monosomy with structural abnormalities, has been reported to be associated with a worse outcome than the traditional complex karyotype (CK). In this retrospective study of 186 AML patients older than 60 years, the prognostic influence of MK was used to further stratify elderly patients with unfavorable cytogenetics. CK was observed in 129 patients (69%), and 110 exhibited abnormalities according to the definition of MK (59%). MK(+) patients had a complete response rate significantly lower than MK(-) patients: 37% vs 64% (P = .0008), and their 2-year overall survival was also decreased at 7% vs 22% (P < .0001). In multivariate analysis, MK appeared as the major independent prognostic factor related to complete remission achievement (odds ratio = 2.3; 95% confidence interval, 1-5.4, P = .05) and survival (hazard ratio = 1.7; 95% confidence interval, 1.1-2.5, P = .008). In the subgroup of 129 CK(+) patients, survival was dramatically decreased for MK(+) patients (8% vs 28% at P = .03). These results demonstrate that MK is a major independent factor of very poor prognosis in elderly AML.

A rare case of oromandibular Rhizopus oryzae infection is described in a 55-year-old woman with acute myeloid leukaemia and decompensated diabetes mellitus. The infection developed during induction chemotherapy when the patient was neutropenic. She was treated with a combination of amphotericin B lipid formulation and caspofungin plus surgery. Debridement surgery included excision of the lower lip, chin, floor of the mouth, a portion of the tongue, as well as mandibular resection at the level of the horizontal branches. Eight weeks of combined antifungal therapy were followed by secondary prophylaxis with amphotericin B lipid formulation during consolidation chemotherapy after achieving complete response of both leukaemia and mucormycosis. Reconstructive surgery was carried out including insertion of a new biomaterial porous mandibular prosthesis, which showed excellent functionality after long-term follow-up, followed by several plastic surgery procedures once good tolerability and no adverse effects of the prosthesis were observed. This case shows that a well-coordinated multidisciplinary approach is critical to increase the chances of clinical success in this life-threatening infection., (Copyright © 2010 S. Karger AG, Basel.)

Background Aims: Starting from experimental data proposing hematopoietic stem cells as candidates for cardiac repair, we postulated that human peripheral blood (PB) CD34+ cells mobilized by hematopoietic growth-factor (G-CSF) would contain cell subpopulations capable of regenerating post-ischemic myocardial damages., Methods: In a phase I clinical assay enrolling seven patients with acute myocardial infarct, we directly delivered to the injured myocardium autologous PB CD34+ cells previously mobilized by G-CSF, collected by leukapheresis and purified by immunoselection. In parallel, we looked for the eventual presence of cardiomyocytic and endothelial progenitor cells in leukapheresis products of these patients and controls, using flow cytometry, reverse transcription-quantitative (RTQ)-polymerase chain reaction (PCR), cell cultures and immunofluorescence analyzes., Results: The whole clinical process was feasible and safe. All patients were alive at an average follow-up of 49 months (range 24-76 months). Improvement of heart function parameters became obvious from the third month following cell reinjection. Left ventricular ejection fraction values progressively and dramatically increased with time, associated with PetScan demonstration of myocardial structure regeneration and revascularization and New York Heart Association (NYHA) grade improvement. Furthermore, we identified PB CD34+ cell subpopulations expressing characteristics of both immature and mature endothelial and cardiomyocyte progenitor cells. In vitro CD34+ cell cultures on a specific medium induced development of adherent cells featuring morphologies, gene expression and immunocytochemistry characteristics of endothelial and cardiac muscle cells., Conclusions: Mobilized CD34+ cells contain stem cells committed along endothelial and cardiac differentiation pathways, which could play a key role in a proposed two-phase mechanism of myocardial regeneration after direct intracardiac delivery, probably being responsible for the long-term clinical benefit observed.