Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data ...on cardiac events associated with PT-Cy are scarce.
This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy.
The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring.
The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no–PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival.
PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy.
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We evaluated prognostic factors in 83 intensively treated adult patients with NPM1 mutated AML. Targeted next-generation sequencing revealed high frequency of co-mutations in epigenetic modifiers or ...proliferation pathways. NPM1 minimal residual disease (MRD), assessed in bone marrow by specific polymerase chain reaction after one chemotherapy course, was >0.01% in 50 patients considered poor responders (PR). On multivariate analysis, including all variables with a p value <.1 on univariate analysis, age >60, performance status (PS) ≥1, presence of FLT3 mutations, DNMT3A-R882, and PR status, were independently associated with lower leukemia-free survival. Age >60, a previous hematological disease and PR status were independent negative predictive factors for overall survival. In our study, early NPM1 MRD was confirmed as an important prognostic factor. All FLT3 and DNMT3A-R882 mutations have also an independent prognostic value. We support the rational for in-depth investigations for a better approach in patients who achieving a first complete remission.
Primary refractory and relapsed acute myeloid leukemia (PR-AML) are associated with a very dismal prognosis. Allogeneic stem cell transplantation (allo-HSCT) is the only salvage option with curative ...potential in this situation. Since the disease status at transplant remains one of the main prognostic factors it is critical to reach complete remission (CR) at this stage. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody conjugated with the cytotoxic antitumor antibiotic calicheamicin, whose results in salvage therapy remain debated. Here, we tested the combination of fractionated GO (fGO, 3mg/m² day 1, 3 and 7) with intensive chemotherapy, mainly consisting in cytarabine (1g/m² twice daily in day 1-5) and mitoxantrone (12mg/m² day 1, 2 and 3) (MYLODAM protocol).
The present single center retrospective analysis aimed to assess the outcomes of PR-AML patients treated by GO associated with intensive chemotherapy. The following prognostic factors were recorded: age, cytogenetics, molecular data, blood cell counts, organ failure, and duration of first complete remission. The primary endpoints of this study were the efficacy and safety profile of this salvage strategy. We also attempted to define predictive factors to survival and response after salvage. The ELN 2017 classification was used for prognostic assessment and definition of response.
Fifty-eight patients were included. Patients' characteristics are shown in Table 1. Median age at salvage was 56 (range 16-74) years. Thirty-six (62%) received MYLODAM and 14 (24%) had fGO combined with cytarabine (1g/m² twice daily in day 1-5) and daunorubicine (60mg/m² day 1,2 and 3). Forty-six patients (79%) were monitored by molecular biology for minimal residual disease (MRD). The overall response rate was 67% (17% CRi, 17% CR and 33% CRMRD-). Median leukemia-free survival (LFS) and overall survival (OS) were 13.5 months (95% CI: 6-21) and 50 months (95% CI: 11-90) respectively (Figs 1 and 2). LFS and OS at 2 years were 36% (95%CI: 23 - 49) and 54% (95%CI: 39 - 68), respectively. Therapy-related mortality was observed in 7% (n=4) of the patients caused by 2 sepsis and 1 hemorrhagic syndrome. Three patients developed a sinusoidal obstruction syndrome (SOS), 2 of moderate and 1 of severe grade leading to death. In multivariate analysis, LFS was associated with FLT3 mutations (HR=0.33, 95%CI: 0.11-0.97) and adverse ELN risk group (HR=3.5, 95% CI: 1.5-8.2).
On the whole, 28 (48%) patients could proceed to allo-HSCT. For this subgroup, LFS and OS at 2 years were 57 % (95% CI: 36 - 77) and 69 % (95% CI: 49 - 89), respectively. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 40% and 45.5%, respectively. At 2 years, non-relapse mortality was 16 % (95% CI: 8.5 - 33.3). Despite policy of our center to prevent SOS in this high risk patients by using Defibrotide prophylaxis, 5 SOS syndromes occurred during allogenic transplant with 3 moderate and 2 very severe forms, with no SOS related-deaths.
In summary, we conclude that, in a “real-life” setting, fGO associated with intensive chemotherapy (mainly MYLODAM) can be an effective and safe salvage regimen in patients with PR-AML, allowing in two-thirds of the cases a response achievement, and in half of the patients a bridge to allo-HSCT with encouraging outcomes.
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Mohty:Sanofi: Honoraria, Speakers Bureau.
More than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to ...achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor.
We included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65).
The overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively.
Our study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.
Treatment of acute myeloid leukemia relapse after allogenic hematopoietic cell transplant is challenging because of the need to overcome disease resistance while avoiding excessive toxicity. We report the use of fractioned gemtuzumab ozogamicin associated with high-dose chemotherapy in 18 patients. The overall response rate was 72% (13/18) including 7 complete remissions. No death was attributed to treatment toxicity.
Azacytidine (AZA) has been used as a promising treatment for relapse after allogeneic transplantation. A clear benefit has been demonstrated when treating patients with a reduced disease burden, thus ...a prophylactic and preemptive approach to these patients has emerged.
We retrospectively analyzed patients with myeloid malignancies treated with azacytidine in the posttransplantation setting between September 2013 and April 2018 in a single tertiary care hospital. Of 32 patients analyzed, 21 were treated for prophylactic use and 11 preemptively, with a median follow-up of 20 months. Prophylactic treatment consisted of AZA at 32 mg/m2 for 5 days every 28 days, and preemptive treatment of AZA 75 mg/m2 for 5 or 7 days per cycle. In addition, 10 patients received one or more donor lymphocyte infusions (DLIs). Two patients presented with infectious complications demanding hospitalization, and 13 patients (10 in the prophylactic group and 3 in the preemptive group) presented graft-versus-host disease (GvHD). Of patients who had GvHD, 3 needed treatment discontinuation. Overall, 12 patients suspended treatment, 8 for disease progression and 1 due to patient request.
