A pilot study of 220 mg/m2 melphalan followed by autologous stem cell transplantation in patients with advanced haematological malignancies: pharmacokinetics and toxicity

We studied the pharmacokinetics and toxicity of 220 mg/m² melphalan (HDM 220) followed by autologous stem cell transplantation in 16 patients with advanced haematological malignancies. Pharmacokinetic parameters (mean values of steady-state volume of distribution 14.6 l/m², total body clearance 313 ml/min/m², elimination half-life 46 min) were the same as those of 140 or 200 mg/m² melphalan in previous reports. HDM 220 was feasible. Extramedullary toxicity was mainly W.H.O. grade 4 mucositis (13/16 patients). The median duration of 41 d (10, not reached) of thrombocytopenia <25 × 10⁹/l was long. In multiple myeloma the response rate was 89% in heavily pretreated patients, suggesting that HDM 220 could be considered earlier in the course of the disease as an alternative consolidation therapy.     

The impact of graft-versus-host disease prophylaxis in reduced-intensity conditioning allogeneic stem cell transplant in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation

The impact of the intensity of graft-versus-host-disease immunoprophylaxis on transplantation outcomes in patients undergoing transplantation following reduced-intensity conditioning is unclear. This study addresses this issue in 228 adult patients above 50 years of age with acute myeloid leukemia in first complete remission given peripheral blood stem cells from HLA-identical siblings after fludarabine and 2 days of intravenous busulfan reduced-intensity conditioning. A total of 152 patients received anti-thymocyte globulin, either in combination with cyclosporine A in 86 patients (group 1), or with cyclosporine A and mycophenolate mofetil or short course methotrexate in 66 patients (group 2). The remaining 76 patients did not receive anti-thymocyte globulin but were given cyclosporine A and methotrexate or mycophenolate mofetil (group 3). Incidences of grade II-IV acute graft-versus-host-disease were comparable in the three groups (16.5%, 29.5% and 19.5% in groups 1, 2 and 3, respectively, P=0.15). In multivariate analysis, the absence of anti-thymocyte globulin was the only factor associated with a higher risk of chronic graft-versus-host-disease (P=0.005), while the use of triple immunosuppression (group 3) was associated with an increased risk of relapse (P=0.003). In comparison to anti-thymocyte globulin and cyclosporine A alone, the other two strategies of graft-versus-host-disease prophylaxis were associated with reduced leukemia-free survival and overall survival (P=0.001 for each parameter), independently of the dose of anti-thymocyte globulin. These data suggest that fine tuning of the intensity of this prophylaxis can affect the outcome of transplantation and that anti-thymocyte globulin and cyclosporine A alone should be the preferred combination with the fludarabine-busulfan reduced-intensity conditioning regimen and sibling donors.     

Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenstr?m’s macroglobulinemia. Results of a retrospective analysis of the Société Fran?aise de Greffe de Moelle et de Thérapie Cellulaire

Background

Patients with poor-risk Waldenström’s macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients.

Design and Methods

We examined the long-term outcome of allogeneic stem cell transplantation in Waldenström’s macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg.

Results

Median age at the time of transplant was 48 years (range, 24–64). The patients had previously received a median of 3 lines of therapy (range, 1–6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11–149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46–81) and 58% (95% CI: 38–75). The 5-year estimated risk of progression was 25% (95% CI: 10–36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant.

Conclusions

Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenström’s macroglobulinemia.     

In vitro functional defects of bone marrow-derived CD34+ progenitors from newly diagnosed mature B-cell malignancies with bone marrow tumor involvement

OBJECTIVE: We hypothesized that the presence of tumor cells in bone marrow (BM) could alter hematopoietic progenitor cell functions. Therefore, we evaluated phenotypic and in vitro functional properties of BM-derived CD34+ progenitors issued from untreated and newly diagnosed patients presenting a mature B-lymphoproliferative disorder (LPD) involving the BM (Inv+). PATIENTS AND METHODS: In vitro proliferation and differentiation capacities of primitive and committed progenitors were evaluated by cobblestone area-forming cell (CAFC) and colony-forming cell (CFC) assays, and ex vivo cell expansion. Migratory capacities of CD34+ cells were explored by chemotaxis assays using a CXCL12alpha gradient. RESULTS: Our results showed that CD34+ cells from Inv+ patients overexpressed CD117 and had a significant decrease of week-3 and -6 CAFC, and CFC frequencies, compared to cells obtained from healthy volunteers and LPD patients without BM involvement (Inv-). In addition, progenitors from Inv+ patients maintained a significantly decreased CFC capacity after ex vivo cell expansion, compared to healthy volunteers. However, the former cells held their migratory capacity in response to CXCL12alpha. CONCLUSION: Functional defects of primitive and committed CD34+ progenitors detected among LPD patients with BM tumor involvement suggest either that tumor cells may induced bystander effects on progenitors or that "unusual" CD34+ cells may exist in the BM that could belong to the proliferating tumor tissue.     

