Leukemia In First Complete Remission Research Articles

Impact of measurable residual disease in combination with CD19 on postremission therapy choices for adult t(8;21) acute myeloid leukemia in first complete remission.

The post-remission therapy (PRT) choices for adult t(8;21) acute myeloid leukemia (AML) in first complete remission (CR1) need to be further explored. We aimed to investigate the impact of measurable residual disease (MRD) combined with CD19 on PRT choices for adult t(8;21) AML in CR1. A total of 150 t(8;21) AML patients were enrolled, including 67 underwent chemotherapy (CMT) and 83 allogeneic hematopoietic stem cell transplantation (allo-SCT) as PRT in CR1. Subgroup analyses were performed according to MRD level after three cycles of chemotherapy combined with CD19 expression. Multivariate analysis indicated MRDhigh after three courses of treatment (HR, 0.14 [95% CI, 0.03-0.66]; p = 0.013) and CD19 negativity (HR, 0.14 [95% CI, 0.02-0.96]; p = 0.045) were risk factors for relapse, while allo-SCT was protective factor for relapse (HR, 0.34 [95% CI, 0.15-0.75]; p = 0.008). Grouped by MRD after three courses of chemotherapy, allo-SCT had lower CIR (p < 0.001) and better OS (p = 0.003) than CMT for MRDhigh patients, CMT showed a higher CIR (35.99% vs. 15.34%, p = 0.100) but comparable OS (p = 0.588) than allo-SCT for MRDlow patients. Grouped by CD19 expression, allo-SCT demonstrated lower CIR (p < 0.001) and better OS (p = 0.002) than CMT for CD19- patients. CMT had a higher CIR (41.37% vs. 10.48%, p = 0.007) but comparable OS (p = 0.147) than allo-SCT for CD19+ patients. Grouped by MRD combined with CD19, MRDhigh /CD19+ subsets were identified out of CD19+ patients benefiting from allo-SCT with lower CIR (p = 0.002) and superior OS (p = 0.020) than CMT. CMT preserved comparable CIR (p = 0.939) and OS (p = 0.658) with allo-SCT for MRDlow /CD19+ patients. MRDlow /CD19- subsets were also identified from MRDlow patients requiring allo-SCT with lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT. Allo-SCT maintained lower CIR (p < 0.001) and superior OS (p = 0.008) than CMT for MRDhigh /CD19- patients. MRD combined with CD19 might optimize PRT choices for adult t(8;21) AML patients in CR1.

Trends in Allogeneic Transplantation for Favorable Risk Acute Myeloid Leukemia in First Complete Remission: A Longitudinal Study of > 15 Years from the ALWP/EBMT

Trends in Allogeneic Transplantation for Favorable Risk Acute Myeloid Leukemia in First Complete Remission: A Longitudinal Study of > 15 Years from the ALWP/EBMT

Comparison of Condensed to Standard Schedule of High Dose Cytarabine Consolidation for Acute Myeloid Leukemia in First Complete Remission

Background Traditionally, acute myeloid leukemia (AML) consolidation therapy for patients less than 60 years old with low to intermediate risk disease has been treated with high dose cytarabine (HDAC) cycles given on days 1, 3, and 5 (HDAC-135). However, more recent publications have assessed alternative dosing, namely administering HDAC on days 1, 2, and 3 (HDAC-123). National Comprehensive Cancer Network (NCCN) Guidelines for AML discuss this alternative dosing for HDAC and do not recommend one over another. A prospective study found that there was no cumulative hematologic toxicity and no change in survival when comparing HDAC-123 to HDAC-135 5. As a result, Northside Hospital began using HDAC-123 in patients less than 60 years old for AML consolidation therapy. The purpose of this study was to assess the safety, efficacy, and health care resource consumption associated with HDAC-135 versus the condensed HDAC-123 regimen at Northside Hospital. Methods This single-center, retrospective study included patients with AML between 18 and 60 years old who received at least one cycle of HDAC-123 or HDAC-135 at Northside Hospital Atlanta's outpatient clinic from January 1, 2018 to January 1, 2023. The primary outcome was time to hematologic recovery of white blood cell (WBC), absolute neutrophil count (ANC), and platelets. Secondary endpoints were the amount of transfusions needed, incidence of documented infections, rate of hospital admission, and length of hospital stay. Results A total of 51 patients were included. Twenty one patients received a cumulative total of 39 cycles of HDAC-123 and 30 patients received a cumulative total of 57 cycles of HDAC-135. Overall, baseline characteristics were similar between groups although hemoglobin and hematocrit were significantly lower in the HDAC-123 group. In the HDAC-123 group compared to the HDAC-135 group, the median day of WBC recovery was 15 and 24 days, respectively (p &amp;lt; 0.001). The median day of ANC recovery was 16 and 28 days, respectively (p &amp;lt; 0.001). The median day of platelet recovery was 16 and 20 days, respectively (p &amp;lt; 0.001). Conclusion The results of this retrospective review support the findings of other studies. HDAC-123 demonstrated a significantly reduced time to WBC, ANC, and platelet recovery compared to HDAC-135. HDAC-123 was also was associated with lower rates of microbiologically documented infections but did require more RBC transfusions. HDAC-123 may be preferred over HDAC-135 for consolidation therapy in patients less than 60 years old.