In the prophylactic group, all patients are alive at 1 year with an event-free survival (EFS) of 95%, as only 1 patient relapsed. In the preemptive group, 1-year EFS was 54% and 1-year overall survival was 82%.
Low-dose AZA in posttransplantation patients with myeloid neoplasms is a well-tolerated therapy with the potential to prevent relapse and maintain stable remissions. Randomized prospective trials are needed to determine patient selection and dosage, timing, and duration of treatment.
Azacytidine has been used as prophylactic or preemptive therapy after allogeneic transplantation in myeloid malignancies, but its use is not yet consensual. We retrospectively analyzed 32 patients in this setting, to evaluate tolerability and outcomes. These results are promising, with a low rate of relapse in prophylactic therapy and a good rate of disease stabilization in preemptive therapy.
•Thiotepa, busulfan, and fludarabine conditioning is safe in a haploidentical transplantation setting.•Antithymocyte globulin (ATG) prophylaxis seems effective for reducing the incidence of acute ...graft-versus-host disease.•The addition of ATG did not increase the risk of infection or nonrelapse mortality.
We report the outcomes of 51 patients who underwent unmanipulated haploidentical hematopoietic stem cell transplantation (haplo-HSCT) with post-transplantation cyclophosphamide (PT-Cy) and antithymocyte globulin (ATG), from peripheral blood stem cells (PBSCs) or bone marrow, after receipt of a TBF (thiotepa, busulfan, and fludarabine) conditioning regimen. Their median age was 55 years (range, 16 to 72 years). Hematologic diagnoses included acute leukemias (n = 31), lymphoid neoplasm (n = 12), myeloproliferative neoplasm (n = 5), and myelodysplastic syndromes (n = 3). Thirty-seven patients (73%) were in complete remission. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and mycophenolate for all patients, associated with ATG in 39 patients (76.5%). The median time to neutrophil engraftment was 17 days (range, 12 to 34 days). The cumulative incidences of grade II-IV and grade III-IV acute GVHD were 27.5% and 14%, respectively. In patients receiving a PBSC graft and ATG prophylaxis, grade II-IV aGVHD occurred in 16% of patients. The use of ATG and a lower thiotepa dose (5 mg/kg versus 10 mg/kg) were associated with a reduced cumulative incidence of grade II-IV acute GVHD (P = .03 and .005, respectively). The 2-year cumulative incidence of chronic GVHD was 29% and was significantly reduced to 13% with the lower thiotepa dose (P = .002). After a median follow-up of 25 months (range, 12 to 62 months), the cumulative incidences of nonrelapse mortality, relapse, overall survival (OS), disease-free survival (DFS), and GVHD-free, relapse-free survival (GFRFS) were 20%, 22.5%, 67%, 58%, and 51%, respectively. Pretransplantation disease status (complete remission versus others) was the main factor associated with OS, DFS, and GFRFS. In conclusion, the TBF conditioning regimen is an appealing platform in the haplo-HSCT setting with PT-Cy in terms of engraftment rate, toxicity, and disease control. We found no benefit of a thiotepa dose of 10 mg/kg compared with a dose of 5 mg/kg. ATG reduced the risk of acute GVHD without comprising outcomes.
•Defibrotide seems effective in preventing sinusoidal obstruction syndrome.•This prophylaxis is associated with an acceptable bleeding events incidence.•Defibrotide prophylaxis might reduce the ...incidence of other early complications.
Sinusoidal obstruction syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a serious complication after hematopoietic stem cell transplantation (HSCT). SOS/VOD usually occurs within 3 weeks of HSCT, but the 2016 European Society for Blood and Marrow Transplantation diagnosis criteria have been revised to include late forms. Prophylactic use of defibrotide is recommended in the pediatric setting, but its value remains uncertain in the adult population. We report here a single-center series of 63 adult patients considered at high risk for SOS/VOD who received defibrotide prophylaxis in combination with ursodeoxycholic acid between May 2012 and August 2016. The median duration of defibrotide therapy was 23 days. Bleeding occurred in 14 patients (21.5%). Defibrotide prophylaxis was discontinued in 7 patients (10.8%): 4 cases (6.3%) due to bleeding and 3 cases (4.6%) because of the need for antithrombotic therapy. Overall, SOS/VOD occurred in 4 cases (6.3%) within 21 days after HSCT (days 13 and 14) in 2 cases and late-onset SOS/VOD (days 57 and 58) in the other 2 cases. SOS/VOD was moderate in 1 case, very severe in 3 cases, with 2 deaths related to SOS/VOD. Cumulative incidence of grades II to IV acute graft-versus-host disease and transplant-associated thrombotic microangiopathy were 22.2% and 3.2%, respectively. With a median follow-up of 31 months (range, 10.7 to 60.3), the rates of 2-year overall survival, progression-free survival, incidence of relapse, and nonrelapse mortality were 56.5%, 49%, 28.7%, and 22.3%, respectively. In our experience defibrotide prophylaxis is associated with a low incidence of SOS/VOD after allogeneic HSCT in a high-risk adult population with an acceptable safety profile.
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