Idarubicin-Intensified Hematopoietic Cell Transplantation Improves Relapse and Survival of High-Risk Acute Leukemia Patients with Minimal Residual Disease.

The optimal conditioning regimen of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk patients with minimal residual disease (MRD) remains controversial. We studied the results in 98 high-risk acute leukemia patients transplanted with idarubicin (IDA)-intensified conditioning regimens between 2012 January and 2017 January. Among these patients, 31 (31.6%) had more than 5% marrow blasts at time of transplantation and 67 patients were in morphologic remission: MRD negative status at time of conditioning was achieved in 39 patients (39.8%), whereas 28 (28.6%) remained carriers of any other positive MRD level in the bone marrow. Three-year relapse estimates of patients with MRD-positive remission was 22.0%, which was remarkably lower than patients with active disease (45.4%, P = .027) but approximate to that of patients in MRD-negative remission (15.5%, P = .522). There were no significant differences in terms of 3-year estimated overall survival (OS) and disease-free survival (DFS) between MRD-positive remission and MRD-negative remission groups (71.4% versus 79.1% [P = .562] and 67.9% versus 76.9% [P = .634], respectively). Moreover, the estimated rates of 3-year OS and DFS of patients in MRD-positive remission were significantly better than those in patients with active disease (71.4% versus 41.9% [P = .033] and 67.9% versus 38.7% [P = .037], respectively). These data indicate that IDA-intensified conditioning allo-HSCT could overcome the negative prognostic impact of MRD.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

PURPOSE: Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS: Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS: In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION: This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Long-term follow-up of patients with poor-risk acute leukemia treated on a phase 2 trial undergoing intensified conditioning regimen prior to allogeneic hematopoietic cell transplantation.

Patients with acute leukemia who undergo allogenic hematopoietic cell transplantation with active disease have high rates of relapse and poor overall survival (OS) post-transplant compared to patients undergoing HCT in remission. Here, we report the long-term outcomes in 32 patients who received a high-intensity conditioning regimen comprising fractionated total body irradiation (FTBI; 1200 cGy) with pharmacokinetic (PK) dosing of intravenous Busulfan (IV BU) targeted to first dose area under curve (AUC) of 700-900 µM/min and etoposide (30 mg/kg) in a prospective phase 2 clinical trial. The median age of the patients at the time of HCT was 37 years (range: 18-50) presenting with high-risk (n = 6) and relapsed/refractory(r/r) acute leukemias (n = 26). All but one patient underwent HCT using peripheral blood stem cells from matched sibling donors. At a median follow-up of 17.3 years (range 14.4-19.0), 11 patients remained alive. The disease-free survival and OS at 15 years was 34% (versus 40% at 5-years post-HCT). The 15-year cumulative incidence of relapse was 26% and non-relapse mortality (NRM) was 38% (95% CI: 21-54%) and the cumulative incidence of chronic GVHD at 15 years was 33% using a prophylactic regimen of cyclosporine A and mycophenolate mofetil. The most common life-threatening late effects were secondary malignancies, metabolic, or cardiac complications with a cumulative incidence of 6.6%, 6.6%, and 13.3%, respectively. No unusual late effects or patterns of relapse were noted on longer followed on patients treated with intensified myeloablative condition regimen. Results from this study supports continued development of intensive conditioning regimens in patients with r/r acute leukemias to improve leukemia free (LFS) and OS in this high-risk population.

[Efficacy and Safety of Cladribine-based Intensified Conditioning Regimen in Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia].

OBJECTIVE: To investigate the efficacy, safety and the risk factors affecting prognosis of high-risk acute myeloid leukemia (AML) patients treated by cladribine-based intensified conditioning regimen. METHODS: The clinical data of 28 patients with high-risk AML treated by cladribine in combination with busulfan plus cyclophosphamide (BuCy) intensified conditioning regimen before allogeneic hematopoietic stem cell transplantation (allo-HSCT) in Zhujiang Hospital, Southern Medical University from October 2016 to June 2020 were analyzed retrospectively. The overall survival (OS) rate, cumulative progression-free survival (PFS) rate, relapse rate, non-relapse mortality (NRM), regimen related toxicity (RRT) and risk factors affecting prognosis of the patients were analyzed. RESULTS: The 1-year OS and PFS of the patients after implantation was (78.8±8.6)% and (79.8±8.1)%, while the 1-year cumulative relapse rate and NRM of the patients was 9.3% and 22.0%, respectively. The 1-year expected OS of MRD- high-risk patients before HSCT was 100%. The 1-year expected OS and PFS of the patients in pre-transplant relapse group was (46.9±18.7)% and (50.0±17.7)%, respectively. The incidence of I/II grade RRT was 39.3%. NO III/IV grade RRT were found in 28 patients. Multivariate analysis showed that pre-transplant relapse was the independent risk factor affecting OS and PFS of the patients. CONCLUSION: The intensified conditioning regimen of cladribine in combination with BuCy can reduce the relapse rate of high-risk AML transplantation, and its RRT is mild, exhibiting good safety. MRD- high-risk patients before HSCT can achieve better transplant benefits, but the prognosis of patients with relapse before transplantation is not significantly improved. Therefore, for non-relapsed high-risk AML patients, this intensified conditioning regimen deserves to be considered.

Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia: a real-world study.