The Presence of Somatic Mutations on Specific Pathways Such As Chromatin Modifier, Spliceosome, and Myeloid Transcription Factor at Diagnosis Was Found to Have Benefit from Allogeneic Hematopoietic Stem Cell Transplantation (HCT) in 1,228 Patients with Acute Myeloid Leukemia in First Complete Remission (CR1)

Introduction Allogeneic stem cell transplant (HCT) brings survival benefit to certain subgroups of acute myeloid leukemia (AML) patients, although it may not be suitable for all cases. Decision for HCT referral is based on the ELN risk grouping, which classifies pts into favorable, intermediate, and adverse risk categories. While HCT is recommended for pts in the intermediate and adverse risk, those in the favorable risk are deferred to receive HCT. However, currently, there is a lack of data directly demonstrating benefits of HCT in specific mutation groups. Patients and Method In this retrospective study, out of 1477 newly diagnosed AML pts 1,228 pts achieved CR1 and had undergone baseline next-generation sequencing (NGS) at diagnosis from January 1997 to January 2020. The data were collected from five different centers located in Toronto, Vancouver, and Montreal, Canada, as well as Hwasun and Seoul, South Korea. NGS was performed in each institution with each institution's standard targeted sequencing panel. To assess the effectiveness of HCT, particular attention will be given to the time from achieving complete remission 1 (CR1) to HCT. To handle immortal time bias, the Mantel-Byar method was used to depict outcomes during the follow-up period. Kaplan-Meier curves were avoided as they can introduce immortal bias, considering the period of time before treatment as part of the treatment arm. Instead, the MBT and landmark methods were employed to address this issue. Allogeneic HCT was treated as a time-dependent variable to prevent immortal bias. Gene mutations were grouped into 6 biologic pathways, including DNA methylation, chromatin modifiers, cohesion complex, activated signaling, tumor suppressor, spliceosome, and myeloid transcription factor (TF) mutations. In the multivariate (MVA) analysis, any mutations with a frequency of &amp;gt;5% were included as well as TP53 which has very grave prognosis. The primary objective of this study is to identify specific groups of AML pts who can derive significant benefits from receiving HCT in CR1, treating HCT as a time-dependent (td) covariate in the analysis. Statistical analyses were conducted using EZR version 1.41. Results The median duration of follow-up among survivors after achieving CR1 was 22.6 months (range: 1-217.9 months). Among the 593 pts, who underwent allogeneic HCT in CR1, the HCT group was composed of younger pts, with a median age of 50 years compared to 56 years in the non-HCT group (p &amp;lt; 0.001). Also, there were fewer pts with NPM1 mutation in the HCT group, accounting for 20.7% compared to 32.4% in the non-HCT group (p &amp;lt; 0.001). Apart from these characteristics, the two groups were similar in other parameters. The 2-year overall survival (OS) was higher in the HCT group, at 66.4%, compared to 54.6% in the non-HCT group (p &amp;lt; 0.0001). Similarly, the 2-year RFS was higher in the HCT group, with a rate of 64.8%, compared to 52.1% in the non-HCT group (p =1.82e-15). Furthermore, HCT as a time-dependent covariate was found to be favorable (Hazard ratio [HR] 0.76, 95% C.I. [0.63-0.91]; p=0.003), as demonstrated in the Simon-Makuch plot (p = 0.003). In the MVA, HCT as a time-dependent covariate retained its favorable impact on RFS (HR 0.67, [0.56-0.82]; p&amp;lt;0.0001). The MVA showed several prognostic factors besides HCT such as NPM1 and CEBPA mutations as favorable factors for RFS, being classified under the European Leukemia Network (ELN) favorable risk group. Conversely, FLT3-ITD, DNMT3A, IDH1, KIT, and TP53 mutations, monosomal karyotype, age &amp;gt; 60 years, and white blood count (WBC) at diagnosis &amp;gt; 55,600/mm^3 were associated with worse RFS. In terms of RFS, the greatest benefit of HCT was observed in the pts having mutations in ASXL1 (HR 0.34 [0.15-0.78]), BCOR (HR 0.29 [0.14-0.61]), IDH1/2 (HR 0.62 [0.42-0.92]), and RUNX1 (HR 0.17 [0.08-0.40]) but no significant benefit in those with KRAS (HR 1.59), NRAS (HR 1.21), PTPN11 (HR 1.23), and WT1 (HR 1.30). According to the biological pathway of somatic mutations, the greatest benefit of HCT in terms of RFS was observed in pts with mutations in the chromatin modifier (HR 0.37 [0.22-0.62]), spliceosome (HR 0.32 [0.16-0.65]), and myeloid TF pathway (HR 0.52 [0.34-0.79]). Conclusion Allogeneic HCT exerts a greater benefit on RFS in AML pts with mutations in the chromatin modifier, spliceosome, and myeloid TF pathways. Further study is warranted to replicate this finding.

