Christian Chabannon

High rate of secondary viral and bacterial infections in patients undergoing allogeneic bone marrow mini-transplantation.

New approaches using nonmyeloablative-conditioning regimens have been developed to cause minimal procedure-related toxicity. Such novel therapeutic options are being explored with good preliminary results concerning feasibility and engraftment. However many aspects remain under-evaluated, and few data are available about viral and nonviral infections after these highly immunosuppressive regimens. We present our preliminary data on 21 patients receiving a highly immunosuppressive conditioning strategy, focusing on early infectious complications. Early viral infections before day 45, especially CMV, occurred at a high rate (65%). Furthermore, 33% of patients presented with late bacterial infections (predominately gram negative) although they were not neutropenic compared to conventional conditioning regimens. Although there is presently real interest in these new conditioning regimens which result in reduced immediate transplant-related mortality, it is important that investigators be aware of these pitfalls which may secondarily increase transplant toxicity. Further studies are needed to confirm these findings. Bone Marrow Transplantation (2000) 26, 251–255.

Bone Marrow Compared with Peripheral Blood Stem Cells for Haploidentical Transplantation with a Nonmyeloablative Conditioning Regimen and Post-transplantation Cyclophosphamide

Recently, the administration of high-dose cyclophosphamide (Cy) after T cell-replete haploidentical stem cell infusion has been reported to be feasible and effective. In the original study, bone marrow (BM) was used as the source of stem cells. Here, we retrospectively analyzed the use of BM versus peripheral blood stem cells (PBSCs) in a cohort of patients receiving haploidentical T cell-replete transplantation after a nonmyeloablative conditioning regimen with postinfusion Cy. In the PBSC versus BM groups, the incidence of acute graft-versus-host disease (GVHD) was 33% versus 25%, respectively, and the incidence of chronic GVHD was 13% versus 13%, respectively. The median time to achieve a safe and unsupported absolute neutrophil and platelet count was 20 versus 21 days and 27 versus 29 days, respectively. The incidence of engraftment was also similar in the 2 cohorts. The 1-year nonrelapse mortality rate was 12% versus 22%, respectively (P = .96). Finally, nonsignificant differences in survival were observed. In conclusion, the use of PBSCs instead of BM after T cell-replete haploidentical transplantation did not appear to be detrimental in terms of either GVHD or engraftment rate. PBSCs could be a valid alternative to BM after transplantation from a haploidentical donor using postinfusion Cy.

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57–10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19–0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80–3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38–11.75]). Conclusions In patients with relapsed/refractory Hodgkin’s lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.

Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation.

The optimal intensity of reduced‐intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo‐HSCT) remains uncertain.

Features of large granular lymphocytes (LGL) expansion following allogeneic stem cell transplantation: a long-term analysis

Large granular lymphocyte (LGL) proliferation typically follows a chronic course during which major features are cytopenia and immune abnormalities. Elevated numbers of LGL were reported in a few cases following allogeneic stem cell transplantation (allo-SCT). In this report, we present a retrospective analysis of LGL cases that occurred following allo-SCT in a cohort of 201 consecutive patients transplanted over a period of 7 years. Six cases were identified and LGL expansion occurred more frequently following a reduced fludarabine and anti-T lymphocyte globulin-based preparative regimen (4 cases/49), than after a conventional myeloablative regimen (2 cases/152). Expansion of LGL was seen between 3 and 15 months following allo-SCT. Hematopoiesis, with mild to severe cytopenia, was a favored target for LGL. Autoimmune manifestations including polyarthritis and hypergammaglobulinemia were also observed. LGL proliferation was observed in the context of chronic antigenic stimulation associated with recurrent viral infections especially CMV. Moreover, five out of these six high risk patients achieved a long-term complete remission concomitant or following LGL expansion. These data suggest that LGL might be a subset of effector lymphocytes which may participate to the graft-versus-tumor effect.

The increase from 2.5 to 5 mg/kg of rabbit anti-thymocyte-globulin dose in reduced intensity conditioning reduces acute and chronic GVHD for patients with myeloid malignancies undergoing allo-SCT

We previously reported that reduced intensity conditioning (RIC) regimen with fludarabine, BU and 2.5 mg/kg of rabbit anti-thymocyte globulin (r-ATG) was effective but associated with a high rate of acute and chronic GVHD. Therefore, we increased the dose of r-ATG to 5 mg/kg. In this report, we analyzed 87 patients with AML or myelodysplastic syndrome (MDS) undergoing allo-SCT from an HLA-identical sibling donor from 2000 to 2010. RIC consisted of fludarabine, BU and r-ATG 2.5 mg/kg on 1 day (r-ATG1; n=53) or 2.5 mg/kg per day over 2 days (r-ATG2; n=22). Grade 2–4 acute GVHD incidence at day 100 was 30.2% and 8.8% in the r-ATG1 and r-ATG2 groups, respectively (P=0.038). Extensive chronic GVHD incidence was 60.4% and 12% in the r-ATG1 and r-ATG2 groups, respectively (P<0.001). The relapse incidences (RI) at 24 months were 18.9% and 28.5% in r-ATG1 and r-ATG2 groups, respectively (P=0.640). Overall and PFS were not different between the r-ATG1 and r-ATG2 groups. r-ATG dose at 5 mg/kg in the setting of RIC seems a good balance allowing GVHD prevention and antitumor effect with a remarkable reduction of GVHD incidence without an identical level of increased relapse rate.

