Clinical implications of measurable residual disease in AML : review of current evidence

Despite the fact that 80% of adult acute myeloid leukaemia patients reach complete morphological remission after induction chemotherapy, many of them relapse. Many studies have shown that detection of minimal residual disease (defined as 'any detectable evidence of persistent leukaemic cells during complete morphological remission') has an added value in prediction of relapse and survival, and is more than just a surrogate marker for already known risk factors in AML. As such, the behaviour of the disease during treatment might become equally or even more important to decide whether or not an upgrade of treatment (such as an allogeneic stem cell transplantation) is necessary to improve outcome. However, there are still many open issues as to what the ideal time point is to measure MRD, which threshold is clinically significant, what sample (peripheral blood or bone marrow) should be used and how we can standardize tests so that results from different labs become comparable. This review gives an overview of currently available evidence regarding technical issues, prognostic impact and MRD-directed treatment in AML

Factors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study

Objective: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of selfperceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. Methods: In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients’ SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients’/primary caregivers’ personal relationship characteristics (family tie, support), were assessed. Results: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients’ SPB-PC was associated with lower Karnofsky performance (β = 0.135, p = 0.058) and ADL (β = 0.148, p = 0.037) scores, and higher HADS (β = 0.283, p<0.001) and FACT-Cog perceived cognitive impairments subscale (β = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. Conclusions: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma

The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting.Journal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Haematopoiesis in autologous transplantation for acute myeloid leukaemia

L’autogreffe de moelle osseuse pour leucémie myéloïde aiguë (LMA) en rémission complète (RC) après chimiothérapie est fréquemment suivie d’une régénération hématologique retardée, responsable en grande partie de la mortalité et de la morbidité de la procédure. Ce travail a analysé l’activité hématopoïétique au sein de ces greffons, en comparaison avec l’activité hématopoïétique au sein de moelles de donneurs sains ou de patients autogreffés pour d’autres maladies, principalement des lymphomes. La faisabilité de l’amplification in vitro des progéniteurs et cellules souches à partir de ces greffons a été également analysée. En culture de moelle à long terme (LTBMC), les cellules mononucléées des greffons pour LMA présentent un déficit hématopoïétique qui n’est cependant pas corrélé avec la lente régénération hématologique après greffe. A l’opposé, les greffons de patients traités pour pathologie non-leucémique montrent une conservation du pool des cellules souches. Dans ce groupe, les données de la LTBMC sont corrélées avec la reprise hématologiques post-greffe. La LTBMC réalisée au départ de cellules mononucléées analyse à la fois le compartiment hématopoïétique et le compartiment stromal. Le dédicit observé pourrait donc être attribué soit à un déficit de la cellule souche hématopoïétique, soit à un déficit du microenvironnement médullaire. Afin de déterminer si les cellules hématopoïétiques sont défectives, l’activité hématopoïétique de populations purifiées de progéniteurs (CD34+DR+) et de cellules souches (CD34+DR-) a été analysée. Les cellules CD34+DR- de patients atteints de LMA en RC produisent un nombre de CFU-GM inférieur à celui produit par leurs équivalents normaux. La production de CFU-GM par la fraction CD34+DR+ est comparable à la normale. Les deux populations cellulaires de patients produisent moins de BFU-E, de HPP-CFC et de LTC-IC que les mêmes populations isolées à partir de moelle normale. Contrairement à la situation normale, la fraction CD34+DR- des patients n’est pas enrichie en LTC-IC. les conditions nécessaires à l’expansion ex vivo des cellules CD34+DR- ont été mises au point sur des cellules normales avant d’être appliquées aux cellules des patients. Nous avons montré que l’expansion de cette population primitive requiert la présence de facteurs diffusibles contenus dans le milieu de culture conditionné par du stroma médullaire. Dans ces conditions de culture permettant d’obtenir une expansion satisfaisante en progéniteurs et un maintien des cellules souches au départ d’échantillons normaux, les moelles de patients ne présentent qu’une expansion médiocre. Même en présence de hautes concentrations de Stem Cell Factor et du ligand Flt3, une faible amplification des progéniteurs et une diminution du nombre de cellules CD34+ a été observé pour les échantillons de patients. Afin de caractériser plus avant le déficit hématopoïétique des greffons pour LMA, une analyse de la viabilité et du cycle cellulaires, ainsi que la recherche de la production d’inhibiteur(s) de l’hématopoïèse par les cellules de patients ont été effectuées. Très rapidement après la mise en culture, on observe un excès de mortalité cellulaire dans les échantillons de patients par rapport aux échantillons normaux. Cette différence n’est plus observée après 7 jours de culture. Nous n’avons montré aucune évidence de blocage de la progression dans le cycle cellulaire ou de production d’inhibiteurs de l’hématopoïèse. En conclusion, les cellules souches des patients en rémission d’une LMA présentent in vitro un déficit hématopoïétique attribuable à un excès de mortalité cellulaires et à un potentiel prolifératif réduit. L’expansion ex vivo au départ de ces greffons est inapplicable dans l’état actuel de nos connaissances. Si la chimiothérapie, la maladie elle-même ou les deux sont responsable du déficit observé reste à déterminerAutologous bone marrow (BM) transplantation for acute myeloid leukaemia (AML) in first complete remission (CR1) after chemotherapy is frequently followed in a delayed haematological recovery, responsible for substantial morbidity and mortality. This work assessed the haemopoietic potential of CR1 AML autografts, compared to normal BM cells and compared to autografts from patients treated for other diseases (mainly lymphomas). The feasibility of ex vivo expansion of progenitors and stem cells was also investigated. By using long-term bone marrow culture (LTBMC) of mononucleated cells (MNC), CR1 AML autografts were shown to be defective in their ability to sustain in vitro haematopoiesis. However, this in vitro defect did not correlate with the slow haematological recovery post-transplant. In contrast, LTBMC of non-AML autografts, whose defect affects the stem cell pool lees than CR1 AML autografts, correlated with the speed of engraftment. LTBMC of MNC analyses both the stromal and the haematopoietic compartments. The observed impaired haematopoiesis may therefore reflect a defect at the stem cell level or a defective microenvironment. We assessed whether the stem cell pool was damaged independently of stromal cell. Therefore, the haemopoietic activity of purified stem cell (CD34+DR-) and progenitor (CD34+DR+) cell populations was analysed. The number of CFU-GM produced by patient CD34+DR- cells was decreased compared to normal, whereas these values were similar to normal fir CD34+DR+ cells. BFU-E, HPP-CGC and LTX-IC were reduced for both patient CD34+DR- and CD34+DR+ subpopulations. In contrast to normal cells, the patient CD34+DR- fraction was not enriched in LTC-IC. The ex vivo expansion requirements of primitive CD34+DR- cells were defined on normal BM cells before being applied to CR1 AML cells. We showed that diffusible factors contained in medium conditioned by BM stroma were necessary to support the expansion of the whole spectrum of haematopoietic cells form CD34+DR- cells. When culture conditions allowing for expansion from a normal stem cell population were applied to patient CD34+DR- cells, no meaningful ex vivo expansion could be obtained. Even at high concentrations of Stem Cell Factor and Flt3-ligand, a low progenitor expansion and a decrease in CD34+ cell numbers were observed for patient samples in contrast to normal samples. In order to better characterise the in vitro haemopoietic defect of CR1 AML cells, viability, cell cycle and production of haematopoiesis inhibitor(s) by patient cells were analysed. Early in culture, an excess in cell mortality was observed in patient samples compared to normal. The difference was no longer observed after 7 days of culture. No evidence for cell cycle arrest or haematopoiesis inhibitor production was shown. in conclusion, stem cells form CR1 AML bone marrow showed defective haemopoietic activity due to early cell mortality and low proliferative potential. No meaningful ex vivo expansion has been obtained. Whether chemotherapy, the disease itself, or both are responsible for this haematopoietic defect remains unkownThèse de doctorat en sciences biomédicales (hématologie)-- UCL, 199

