Fanny Rialland

Infectious Complications after Unrelated Umbilical Cord Blood Transplantation in Adult Patients with Hematologic Malignancies

Unrelated umbilical cord blood (UCB) is being increasingly used as an alternative stem cell source for allogeneic stem cell transplantation (allo-SCT). This retrospective study assessed infectious complications occurring in adult patients after UCB transplantation (UCBT). 31 patients received a single (n=4) or double UCBT (n=27) with a median dose of 4.7x10(7) nucleated cells/kg (range: 2.4-7.7). Patients received either a reduced-intensity conditioning (RIC; n=23) or a standard myeloablative (MA) regimen (n=8). The cumulative incidence of neutrophil recovery was 90%. Neutrophil recovery was achieved at a median time of 24 (range: 8-60) days after UCBT. The cumulative incidences of bacterial, fungal, and parasitic infections were, respectively, 16%, 10%, and 6%. Bloodstream infections were neither lethal nor required any intensive care therapy. Similarly, invasive fungal infections and parasitic infections did not cause any death in those patients with sustained engraftment. Although the cumulative incidence of cytomegalovirus (CMV) recurrence was 21%, no CMV disease was observed. With a median follow-up of 10 (range: 3-30) months, 10 patients have died (relapse, n=5; nonrelapse mortality, [NRM] n=5). Overall, the cumulative incidence of infectious-related mortality (IRM) was 8%. In conclusion, this data suggests that UCBT can be performed in adult patients with hematologic malignancies with an acceptable incidence of IRM provided a sufficient dose of nucleated cells is infused to the patient.

Larger number of invariant natural killer T cells in PBSC allografts correlates with improved GVHD-free and progression-free survival

We studied the impact of a set of immune cells contained within granulocyte colony-stimulating factor-mobilized peripheral blood stem cell grafts (naïve and memory T-cell subsets, B cells, regulatory T cells, invariant natural killer T cells [iNKTs], NK cells, and dendritic cell subsets) in patients (n = 80) undergoing allogeneic stem cell transplantation (SCT), using the composite end point of graft-versus-host disease (GVHD)-free and progression-free survival (GPFS) as the primary end point. We observed that GPFS incidences in patients receiving iNKT doses above and below the median were 49% vs 22%, respectively (P= .007). In multivariate analysis, the iNKT dose was the only parameter with a significant impact on GPFS (hazard ratio = 0.48; 95% confidence interval, 0.27-0.85;P= .01). The incidences of severe grade III to IV acute GVHD and National Institutes of Health grade 2 to 3 chronic GVHD (12% and 16%, respectively) were low and associated with the use of antithymocyte globulin in 91% of patients. No difference in GVHD incidence was reported according to the iNKT dose. In conclusion, a higher dose of iNKTs within the graft is associated with an improved GPFS. These data may pave the way for prospective and active interventions aiming to manipulate the graft content to improve allo-SCT outcome.

Escalated lymphodepletion followed by donor lymphocyte infusion can induce a graft-versus-host response without overwhelming toxicity

Treatment of relapse of hematological malignancies following allogeneic hematopoietic SCT (allo-HSCT) remains very challenging and relies usually on the readministration of chemotherapy combined with donor lymphocyte infusion (DLI). To enhance DLI effectiveness, lymphodepletion (LD) with fludarabine (Flu) and/or CY before the injection of lymphocytes is an attractive modality to modify the immune environment, leading possibly to suppression of regulatory T cells (Treg) and exposing the patient to cytokine activation. However, LD before DLI may lead to induction of deleterious GVHD. To avoid inducing overwhelming toxicity, we proceeded by escalating doses of both LD and DLI. Eighteen patients with various non-CML hematological malignancies who relapsed following allo-HSCT were treated with chemotherapy and LD-DLI or LD-DLI upfront. T-cell subpopulation and DC levels as well as cytokine plasma levels (IL-7, IL-15) were measured before and following LD-DLI. Cumulative incidence of acute grade II–IV GVHD was 29.4% similar to that reported in patients receiving DLI without LD. In addition, Flu alone with low dose of DLI was not associated with severe GHVD. CY/Flu at the respective doses of 600 mg/m2 on day 1 and Flu 25 mg/m2/day on days 1–3 did not result in a marked decrease of Treg cells, nor in endogenous IL-7 and IL-15 production. However, a peripheral expansion of DCs was observed. These findings suggest that the escalated dose procedure appears safe and prevent overwhelming toxicity. A dose-limiting toxicity has not yet been reached.

