Nicole Straetmans

Infectious complications after 2-chlorodeoxyadenosine therapy.

Abstract: Infection is a common adverse event after therapy with nucleoside analogs, including 2‐chlorodeoxyadenosine (CdA). However, the incidence of CdA‐related infections has been poorly documented. In this study we compare, in the same patient population, the incidence of infectious episodes during the 6‐month period before CdA to their incidence during the 6 months after initiating therapy. Ninety‐five patients with hematological malignancies were studied. The incidence of infectious episodes almost doubled after CdA (0.87 vs. 0.47 during the pre‐CdA period). The following factors were associated with an increased risk of infection after therapy: a history of previous chemotherapy, infection during the pre‐CdA period and a diagnosis of chronic lymphocytic leukemia or of non‐Hodgkins lymphoma. Age, neutrophil and lymphocyte count at onset of CdA and time interval between diagnosis and therapy with CdA did not correlate with the infectious risk. The pattern of infections was modified after therapy with an increase of herpes virus infections (1 vs. 8 episodes, p = 0.04) and of fever of unknown origin (6 vs. 17 episodes, p = 0.03). In conclusion, a population at high risk for developing infectious complications after CdA therapy can be identified. Specific measures aimed at reducing the incidence of infectious events should concentrate on this population.

Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma.

Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2′-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkins lymphoma. CdA was given at a fixed dose (5.6 mg/m2/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m2, and was escalated by 100 mg/m2 increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m2, was 300 mg/m2. Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% CI, 36–76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenström macroglobulinemia.

Myelodysplastic syndrome with monosomy 5 and/or 7 following therapy with 2-chloro-2'-deoxyadenosine.

A few cases of secondary neoplasms occurring after treatment with 2‐chloro‐2′‐deoxyadenosine (2CdA) have been reported, mostly in patients previously exposed to other anti‐cancer drugs including alkylating agents (AA). Here we report on the occurrence of a myelodysplastic syndrome (MDS) with monosomy 5 and/or 7 in two patients after 2CdA treatment, without or prior to other toxic exposure. In light of a literature review and given the involvement of chromosomes frequently abnormal in secondary leukaemias, we suggest that 2CdA may induce therapy‐related MDS (t‐MDS).

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-1α (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-1α 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+.

Haemopoietic defect and decreased expansion potential of bone marrow autografts from patients with acute myeloid leukaemia in first remission.

Autologous bone marrow (BM) transplantation for acute myeloid leukaemia (AML) in complete remission (CR) is frequently followed by a slow haemopoietic recovery. We assessed the haemopoietic capacity of purified BM stem cell (CD34+DR−) and progenitor cell (CD34+DR+) populations from patients with AML in CR, and compared these data with those of normal BM. The feasibility of ex vivo expansion in stroma‐conditioned medium supplemented with cytokines was also investigated.

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

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 self‐perceived burden to the primary caregiver (SPB‐PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation.

In vitro evaluation of the haemopoietic defect of CD34+ cells from patients with acute myeloid leukaemia in first remission

Haemopoietic cells from patients with acute myeloid leukaemia (AML) in first complete remission (CR1) show in vitro a haemopoietic defect and a decreased expansion potential. To better characterize this haemopoietic defect, CR1 AML and normal CD34+ cells were analysed for immunophenotype, viability, cell cycle and progenitor content before and during expansion culture in stroma‐conditioned medium supplemented with cytokines. The production of haemopoiesis inhibitor by patient cells and the influence of high concentrations of stem cell factor (SCF) and Flt3‐ligand (FL) on cell survival and ex vivo expansion potential were also studied. Before expansion, patient CD34+ cells showed viability and cell‐cycle phase distribution similar to normal but lower percentages of CD34+DR− or CD34+CD38− cells and lower progenitor content. After 48 h of culture ±30% of patient cells had died regardless of the cytokine combination used, whereas only 15% of normal cells died. After 7 d of culture, viability and cell cycle analyses showed comparable data for normal and patient samples. Co‐culture of patient and normal cells did not show any evidence for haemopoiesis inhibitor production by patient cells. Even at high cytokine concentrations, a low progenitor expansion and a decrease in CD34+ cell numbers was observed for patient samples in contrast to normal samples. In conclusion, CR1 AML CD34+ cells showed excessive early cell mortality. No evidence for cell‐cycle arrest or haemopoiesis inhibitor production was shown. SCF and FL used at high concentrations did not correct the patient cell expansion defect.

A Belgian consensus protocol for autologous hematopoietic stem cell transplantation in multiple sclerosis

Multiple sclerosis is considered to be an immune mediated inflammatory disorder of the central nervous system. It mainly affects young, socioeconomic active patients. Although our armamentarium for this disease has significantly evolved in recent years some patients remain refractory to conventional therapies. In these cases, autologous hematopoietic stem cell transplantation can be considered as a therapeutic option. Decreasing morbidity, mortality, and increasing patient awareness have led to rising inquiry by our patients about this treatment option. With the aim of a standardized protocol and data registration, a Belgian working party on stem cell therapy in multiple sclerosis was established. In this paper, we report the consensus protocol of this working party on autologous hematopoietic stem cell transplantation in multiple sclerosis.

Cognitive compensatory processes of older, clinically fit patients with hematologic malignancies undergoing chemotherapy: a longitudinal cohort study.

Despite the well‐known negative impacts of cancer and anticancer therapies on cognitive performance, little is known about the cognitive compensatory processes of older patients with cancer. This study was designed to investigate the cognitive compensatory processes of older, clinically fit patients with hematologic malignancies undergoing chemotherapy.