Prophylactic/preemptive donor lymphocyte infusion (p/pDLI) and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia (RRAL), but real-world data remain scarce. We conducted a multicenter, population-based analysis of 932 consecutive patients. The three-year leukemia-free survival (LFS) rates were 56% for patients receiving both p/pDLI and intensified myeloablative conditioning (MAC) (intenseMAC) and 30% for those who received neither therapy per landmark analysis. Multivariable analyses were run separately for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse mortality. IntenseMAC was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL, while there was no impact of intenseMAC observed in AML. p/pDLI achieved superior outcomes in both matched-sibling donor (MSD) and haploidentical donor transplantation, while intenseMAC only influenced MSD outcomes. Data suggest that RRAL patients receiving "total therapy" by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS, with p/pDLI being safer with a more extensive impact relative to intenseMAC. Patients with RRAL can tolerate both interventions and achieve a reasonable outcome.

The Confirmation of Safety for the Intensified Conditioning Regimens: A Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Non-Remission Hematological Malignant Diseases.

Background: The prognosis of allogeneic hematopoietic stem cell transplantation (HSCT) for non-remission hematological malignant diseases is usually unfavorable. The most uncontrollable factor is residual disease or relapse. To overcome this problem, intensified conditioning regimens- sequential and/or additional chemotherapy to the standard regimen- could be effective. However, increasing the intensity of conditioning might also lead to more complications. Materials and Methods: We retrospectively analyzed 81 patients with non-remission disease who received allogeneic HSCT in our institution between 2007 and 2011. Results: 55.6% in 36 myeloablative conditioning patients and 46.7% in 45 reduced-intensity conditioning patients received intensified conditioning. The 5-year probability of overall survival was 35.0% and 17.1% in the standard and intensified group, respectively (p=0.027). Relapse mortality was 30% in the standard regimen group and 36.6% in the intensified regimen group (p=0.54). Transplant-related mortality (TRM) at 30 and 100 days was 5%, 17.1% (p=0.086) and 27.5%, 34.2% (p=0.52) in the standard and intensified group, respectively. There was no difference in TRM between the 2 groups at 30 days and 100 days. Conclusion: The results of the study confirm the safety of the intensified conditioning regimen. Meanwhile, it could be considered as one of the few methods available to reduce the tumor burden before HSCT for refractory malignant diseases.

Sequential intensified conditioning followed by prophylactic DLI could reduce relapse of refractory acute leukemia after allo-HSCT.

The major obstacle is leukemia relapse for refractory leukemia undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously introduced a strategy of sequential intensified conditioning and early rapid immunosupressant withdrawal for refractory leukemia undergoing allo-HSCT, with 5-year overall survival (OS) and 3-year relapse rate of 44.6% and 33.3%. To reduce leukemia relapse, prophylactic donor lymphocyte infusion (DLI) was administered based on our historical strategy. A total of 153 refractory advanced acute leukemia patients were enrolled in this prospective study. According to the availability of donor lymphocytes and the criteria for DLI, 144 patients surviving day +60 were divided into two groups (80 DLI versus 64 non-DLI). The relapse rate was less and OS was better in patients receiving DLI than in those not receiving DLI (22.7% vs 33.9%, P=0.048; 58.1% vs 54.9%, P=0.043). The non-relapse mortality (NRM) was similar between DLI and non-DLI groups (P=0.104). Overall, the 5-year overall and disease-free survival post-transplantation were 51.1%±5.7% and 49.2%±5.3%. The 5-year relapse rate and NRM were 27.3%±4.4% and 29.7%±5.3%. Multivariate analysis revealed that lower bone marrow blasts on day 0, DLI and chronic graft-versus-host disease were associated with less relapse and better OS. The strategy of sequential intensified conditioning followed by early immunosupressant withdrawal and DLI could reduce relapse of refractory acute leukemia after allo-HSCT and improve survival.

Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group.

Comparison of outcomes of idarubicin intensified TBI-CY and traditional TBI-CY conditioning regimen for high-risk acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation: A single center experience.

High-risk acute lymphoblastic leukemia (ALL) carries a very poor prognosis, even after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Exploring novel conditioning regimen to more effectively eliminate leukemic clone while not alter transplant-related mortality (TRM) has become focus of attention. We retrospectively evaluated outcomes of 87 high-risk ALL patients undergoing allo-HSCT: 47 patients received idarubicin (IDA) intensified TBI-CY and 40 patients received traditional TBI-CY regimen. In IDA intensified group, patients received TBI (8Gy) on day-8, IDA of 15mg/m2/d from day-6 to -5, followed by CY (60mg/kg/d) on day-3 to -2. The cumulative incidence of relapse was significantly lower in IDA intensified group compared with TBI-CY group (P=0.018). Oropharyngeal mucositis was observed more frequent in IDA intensified group (P=0.013), while not followed by increased TRM. Very high-risk ALL patients benefit from IDA intensified regimen with only two of eight patients in no remission (NR) pre-transplantation and two of twelve ph+ALL patients relapsed after transplantation. After a median follow-up for all survivors of 21 months (range, 12-53 months), 2-year estimated OS and DFS was 66.2% vs 45.3% (P=0.031) and 62.5% vs 43.5% (P=0.044), respectively. In conclusion, IDA intensified TBI-CY regimen may reduce relapse while not increasing TRM, providing better survival for high-risk ALL patients undergoing allo-HSCT.