Trends in Allogeneic Stem Cell Transplantation for Good Risk Acute Myelogenous Leukemia in First Complete Remission: A Longitudinal Study of &amp;gt; 15 Years from the ALWP/EBMT

Background: Favorable acute myelogenous leukemia (AML) includes AML with t (8:21), inv (16), and those with NPM1 without FLT3- ITD without adverse cytogenetics (ELN 2022). The incidence of relapse (RI) in favorable-risk AML with chemotherapy is 35%-40%. Although RI is ~20% lower with allogeneic transplantation (HSCT), transplantation is usually not indicated in favorable risk AML at first complete remission (CR1) due to transplant-related mortality. However, in recent years, HSCTs have been associated with significantly lower non relapse mortality (NRM) and better outcomes. Methods:Our aim was to assess outcomes of HSCT in favorable risk AML (t (8:21), inv (16), and NPM1 mutFLT3 WT) in CR1, comparing 3 time periods: 2005-2009, 2010-2014, and 2015-2021. Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors performed using a Cox proportional-hazards regression model for main outcomes. Results: 1850 patients (pts) were included, 526 with t (8:21), 625 with inv (16), and 699 with NPM1 mutFLT3 WT (normal karyotype). 222 pts were transplanted in 2005-2009, 392 in 2010-2014, and 1236 in 2015-2021. As the follow-up period differed, being 103.1 (IQR, 92.1-114.0), 78.3 (IQR, 69.4-86.3), and 32.0 (IQR, 29.5-34.5) months, respectively (p&amp;lt;0.0001), all survival events were censored at 3 y. Pts undergoing HSCT in 2015-2021 were older, with a median age of 50.9 (range 18.2-76.4) vs40.4 (range 18.3-67.7) and 42.4 (range 18.4-71) y, in those transplanted in 2005-2009 and 2010-2014, respectively (p&amp;lt;0.0001). More pts &amp;gt;50 y of age were transplanted in the latest period with 52.7% vs the 2 earlier periods 27.9% and 32.1% (p&amp;lt;0.0001) and figures for &amp;gt;60 y were 25.4% vs 8.1% and 11% (p&amp;lt;0.0001), respectively. In 2005-2009 the most frequent diagnosis was t (8:21) at 44.6%, while in 2015-2021, it was NPM1 mutFLT3 WT at 45.6% (p&amp;lt;0001). In 2005-2009, the most frequent donors were matched siblings (MSD) (63.1%), while in 2015-2021 they were unrelated (UD) (50.7%). Haploidentical (haplo) transplants increased from 5.9% to 14.5% (p&amp;lt;0.0001). Bone marrow grafts decreased from 24.8% to 13.2%, while peripheral blood (PB) grafts increased from 75.2% to 86.8% (p&amp;lt;0.0001). Conditioning was myeloablative in 69.8%, 64.8%, and 60.2% and was reduced intensity in 30.2%, 35.2%, and 39.8% in pts transplanted in 2005-2009, 2010-2014, and 2015-2021 (p=0.014). Graft-versus-host disease (GVHD) prophylaxis with in vivo T cell depletion or post-transplant cyclophosphamide (PTCy) was more frequent in 2015-2021 compared to the other two periods (p&amp;lt;0.0001). Day 60 engraftment (ANC &amp;gt;0.5 x 10 9/L) was 98.2 % vs 98.4% vs 98.5% (p=0.17). Day 180 incidence of acute (a) GVHD grade II-IV was 18.2%, 21.1%, and 21.6%; grade III-IV was 5.1% 5.7%, and 7.3% while the incidence of 3-y chronic (c) GVHD was 49.3%, 50.4% and 39.2%. On MVA the incidence of total cGVHD was reduced in HSCTs performed &amp;gt;2015 compared to those performed in 2005-2009, hazard ratio (HR) =0.74 (95% CI 