Reconstitution of Natural Killer Cells in HLA-Matched HSCT after Reduced-Intensity Conditioning: Impact on Clinical Outcome

Recent advances in the development of reduced-intensity conditioning (RIC) have allowed a broader range of patients to access allogeneic hematopoietic stem cell transplantation (HSCT). Reconstitution of an effective immune system post-transplant, including natural killer (NK) cells, is critical for both tumor control and infectious disease control or prevention. The development and functions of NK cells in such settings remain elusive. Here we analyzed NK cell development in HLA-matched HSCT from related or unrelated donors, after RIC that included antithymocyte globulin (N = 45 patients). Our data reveal that NK cells quickly recover after RIC-HSCT, irrespective of donor type. Rapidly re-emerging NK cells, however, remain immature for more than 6 months. Effector functions resemble that of immature NK cells because they poorly produce IFN-γ and TNF-α in response to target cell stimulation, despite a rapid acquisition of degranulation ability and MIP-1β production. Strikingly, rapid reconstitution of cytokine production correlates with a lower relapse incidence (P = .01) and a better survival rate (P < .0001) at 1 year post-transplant, whereas degranulation capacity was associated with less relapse (P = .05). Our study demonstrates rapid quantitative reconstitution of the NK cell compartment despite administration of potent immune suppressive drugs as part of the conditioning regimen and after transplantation. However, there is a prolonged persistence of functional defects, the correction of which positively correlates with clinical outcome.

CD34 + cell enumeration in peripheral blood and apheresis samples, using two laboratory diagnostic kits or an institutional protocol

In order to prepare the substitution of a commercially available diagnostic kit, ProCOUNT (Becton Dickinson) or Stem-Kit (Coulter Immunotech), for our institutional protocol, we compared the three techniques for the numeration of CD34+ progenitor cells in 50 peripheral blood and 51 apheresis samples, obtained from cancer patients or healthy donors. We show here that the three techniques yield results of the same order of magnitude. Although statistical analyses demonstrate significant differences between the three methods, these differences turned out to be clinically insignificant in most situations. Observed differences mostly affect samples with the highest content of CD34+ cells, while the three assays provide equivalent results for values that are close to clinically relevant thresholds (20 × 103 CD34+ cells/ml in peripheral blood to start apheresis, and accumulated number above 3 × 106 CD34+ cells/kg to stop apheresis). This study also supports the view that institutional protocols can provide a highly reliable determination of CD34+ cells counts and percentages. However, because institutional protocols often use research reagents and vary from institution to institution, the use of diagnostic kits may be prefered as one way to improve quality assurance in the practice of cell therapy.

Decreased RBCTs after reduced intensity conditioning allogeneic stem cell transplantation: predictive value of prior Hb level.

BACKGROUND: RBCT (RBCT) requirements of stem cell transplant (SCT) recipients are often substantial and may be related to transplant type.

Reduced-toxicity conditioning prior to allogeneic stem cell transplantation improves outcome in patients with myeloid malignancies

The introduction of reduced intensity/toxicity conditioning regimens has allowed allogeneic hematopoietic cell transplantation to be performed in patients who were previously considered too old or otherwise unfit. Although it led to a reduction in non-relapse mortality, disease control remains a major challenge. We studied the outcome of 165 patients with acute myeloid leukemia (n=124) or myelodysplastic syndrome (n=41) transplanted after conditioning with fludarabine (30 mg/m2/day for 5 days), intravenous busulfan (either 260 mg/m2: reduced intensity conditioning, or 390–520 mg/m2: reduced toxicity conditioning), and rabbit anti-thymoglobulin (2.5 mg/kg/day for 2 days). The median age of the patients at transplantation was 56.8 years. The 2-year relapse incidence was 29% (23% versus 39% for patients transplanted in first complete remission and those transplanted beyond first complete remission, respectively; P=0.008). The 2-year progression-free survival rate was 57% (95% CI: 49.9–65). It was higher in the groups with favorable or intermediate cytogenetics than in the group with unfavorable cytogenetics (72.7%, 60.5%, and 45.7%, respectively; P=0.03). The cumulative incidence of grades 2–4 and 3–4 acute graft-versus-host disease at day 100 was 19.3% and 7.9%, respectively. The cumulative incidence of chronic graft-versus-host disease at 1 year was 21.6% (severe forms: 7.8%). Non-relapse mortality at 1 year reached 11%. The 2-year overall survival rate was 61.8% (95% CI: 54.8–69.7). Unfavorable karyotype and disease status beyond first complete remission were associated with a poorer survival. This well-tolerated conditioning platform can lead to long-term disease control and offers possibilities of modulation according to disease stage or further development.