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.     

Peripheral T-cell expansion and low infection rate after reduced-intensity conditioning and allogeneic blood stem cell transplantation

Peripheral blood stem cell transplantation after reduced-intensity conditioning (RIC-PBSCT) regimen is an alternative to conventional regimens with less immediate toxicity. Since immune recovery is of crucial importance for the control of infections, we retrospectively studied the recovery of T-, B- and NK cell subsets in 20 consecutive patients undergoing RIC-PBSCT. We also studied the thymic output using T-cell receptor excision circle assay. Engraftment was rapid and few infectious complications were seen: three early (before 2.5 months) cases of asymptomatic cytomegalovirus reactivation, two late Gram-negative bacterial infections and no fungal infection. While CD4+ T-cell reconstitution was slow, CD8+ T-cell counts were close to normal values at 4 months. Median CD19+ B-cell counts reached normal values at 11 months. Rapid CD56+ NK cell reconstitution was noticed as early as 1.5 months. Low T-cell receptor excision circle numbers and preponderance of memory-type subsets among T cells further suggested that CD8+ T-cell reconstitution resulted predominantly from peripheral expansion and that thymic-dependent reconstitution was severely impaired. In conclusion, large peripheral T-cell expansion may compensate for late thymic-dependent lymphopoiesis, and may, with other factors such as NK and B-cell reconstitution and careful antiinfectious prophylaxis, help limit the incidence of severe infections after RIC-PBSCT.     

Total body irradiation using helical tomotherapy: Set-up experience and in-vivo dosimetric evaluation

PurposeHelical Tomotherapy (HT) appears as a valuable technique for total body irradiation (TBI) to create highly homogeneous and conformal dose distributions with more precise repositioning than conventional TBI techniques. The aim of this work is to describe the technique implementation, including treatment preparation, planning and dosimetric monitoring of TBI delivered in our institution from October 2016 to March 2019.Material and methodPrior to patient care, irradiation protocol was set up using physical phantoms. Gafchromic films were used to assess dose distribution homogeneity and evaluate imprecise patient positioning impact. Sixteen patients’ irradiations with a prescribed dose of 12 Gy were delivered in 6 fractions of 2 Gy over 3 days. Pre-treatment quality assurance (QA) was performed for the verification of dose distributions at selected positions. In addition, in-vivo dosimetry was carried out using optically stimulated luminescence dosimeters (OSLD).ResultsPlanning evaluation, as well as results of pre-treatment verifications, are presented. In-vivo dosimetry showed the strong consistency of OSLD measured doses. OSLD mean relative dose differences between measurement and calculation were respectively +0,96% and ?2% for armpit and hands locations, suggesting better reliability for armpit OSLD positioning. Repercussion of both longitudinal and transversal positioning inaccuracies on phantoms is depicted up to 2 cm shifts.ConclusionThe full methodology to set up TBI protocol, as well as dosimetric evaluation and pre-treatment QA, were presented. Our investigations reveal strong correspondence between planned and delivered doses shedding light on the dose reliability of OSLD for HT based TBI in-vivo dosimetry.     

Reduced-intensity conditioning allogeneic stem cell transplantation for relapsed/refractory mantle cell lymphoma: a multicenter experience

Background Despite therapeutic approach that combines rituximab-containing chemotherapy, followed or not by autologous stem cell transplantation (auto-SCT), mantle cell lymphoma (MCL) patients experience relapses. Reduced-intensity conditioning allogeneic stem cell transplantation (RIC-allo-SCT) at time of relapse may represent an attractive strategy. Patients and methods We report a multicenter retrospective analysis. Seventy MCL patients underwent RIC-allo-SCT in 12 centers. Results Median age at transplantation was 56 years and median time from diagnosis to transplantation was 44 months. The median number of previous therapies was 2 (range, 1-5) including autologous transplantation in 47 cases. At time of transplantation, 35 patients were in complete remission, 20 were in partial response and 15 in stable disease or progressive disease. The median follow-up for living patients was 24 months. The 2-year event-free survival (EFS) and overall survival (OS) rates were 50% and 53%, respectively. The 1- and 2-year transplant-related mortality rates were 22% and 32%, respectively. The statistical analysis demonstrated that disease status at transplantation was the only parameter influencing EFS and OS. Conclusions These results suggest that RIC-allo-SCT may be an effective therapy in MCL patients with a chemo-sensitive disease at time of transplantation, irrespective of the number of lines of prior therapy. Studies are warranted to investigate the best type of RIC regimen.     

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.     

Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto‐SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM‐TC

This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto‐SCT; n = 82; median age: 48 years; median follow‐up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow‐up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good‐risk cytogenetics and lower number of previously transplanted patients, 3‐year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo‐SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11–0.82, P = 0.02), but higher non‐relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46–11.9, P = 0.008). Results from this large study suggest that UCB allo‐SCT provides better disease control than auto‐SCT, which is especially important in the setting of high‐risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo‐SCT.     

Prise en charge d’une réactivation/infection à CMV chez l’allogreffé et prise en charge de la réactivation EBV/syndrome lymphoproflifératif à EBV chez l’allogreffé de cellules souches hématopoïétiques

In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the third annual series of workshops which brought together practitioners from all member centers and took place in October 2012 in Lille. Here the SFGM-TC addressed the issue of post-transplant CMV and EBV reactivation, and EBV-related Lymphoproliferative Disorders.