0.56-0.99, p=0.046) and GVHD-free, relapse-free survival (GRFS) improved for pts transplanted from 2010-2014 vs those transplanted in 2005-2009, HR=0.74 (95% CI 0.56-0.98, p=0.037) (Figure 1). All other HSCT outcome parameters including NRM, RI, leukemia-free survival (LFS), and overall survival (OS) did not differ (Figure 1) with no improvement &amp;gt;2015 compared to 2010-2014 (Figure-1 A). LFS, OS, and GRFS were superior in pts with t (8:21) with HR=1.32 (95% CI 1.03-1.68, p=0.026), HR=1.38 (95% CI 1.04-1.83, p=0.027) and HR=01.25 (95% CI 1.02-1.53, p=0.035), respectively. Other poor prognostic factors were older pt age (by 10 y) for NRM and OS; 10/10 and 9/10 UD vs MSD for aGVHD II-IV (9/10 also for III-IV aGVHD) and haplo vs MSD for NRM, OS, aGVHD II-IV, and total cGVHD. The combination of female donor to male pt was a poor prognostic factor for NRM, OS, GRFS, and cGVHD. In vivo T cell depletion was a positive prognostic factor for GRFS and reduced incidence of aGVHD and cGVHD. PTCy was associated with a lower incidence of cGVHD and PB grafts with an increased risk of total cGVHD. Conclusions: In this retrospective analysis of HSCT in pts with favorable risk AML in CR1, transplanted over 16 years, we observed an increased number of transplants in pts &amp;gt;60y, from UD and haplo with PB grafts and in vivo T cell depletion or PTCy as GVHD prophylaxis. Most importantly, 3-y GRFS improved &amp;gt;2010 and total cGVHD reduced &amp;gt;2015, while other HSCT outcome parameters have not changed.

Autologous stem cell transplantation in adult patients with intermediate-risk acute myeloid leukemia in first complete remission and no detectable minimal residual disease. A comparative retrospective study with haploidentical transplants of the global committee and the ALWP of the EBMT

In patients with acute myeloid leukemia (AML) of intermediate-risk (IR) in first remission (CR1) with no measurable residual disease (MRD negative), the choice of the best consolidation is questionable. 1122 adult patients from 196 centers, transplanted in 2010-21 were analyzed: 547 received an autologous stem cell transplantation (ASCT) and 575 a Haploidentical donor transplant. Because of a significant interaction, comparisons were done separately for patients with wild-type FLT3 (FLT3-wt) and FLT3-ITD mutation (FLT3-ITD). In FLT3-wt patients, haploidentical transplants had two year lower relapse incidence (RI) (16.9% versus 32.6%; HR = 0.40, p < 0.001), higher NRM higher (17.2% vs 3.5%; HR = 7.02, p < 0.001), similar LFS (65.9% vs 63.8%; p = 0.37) and lower OS (73.2% vs 80.6%; HR = 1.69, p = 0.018). In FLT3-ITD patients, haploidentical transplants had two year lower RI (8.2% vs 47.8%; HR = 0.14, p < 0.001) higher NRM (20.2% vs 5.6%; HR = 3.43, p = 0.002), better LFS (71.5% vs 46.6%; HR = 0.53, p = 0.007) and similar OS (73.5% vs 61.9%; p = 0.44). In IR AML patients with FLT3-wt in MRD negative CR1, autologous stem cell transplantation is a valid option, while in patients with FLT3-ITD, haploidentical transplant is better. Whether autologous transplantation is superior to chemotherapy in FLT3-wt patients and the role of maintenance therapy with FLT3 inhibitors remain to be studied.