Pericarditis induced by high-dose cytosine arabinoside chemotherapy

Pericarditis is a rare side effect of chemotherapy. We report here the case of a patient treated with high-dose cytosine arabinoside (HD ara-c) who developed severe pericarditis. Interruption of HD ara-c and initiation of corticosteroid treatment were effective in resolving the pericardial effusion. This case illustrates this rare but potentially life-threatening cardiac complication of HD ara-c therapy as well as the beneficial effect of corticosteroid treatment

Stromal factors support the expansion of the whole hemopoietic spectrum from bone marrow CD34+DR- cells and of some hemopoietic subsets from CD34+ and CD34+DR+ cells.

Ex vivo expanded bone marrow CD34+DR- cells could offer a graft devoid of malignant cells able to promptly reconstitute hemopoiesis after transplant. We investigated the specific expansion requirements of this subpopulation compared to the more mature CD34+ and CD34+DR+ populations. The role of stromal factors was assessed by comparing the expansion obtained when the cells were cultured in (1) long-term bone marrow culture (LTBMC) medium conditioned by an irradiated human BM stroma (CM), (2) medium supplemented with 15% FBS (FBSM) and (3) non-conditioned LTBMC medium (LTM) for 21 days. The effect of the addition of G-CSF (G) and/or of MIP-1alpha (M) to a combination of IL-3, SCF, IL-6 and IL-11 (3, S, 6, 11) was analyzed. Compared to CD34+DR- cells, CD34+ and CD34+DR+ cells gave rise to a similar number of viable cells and to a lower progenitor expansion. The expansion potential of CD34+ and CD34+DR+ cells was equivalent in CM and in FBSM except for both the emergence of CD61 + megakaryocytic cells and LTC-IC maintenance which were improved by culture in CM. In contrast, expansion from CD34+DR- cells was enhanced by CM for all the parameters tested. Compared to FBSM, CM induced a higher level of CFU-GM and BFU-E expansion and allowed the emergence of CD61+ cells. HPP-CFC were maintained or expanded in CM but decreased in FBSM. Compared to input, the number of LTC-IC remaining after 21 days of CD34+DR- expansion culture was strongly decreased in FBSM and variably maintained or expanded in CM. Comparison with LTM indicated that stroma conditioning is responsible for this effect. G-CSF significantly improved CFU-GM and HPP-CFC expansion from CD34+DR- cells without being detrimental to the LTC-IC pool. The growth of CD61+ cells was significantly enhanced by G-CSF in CM. Addition of MIP-1alpha had no significant effect either on progenitor expansion or on LTC-IC, regardless of culture medium. We conclude that factors present in stroma- conditioned medium are necessary to support the expansion of the whole spectrum of hematopoietic cells from CD34+DR- cells and to support the expansion of cell subsets from CD34+ and CD34+DR+