While bone marrow (BM) grafts were initially used for T-replete HLA-haploidentical related donors transplantation (Haplo-SCT) with post-transplantation cyclophosphamide (PT-Cy), the use of peripheral ...blood stem cell (PBSC) remains debated. We thus conducted a detailed analysis evaluating the incidence, risk factors, and prevalence of GVHD after PBSC Haplo-SCT with PT-Cy. One hundred and eighty-one patients with hematological diseases were included. Median time for neutrophil and platelet recovery was 21 and 30 days, respectively. The cumulative incidence of grade 3-4 acute GVHD and severe chronic GVHD were 8% and 4%, respectively, approaching what was observed after BM Haplo-SCT. NRM at 2 years was 21%, and 41% of the non-relapse deaths were caused by GVHD. The cumulative incidence of relapse at 2 years was 17% in the whole cohort, and 13% among AML patients (n = 54), suggesting a high GVL effect. As surrogate markers for good quality of life, we observed a 2-year GVHD-relapse-free survival probability of 50% and found that 6% and 2% of disease-free patients at 2 years were still living with GVHD and immunosuppressive treatments, respectively. Haplo-SCT with PT-Cy using PBSC grafts results in low incidence GVHD and promising disease control, making PBSCs a valuable alternative to BM graft in this setting.
We report the outcome of 68 patients with advanced peripheral T-cell lymphoma receiving transplantation from haploidentical or from conventional donors. The 4-year OS, PFS, 2-year cumulative ...incidence of relapse and 2-year GRFS was 75%, 70%, 21%, and 51%, respectively. Survival was not affected by donor type. The 2-year NRM was 9%, lower after related or haploidentical donor (21% vs 0% vs 7%; p = 0.06). Grade 2-4 aGVHD cumulative incidence was significantly different after transplantation from haploidentical vs matched sibling vs unrelated donor, and (24% vs 35% vs 58%, p = 0.024). The familial donor cohort was compared to the unrelated cohort. Familial donor induced less grade 2-4 aGVHD, with a trend to less grade 3-4 aGVHD or moderate-severe cGVHD. The OS and PFS were not different, while the relapse risk and NRM were reduced. Allo-SCT is highly effective in T-cell lymphoma, with low NRM and low relapse rate. The incidence of aGVHD was lower after haploidentical transplantation. Related donor may challenge unrelated transplant reducing the risk of relapse and NRM.
Background. Chronic disseminated candidiasis (CDC) is typically observed during neutrophil recovery in patients with acute leukemia and requires protracted antifungal therapy. Objective. Our ...objective was to document the efficacy and tolerance of corticosteroid therapy (CST) in patients with symptomatic CDC, including those who experienced fever and abdominal pain despite ongoing antifungal therapy. Methods. We performed a retrospective, multicenter study involving 10 pediatric and adult patients who experienced ongoing symptomatic CDC despite receipt of appropriate antifungal therapy for whom adjuvant oral CST was initiated. Results. All cases of CDC were proven or probable, as determined on the basis of the European Organization for Research and Treatment of Cancer-Mycosis Study Group definition criteria, and occurred in patients with leukemia. CDC-attributable clinical symptoms resolved with CST, which was started a mean of 33.8 days after antifungal therapy had been initiated. Fever and abdominal pain disappeared a median of 4–5 days, and serum fibrinogen and C-reactive protein levels returned to normal values within 14–30 days. The median duration of hospitalization after CST initiation was 8.8 days. Hepatosplenic microabscesses decreased or disappeared within a mean period of 107 days (range, 30–210 days). No relapses of CDC were observed during a median duration of follow-up of 6.5 years (range, 4–9 years). Conclusions. In children and adults who experience persistently symptomatic CDC despite ongoing receipt of antifungal therapy, CST involving a prednisone equivalent at a dosage of ⩾0.5 mg/kg per day for at least 3 weeks is associated with a prompt resolution of symptoms and of inflammatory response. These findings support the pathophysiological hypothesis that CDC belongs to the spectrum of fungus-related immune reconstitution inflammatory syndrome.