Etoposide plus cytarabine versus cyclophosphamide or melphalan in busulfan-based preparative regimens for autologous stem cell transplantation in adults with acute myeloid leukemia in first complete remission: a study from the Acute Leukemia Working Party of the EBMT.

We retrospectively compared the impact of the conditioning regimen in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) that received high-dose myeloablative chemotherapy followed by autologous stem cell transplantation (ASCT) from 2010 to 2021 with either high-dose cytarabine, etoposide and busulfan (BEA), busulfan with cyclophosphamide (BUCY) or busulfan and high-dose melphalan (BUMEL) registered in the EBMT database. Overall 1560 patients underwent ASCT, of which 156, 1143 and 261 received BEA, BUCY and BUMEL, respectively. Compared to BUCY and BUMEL, BEA patients were younger (p < 0.001) and less frequently had NPM1 mutations (p = 0.03). Transplant outcomes at 5 years with BEA, BUCY and BUMEL were: cumulative incidence of relapse 41.8%, 46.6% and 51.6%; non-relapse mortality (NRM) 1.5%, 5.2% and 7.3%; probability of leukemia-free survival (LFS) 56.7%, 48.2% and 41.1%; and overall survival (OS) 71.3%, 62.3% and 56%, respectively. In multivariable analysis the BEA regimen showed significant improvement in OS compared to BUCY (hazard ratio [HR] 0.65; 95% CI, 0.42-0.83; p = 0.048) and BUMEL (HR 0.59; 95% CI, 0.37-0.94; p = 0.029). In conclusion, high-dose myeloablative combination chemotherapy with BEA offered improved outcomes compared to classical BUCY or BUMEL in patients with AML in CR1 undergoing ASCT.

More than two courses of pre-transplant consolidation therapy benefits patients with acute myeloid leukemia in the first complete remission who underwent human leukocyte antigen-matched sibling allografts: a multicenter study.

Although the need for consolidation chemotherapy after successful induction therapy is well established in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the value of consolidation chemotherapy before allogeneic hematopoietic stem cell transplantation remains controversial. We retrospectively compared the effect of the number of pre-transplant consolidation chemotherapies on outcomes of human leukocyte antigen-matched sibling stem cell transplantation (MSDT) for patients with AML in CR1 in multicenters across China. In our study, we analyzed data of 373 AML patients in CR1 from three centers across China. With a median follow-up of 969 days, patients with ≥ 3 courses of consolidation chemotherapy had higher probabilities of leukemia-free survival (LFS) (85.6% vs . 67.0%, P < 0.001) and overall survival (89.2% vs . 78.5%, P = 0.007), and better cumulative incidences of relapse (10.5% vs . 19.6%, P = 0.020) and non-relapse mortality (4.2% vs . 14.9%, P = 0.001) than those with ≤ 2 courses of consolidation chemotherapy. Pre-transplantation minimal residual disease-negative patients with AML in CR1 who received MSDT with ≥ 3 courses of consolidation chemotherapy had a higher probability of LFS (85.9% vs . 67.7%, P = 0.003) and a lower cumulative incidence of relapse (9.6% vs . 23.3%, P = 0.013) than those with ≤ 2 courses. Our results indicate that patients with AML in CR1 who received MSDT might benefit from pre-transplant consolidation chemotherapy.

Outcomes of Tyrosine Kinase Inhibitors Maintenance Therapy with or without Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission: A Systematic Review and Meta-Analysis.