Impact on long-term OS of conditioning regimen in allogeneic BMT for children with AML in first CR: TBI + CY versus BU + CY: a report from the Société Française de Greffe de Moelle et de Thérapie Cellulaire

Allogeneic hematopoietic SCT (HSCT) appears to be an efficient tool to cure high-risk AML in first CR but the choice between BU-based or TBI-based conditioning regimens still remains controversial. In order to analyze the impact of conditioning regimen on long-term survival, we conducted a retrospective analysis from French registry data including all consecutive patients under 18 years old (n=226) from 1980 to 2004 transplanted for AML in CR1 from sibling (n=142) or matched unrelated donors and given either TBI-1200 cGy and CY 120 mg/kg (TBI-Cy, n=84) or BU 16 mg/kg and CY 200 mg/kg (BuCy200, n=142). Patient subgroups were comparable for all criteria except for median age at diagnosis and HSCT and for donor type. Both 5-year OS and disease-free survival (DFS) were significantly better in BuCy200 group (P=0.02 and 0.005, respectively). In multivariate analysis, both HLA matching and BuCy200 appeared as good prognostic factors for treatment-related mortality and DFS. Grade 2–4 acute GvHD and chronic GvHD rates were statistically higher in TBI-Cy group than in Bu-Cy200 one with a RR at 2 (P=0.002). In total, Bu-Cy200 conditioning regimen gives better outcome compared with TBI-Cy irrespective of the stem cell source and the donor type.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning regimen in children: a single-center experience.

This single‐center retrospective study reported the outcome of 19 children treated with a reduced‐intensity conditioning (RIC) regimen prior to allogeneic stem cell transplantation (allo‐SCT), for hematologic malignancies (n = 17), bone marrow failure (n = 1), and neuroblastoma (n = 1). Children were ineligible for standard myeloablative conditioning because of severe comorbidities (n = 9), a previous auto or allo‐SCT (n = 7) or a prior history of extensive chemotherapy (n = 3). All patients underwent a fludarabine‐based RIC regimen, and received grafts from matched‐related donors (n = 5), match‐unrelated donors (n = 6), or unrelated cord blood (UCB, n = 8). In this series, two patients treated with UCB failed to engraft and 63% achieved full donor chimerism at day 100 after allo‐SCT. With a median follow‐up of 537 d (range, 115–4136), treatment‐related mortality was 16% and overall survival was 47%. The principal cause of death was disease relapse (n = 7). Acute graft versus host disease (GVHD) occurred in 53% of patients, while only 10% developed extensive chronic GVHD. Overall, results from this series suggest that RIC allo‐SCT can be a valid alternative treatment option in unfit children with malignant hematological diseases. Prospective studies are needed to enlarge pediatric experience in this domain and better identify those children more suitable for a RIC allo‐SCT approach.