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potentially curative and useful strategy in high-risk relapsing CLL. Minimal Residual Disease (MRD) assessment at 12 months ...post-HSCT is predictive of relapse. This phase 2 study aimed to achieve M12 MRD negativity (MRDneg) using MRD-driven immune-intervention (Md-PII) algorithm based on serial flow-cytometry blood MRD, involving cyclosporine tapering followed if failure by donor lymphocytes infusions. Patients had high-risk CLL according to 2006 EBMT consensus, in complete or partial response with lymphadenopathy < 5 cm and comorbidity score ≤ 2. Donors were HLA-matched sibling or matched unrelated (10/10). Forty-two enrolled patients with either 17p deletion (front-line, n=11; relapse n=16) or other high-risk relapse (n=15) received reduced intensity-conditioning regimen before HSCT and were submitted to Md-PII. M12-MRDneg status was achieved in 64% versus 14.2% before HSCT. With a median follow-up of 36 months (range, 19-53), 3-year overall survival, non-relapse mortality and cumulative incidence of relapse are 86.9% (95%CI, 70.8-94.4), 9.5% (95%CI, 3.7-23.4) and 29.6% (95%CI, 17.3-47.7). Incidence of 2-year limited and extensive chronic graft versus host disease (cGVHD) is 38% (95%CI, 23-53) and 23% (95%CI, 10-36) including 2 cases post Md-PII. Fifteen patients converted to MRDneg either after CsA withdrawal (n=12) or after cGVHD (n=3). As a time-dependent variable, MRDneg achievement at any time-point correlates with reduced relapse (HR=0.14 0.04-0.53, p=0.004) and improvement of both progression free (HR=0.18 0.06-0.6, p<0.005) and overall (HR: 0.18 0.03-0.98, p=0.047) survival. These data highlight the value of MRD-driven immune-intervention to induce prompt MRD clearance in the therapy of CLL.
Shwachman‐Diamond syndrome with Shwachman‐Bodian‐Diamond syndrome (SBDS) biallelic variants is a rare disorder that predisposes the carrier to malignant hemopathies but solid‐cancer predisposition is ...poorly known. Among 155 cases entered in the French Registry for Severe Chronic Neutropenia, three were identified with malignant solid tumors (ovary, breast, and esophagus). All cancers occurred during the fifth decade and, despite being localized at diagnosis, were rapidly fatal thereafter. No cancer was observed post transplantation in the 14 HSCT survivors. Based on the literature and our patient data, we can merely advance that this complication is predominantly diagnosed in adults.
We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan ...(FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM‐TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission CR1 72%, median follow‐up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow‐up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05–4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02–4.61, P = 0.04) and a trend for lower leukemia‐free survival (LFS, HR: 1.75; 95%CI: 0.94–3.26, P = 0.08). These results were confirmed using a propensity score‐matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2‐year OS FB2A2: 38% 14.5–61.6 vs. CloB2A2: 79.2% 62.9–95.4, P = 0.01; 2‐year LFS FB2A2: 38% 16–59.9 vs. CloB2A2: 70.8% 52.6–89, P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2‐year RI FB2A2: 41.2% 19–62.4 vs. CloB2A2: 16.7% 5–34.2, P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.
CloB2A2 RIC regimen provided better OS and leukemia‐free survival compared to the standard FB2A2 RIC regimen in allografted acute myeloid leukemia (AML) patients. The better survivals observed in the CloB2A2 AML subgroup was due to a lower risk of relapse, confirming the higher antileukemic activity of clofarabine versus fludarabine.
Although clinical benefits have been reported in several human hematopoietic gene therapy trials, a remaining important goal is the transition to nonmyeloablative pretransplantation conditioning to ...decrease toxicity. Previous attempts at reduced intensity conditioning in nonhuman primates have resulted in only temporary vector marking of autologous blood cells or their persistence at low levels, well below the thresholds for clinical efficacy. In addition, we reasoned that lentiviral vector particles displaying cytokines at their surface have the potential to preserve stem cell fitness better than current ex vivo transduction protocols, which involve exposure to cytokine overstimulation. Here we show that the classically nonmyeloablative agent fludarabine (30 mg/m(2)/day for 3 days) together with low-level total body irradiation (2 Gy) and the use of a stem cell factor-displaying simian immunodeficiency virus-based vector, resulted in sustained, single-copy vector marking of autologous blood cells in two macaques over 3 years posttransplantation at levels averaging 1% of all lineages. This percentage is within the range of anticipated efficacy levels for hemophilia and related diseases and forms a basis for further improvement.
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