We conducted a systematic review and meta-analysis to compare outcomes of tyrosine kinase inhibitor (TKI) maintenance therapy with or without allogeneic hematopoietic stem cell transplantation (HSCT) in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in first remission (CR1). A literature search was performed on PubMed, Cochrane, and Clinical trials.gov. After screening 1720 articles, 12 studies were included. Proportions and odds ratios (OR) with 95% confidence intervals (CI) were computed. I2 provides an estimate of the percentage of variability in results across studies that is due to real differences and not due to chance. Of 1039 patients, 635 (61%) had TKI alone and 404 (39%) patients had HSCT followed by TKI. At 3 years, a trend towards poor overall survival (OS; OR 0.67, 95% CI 0.39-1.15, I2=68%), (disease-free survival; OR 0.58, 95% CI 0.26-1.29, I2=76%), and higher relapse rate (RR; OR=2.52, 95% CI=1.66-3.83, I2=26%) was seen with TKI alone compared to HSCT-TKI. Although HSCT followed by TKI maintenance in Ph+ ALL has long been considered standard of care, the introduction of potent third-generation TKIs and bispecific T-cell engagers such as Blinatumomab has significantly improved outcomes while sparing the need for HSCT in newly diagnosed patients.

Anti-MDA5 antibody-positive rapidly progressive interstitial lung disease after allogeneic hematopoietic cell transplantation successfully treated with triple immunosuppressive therapy

A 34-year-old man with KMT2A-MLLT1 acute myeloid leukemia in first complete remission underwent allogeneic peripheral blood stem cell transplantation from his HLA-matched sister after conditioning with busulfan/cyclophosphamide. He did not have severe graft-versus-host disease, but he developed interstitial pneumonia six months after transplantation when his oral cyclosporine A (CsA) dose was reduced to 10 mg/day. He was given prednisolone (PSL), which temporarily improved his respiratory condition, but he quickly deteriorated when PSL was reduced. Anti-MDA5 antibody was found to be positive after additional testing, and a three-drug combination of intravenous cyclophosphamide+PSL+CsA was initiated for anti-MDA5 antibody positive rapidly progressive interstitial lung disease, which was effective for interstitial pneumonia. He received a successful living-donor lung transplant from his younger brother and sister. We present a case of rapidly progressive anti-MDA5 antibody positive interstitial lung disease in which the patient's respiratory condition improved after triple therapy and subsequent living-donor lung transplantation.

Risk Factors Influencing Transplant Outcomes of Adults with Acute Lymphoblastic Leukemia in First Complete Remission: A Retrospective Analysis from the ALWP of the EBMT