Factor XIII replacement in stem-cell transplant recipients with severe hemorrhagic cystitis: a report of four cases

BACKGROUND: Hemorrhagic cystitis (HC) is an important cause of morbidity in patients undergoing allogeneic stem-cell transplantation (SCT). Various causes have been identified, such as the use of high-dose cyclophosphamide or busulfan and the occurrence of acute graft-versus-host disease or viral infections (cytomegalovirus, adenovirus, polyomavirus). METHODS: The clinical course of four patients treated with factor XIII (FXIII) concentrate for severe HC after allogeneic SCT is described. RESULTS: Four patients were treated with one or two infusions of 50 IU/kg of FXIII concentrate. Only one patient showed a plasmatic FXIII decrease before treatment. Three of the four patients responded to this treatment, and HC completely resolved in two of them. No adverse event was observed. CONCLUSION: The use of FXIII concentrate can improve the major symptoms of HC in patients with decreased or normal FXIII plasma level after allogeneic SCT.     

Use of real-time PCR to process the first galactomannan-positive serum sample in diagnosing invasive aspergillosis

Positive galactomannan (GM) anti-genemias are included as a microbiological item in the diagnosis of probable or possible invasive aspergillosis (IA). Because false-positive GM results frequently occur, at least two positive results on two different samples are required. Waiting for clinical specimens can delay the initiation of treatment. As an alternative, we wondered whether detection of circulating Aspergillus DNA on the first positive GM serum sample could aid in diagnosing IA. Therefore, we retrospectively screened the first GM-positive serum samples from 29 patients from our hematology unit for Aspergillus DNA using real-time PCR. We compared the real-time PCR results with the final classification of proven, probable, and possible IA according to consensual criteria. No clear correlation between PCR results and the classification with the medical files could be shown. However, a positive PCR result was associated with a poor prognosis (Fisher's test; P=0.01). Our preliminary data suggest that a positive PCR result could indicate a more advanced stage of the disease. Therefore, concomitant positive PCR and GM results may justify the initiation of antifungal therapy in neutropenic patients. In contrast, a negative PCR on the first positive GM sample may argue for postponing costly antifungal administration until additional arguments for the diagnosis of IA are presented.     

Variability of Voriconazole Plasma Concentrations after Allogeneic Hematopoietic Stem Cell Transplantation: Impact of Cytochrome P450 Polymorphisms and Comedications on Initial and Subsequent Trough Levels

Voriconazole (VRC) plasma trough concentrations (C_min) are highly variable, and this could affect treatment efficacy and safety in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). We aimed to describe the intra- and interindividual variation of VRC C_min throughout the course of VRC therapy and to identify the determinants of this variation. Clinical data, medications, and VRC C_min (n = 308) of 33 AHSCT patients were retrospectively collected. Cytochrome P450 (CYP450) genotypes of CYP2C19, CYP3A4, and CYP3A5 patients were retrospectively determined before allografting, and a combined genetic score was calculated for each patient. The higher the genetic score, the faster the metabolism of the patient. The VRC C_min inter- and intraindividual coefficients of variation were 84% and 68%, respectively. The VRC dose (D) was correlated to VRC C_min (r = 0.412, P < 0.0001) only for oral administration. The administration route and the genetic score significantly affected the initial VRC C_min. Considering oral therapy, patients with a genetic score of <2 had higher initial VRC C_min/D than patients with a genetic score of >2 (P = 0.009). Subsequent VRC C_min remained influenced by the genetic score (P = 0.004) but were also affected by pump proton inhibitor comedication (P < 0.0001). The high variability of VRC C_min in AHSCT patients is partially explained by the route of administration, treatment with pump proton inhibitors, and the combined genetic score. This study suggests the interest in combined genetic score determination to individualize a priori the VRC dose and underlines the need for longitudinal therapeutic drug monitoring to adapt subsequent doses to maintain the VRC C_min within the therapeutic range.     

Low-dose sufentanil dœs not potentiate intra-thecal morphine for perioperative analgesia after major colorectal surgery

PURPOSE: Both intrathecal sufentanil (ITS) and intrathecal morphine (ITM) improve analgesia in obstetrical or cardiac procedures. From a pharmacokinetic standpoint, combining these two opioids may improve perioperative analgesia. We performed a prospective randomized double-blind study to compare the analgesic efficacy of ITM alone vs a mixture of a low dose of ITS plus ITM for perioperative pain relief in colorectal surgery. METHODS: Eighty adult patients undergoing colorectal surgery were randomly allocated to receive either 0.4 mg ITM alone or 10 microg ITS plus 0.4 mg ITM before general anesthesia. Intraoperative intravenous sufentanil consumption, postoperative morphine consumption delivered with a patient controlled analgesia device, pain scores, patient satisfaction and adverse effects were recorded for the first 48 hr postoperatively. RESULTS: No differences were observed between groups with respect to intraoperative sufentanil consumption (39 +/- 23 microg in group ITM and 40 +/- 25 microg in group ITS plus ITM, P = 0.85) and in postoperative morphine consumption in postanesthesia care unit (6 +/- 5 mg vs 6 +/- 5 mg, P = 0.59), at 24 hr (26 +/- 17 vs 24 +/- 15 mg, P = 0.59) and at 48 hr (47 +/- 31 vs 44 +/- 22 mg, P = 0.58). Similarly, no differences were observed in regards to pain relief, patient satisfaction and incidence of adverse effects. CONCLUSIONS: These results do not support the addition of 10 microg ITS to 0.4 mg ITM for colorectal surgery, as low dose sufentanil does not improve intraoperative and postoperative analgesia in this setting.