Improvement of overall survival after allogeneic hematopoietic stem cell transplantation for children and adolescents: a three-decade experience of a single institution

Allogeneic stem cell transplantation (allo-SCT) has become an essential component of the treatment for a variety of diseases in pediatric patients. During the past decades, advances in the transplant technology, availability of hematopoietic stem cells and supportive care not only have resulted in improved outcomes, but also have expanded the transplant options. However, these features have been studied mainly in adult populations. This investigation analyzed changes in patient profile, transplantation, graft characteristics and outcome among 250 children and adolescent patients who received allo-SCT in a single center between 1983 and 2010. In the 2000–2010, compared with the 1983–1999 period, a significantly higher 5-year overall survival (64% versus 52%, P=0.03) was observed together with a significant decrease of non-relapse mortality (27% versus 9%, P=0.0002). The progression-free survival was comparable between the two periods (49% versus 57%; P=0.17). The 5-year cumulative incidence of relapse was 24% between 1983 and 1999, and 34% between 2000 and 2010 (P=0.08). Major advances in supportive care practice have been made over the past decade, resulting in a significant survival benefit for the pediatric population undergoing allo-SCT. However, post-transplant relapse remains the leading cause of failure of this therapeutic approach, and preventing relapse represents a major challenge today.

Cytogenetics and outcome of allogeneic transplantation in first remission of acute myeloid leukemia: the French pediatric experience

We analyzed the impact of cytogenetics on 193 children enrolled in two successive French trials (LAME89/91 and ELAM02), who received hematopoietic stem cell transplantation during CR1. Detailed karyotype was available for 66/74 (89%) in LAME89/91 and 118/119 (99%) in ELAM02. Several karyotype and transplant characteristics differed according to therapeutic protocol: unfavorable karyotypes were more frequent in ELAM02 (36% vs 18%), pretransplant chemotherapy included high-dose cytarabine in ELAM02 and not in LAME89/91, IV replaced oral busulfan in the conditioning regimen, methotrexate was removed from post-transplant immunosuppression, and matched unrelated donor and cord blood transplantation were introduced. Five-year overall survival (OS) was 78.2% in LAME89 and 81.4% in ELAM02. OS was significantly lower for the unfavorable cytogenetic risk group in LAME89/91 when compared with intermediate and favorable groups (50% vs 90.6 and 86.4%, P=0.001). This difference was no longer apparent in ELAM02 (80.9% vs 71.3% and 5/5, respectively). Survival improvement for children with unfavorable karyotype was statistically significant (P=0.026) and was due to decrease in relapse risk. Five-year transplantation-related mortality was 6.75% in LAME89/91. In ELAM02, it was 3.2% for patients with a sibling donor and 10.9% with an unrelated donor or cord blood. We conclude that the outcome of children with unfavorable karyotype transplanted in CR1 has improved.

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

Major impact of an early bone marrow checkpoint (day 21) for minimal residual disease in flow cytometry in childhood acute lymphoblastic leukemia.

The early persistence of minimal residual disease (MRD) is considered a poor prognostic factor indicative of chemoresistance in acute lymphoblastic leukemia. In French children, chemosensitivity is assessed at day 21 post‐induction by cytomorphology. Here, it was investigated whether a more precise evaluation could be obtained at this time point with multiparameter flow cytometry (MFC).

Unrelated cord blood transplantation in patients with idiopathic refractory severe aplastic anemia: a nationwide phase 2 study

Outcomes remain poor for refractory severe aplastic anemia (SAA) patients. Alternative donor transplantation may be considered, but results from previous studies are not encouraging. We conducted a prospective nationwide phase 2 study to assess unrelated cord blood (CB) transplantation (CBT) efficacy and safety in refractory SAA patients (Aplastic Anemia and Cord Blood Transplantation protocol). To demonstrate a significant difference in 1-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients and therefore included 26 (median age, 16 years). Eligibility criteria required 1 or 2 unrelated CB units, containing separately or together >4 × 107 frozen nucleated cells (NCs) per kilogram of recipient body weight. Conditioning regimen comprised fludarabine (FLU), cyclophosphamide (CY), antithymocyte globulin (ATG), and 2-Gy total body irradiation (TBI). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively. Twenty-three patients were alive at 1 year, with an 88.5% overall survival (OS) rate, differing significantly from the expected 20% (P < .0001; 84% OS at 2 years). CBT with units containing ≥4 × 107 frozen NCs per kilogram is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors. This trial was registered at www.clinicaltrials.gov as #NCT01343953.