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) remains a standard of care for adult patients with acute lymphoblastic leukemia (ALL) at high risk of relapse, i.e. high-risk features at time of diagnosis (ex. Philadelphia (Ph) positive ALL), or detectable minimal residual disease (MRD+). The aim of our study was to identify risk factors influencing transplant outcomes in ALL patients transplanted between 2015 and 2021. Methods: We included adults undergoing allo-HSCT for ALL in CR1 with available data of ALL phenotype, Ph-status, and MRD pre-transplant. All donor types and stem cell sources were eligible, except cord blood. Ex-vivo T-cell depletion (TCD) represented an exclusion criterion. Results: We identified 2349 transplanted patients including 870 from HLA-matched sibling (MSD), 1150 from unrelated (79% 10/10 and 21% 9/10 UD), and 329 from haploidentical donors (Haplo). Median age was 42.6 (range 18-76.1) years. Median follow-up was 23.5 (95% CI 21.8-24.2) months. The entire cohort was composed of 667 patients (28.4%) with Ph-negative B-ALL, 1325 (56.4%) with Ph-positive B-ALL and 357 (15.2%) with T-ALL. Median time from diagnosis to allo-HSCT was 5.8 (range 1.3-18) months. Stem cell source was peripheral blood (PB) in 85.3% of cases. Conditioning regimen was reduced-intensity (RIC) in 21% and myeloablative (MAC) in 79% of cases. Total body irradiation (TBI) was used in 65.8% of patients, mostly as a MAC (93.9%). Pre-transplant MRD+ was reported in 35.4% while in-vivo TCD was used in 51.5% of cases. At 180 days, cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (aGVHD) were 29.2% (95% CI 27.3-31.1) and 10.1% (95% CI 8.9-11.4), respectively. Two-years overall and extensive chronic GVHD (cGVHD) were 34% (95% CI 31.7-36.3) and 15% (95% CI 13.2-16.8), respectively. At two years, relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were 22.2% (95% CI 20.3-24.2), 15.4% (95% CI 13.8-17.1), 62.3% (95% CI 60-64.6) 73.9% (95% CI 71.7-76) and 48% (95% CI 45.6-50.3), respectively. By multivariate analysis, MSD (reference group) was associated to higher RI compared to 9/10 UD (HR 1.47, 95% CI 1.01-2.12; p<0.05) and Haplo (HR 1.64, 95% CI 1.15-2.27; p<0.01) but lower NRM and grade II-IV aGVHD compared to both 9/10 and 10/10 UD (for NRM HR 0.54, 95% CI 0.36-0.81; p<0.01 and HR 0.65, 95% CI 0.48-0.88; p<0.01; for aGVHD: HR 0.58, 95% CI 0.44-0.78; p<0.01 and HR 0.70, 95% CI 0.56-0.87; p<0.01). Compared to Ph-negative ALL (reference group), Ph-positive ALL was associated with a lower RI (HR=0.61, 95% CI 0.49-0.77; p<0.01) and higher LFS (HR=0.71, 95% CI 0.60-0.85; p<0.01), OS (HR=0.59, 95% CI 0.48-0.72; p<0.01) and GRFS (HR=0.81, 95% CI 0.70-0.94; p<0.01), while T-ALL was associated to lower NRM (HR 0.58, 95% CI 0.37-0.91: p<0.02) and cGVHD (HR 0.73, 95% CI 0.54-0.98; p<0.04). MRD+ group faced higher RI (HR=1.74, 95% CI 1.42-2.12; p<0.01), lower LFS (HR=1.41, 95% CI 1.21-1.65; p<0.01), OS (HR=1.31, 95% CI 1.08-1.58; p<0.01) and GRFS (HR=1.31, 95% CI 1.14-1.49; p<0.01). Use of TBI enabled lower RI (HR 0.78, 95% CI 0.61-0.99; p=0.04), higher LFS (HR=0.80, 95% CI 0.67-0.96; p<0.02) but higher grade II-IV aGVHD (HR 1.54, 95% CI 1.23-1.92; p<0.01) and cGVHD (HR 1.47, 95% CI 1.16-1.87; p<0.01) compared to chemotherapy. Patients receiving a RIC had a higher RI (HR=1.52, 95% CI 1.17-1.98; p<0.01) and a lower NRM (HR=0.55, 95% CI 0.39-0.77; p<0.01). In vivo TCD allowed lower risk of cGVHD (HR=0.69, 95% CI 0.55-0.85; p<0.01) and higher GRFS (HR=0.78, 95% CI 0.66-0.91; p<0.01). PB stem cells and female-donor to male-recipient were independently associated to higher risk of cGVHD. Elderly patients faced lower LFS, OS and GRFS. Conclusions: Our study reported overall favorable outcomes in the population of recently allografted patients with ALL in CR1 (LFS> 60% et OS> 70% at 2 years). Prognostic role of pre-transplant MRD is confirmed. Results in Ph-positive ALL are not inferior compared to Ph-negative ALL, most probably due to the use of tyrosine kinase inhibitors. Whether incorporation of novel agents will change the role of allo-HSCT in Ph-positive ALL is under investigation. Use of TBI and HLA mismatches are both associated with lower RI despite a higher risk of GVHD, highlighting the importance of tailoring GVHD prophylaxis in these settings.

Autologous Versus Haploidentical Stem Cell Transplantation in Adult Patients with Intermediate Risk Actue Myelogenous Leukemia in First Complete Remission and Undetectable Minimal Residual Disease: A Global Preliminary Analysis of Chinese Data

Background: Stem cell transplantation (SCT) is a potentially curative post-remission therapy for intermediate-risk acute myeloid leukemia (AML) patients. For patients in first remission (CR1) with negative measurable residual disease (MRD) and without a HLA-matched donor, both autologous SCT (ASCT) and haploidentical donor SCT (haplo-SCT) were acceptable options, but it is controversial that which one is preferred. Methods: A retrospective study was conducted in 8 Chinese centers. The inclusion criteria were: 1) adult patients >18 years old; 2) diagnosis as AML with intermediate-risk according to ELN 2017; 3) ASCT or haplo-SCT underwent between 2010-2019; 4) in CR1 and MRD negative before transplant. The Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), cumulative incidence of relapse (CIR), treatment-related mortality (TRM), and graft-versus-host disease-free and relapse-free survival (GRFS). Results: Totally 299 patients were enrolled in this study, including 97 recepients after ASCT and 202 recipients after haplo-SCT (Table 1). The median follow-up was 28 months in ASCT group versus 35 months in haplo-SCT group. Compared to haplo-SCT, patients after ASCT had increased 3-year CIR (27.0% ± 0.2% versus 13.5% ± 0.1%, p = 0.004) but reduced 3-year TRM (3.5% ± 0.0% versus 12.0% ± 0.0%, p = 0.013), which led to similar 3-year OS (80.8% ± 4.3% versus 79.2% ± 3.1%, p = 0.796) and PFS (69.5% ± 5.0% versus 73.7% ± 3.3%, p = 0.504). Moreover, the 3-year GRFS was remarkable better in ASCT group (69.5% ± 5.0% versus 55.9% ± 3.6%, p = 0.009) (Figure 1), which implied a survival with superior quality of life (QoL). In multivariate analysis, haplo-SCT independently related to an improved CIR, while increased TRM and reduced GRFS. Additionally, age more than 50 was associated with the worse OS, CIR and GRFS. Conclusions: We concluded that both ASCT and haplo-SCT were applicable for patients with intermediate-risk AML in MRD-negative CR1, but the absence of GVHD might potentially favor the QoL for patients receiving ASCT. Randomized trials are needed to confirm our conclusion. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CNS Involvement at Initial Diagnosis and Risk of Relapse After Allogeneic HCT for Acute Lymphoblastic Leukemia in First Complete Remission.

Outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adult acute lymphoblastic leukemia (ALL) have improved over time. Studies have shown that total body irradiation (TBI) is the preferable type of myeloablative conditioning (MAC). However, outcomes based on central nervous system (CNS) involvement, namely CNS-positive versus CNS-negative, have not been compared. Here, we evaluated outcomes of 547 patients (CNS-positive = 96, CNS-negative = 451) who were allografted in the first complete remission (CR1) between 2009 and 2019. Primary endpoint was leukemia-free survival (LFS). Median follow-up was not different between the CNS-positive and CNS-negative groups (79 versus 67.2 months, P = 0.58). The CNS-positive group were younger (median age 31.3 versus 39.7 years, P = 0.004) and were allografted more recently (median year 2012 versus 2010, P = 0.003). In both groups, MAC was the preferred approach (82.3% versus 85.6%, P = 0.41). On multivariate analysis, the CNS-positive group had higher incidence of relapse (RI) (hazard ratio [HR] = 1.58 [95% confidence interval (CI) = 1.06-2.35], P = 0.025), but no adverse effect on LFS (HR = 1.38 [95% CI = 0.99-1.92], P = 0.057) or overall survival (OS) (HR = 1.28 [95% CI = 0.89-1.85], P = 0.18). A subgroup multivariate analysis limited to CNS-positive patients showed that a TBI-based MAC regimen resulted in better LFS (HR = 0.43 [95% CI = 0.22-0.83], P = 0.01) and OS (HR = 0.44 [95% CI = 0.21-0.92], P = 0.03) and lower RI (HR = 0.35 [95% CI = 0.15-0.79], P = 0.01). Another subgroup analysis in CNS-negative patients showed that MAC-TBI preparative regimens also showed a lower RI without a benefit in LFS or OS. While a MAC-TBI allo-HCT regimen may not be suitable to all, particularly for older patients with comorbidities, this approach should be considered for patients who are deemed fit and able to tolerate.

Should Minimal Residual Disease Guide the Way? The Evolving Role of Allogeneic Hematopoietic Cell Transplantation for Adults With Ph+ Acute Lymphoblastic Leukemia in First Complete Remission

Should Minimal Residual Disease Guide the Way? The Evolving Role of Allogeneic Hematopoietic Cell Transplantation for Adults With Ph+ Acute Lymphoblastic Leukemia in First Complete Remission

Effect of pediatric- versus adult-type chemotherapy regimens on outcomes of allogeneic hematopoietic stem cell transplants for adult T-cell acute lymphoblastic leukemia in first complete remission.

The optimal chemotherapy regimen pre-transplantation for adult T-cell acute lymphoblastic leukemia (T-ALL) patients remains unknown. Here, we compared the transplant outcomes in 127 subjects receiving pediatric- (N = 57) or adult-type (N = 70) regimens pre-transplant. The corresponding 3-year cumulative incidences of relapse (CIR) was 7% (95% CI: 3-11%) and 29% (95% CI: 23-35%; P = 0.02), leukemia-free survivals (LFS) was 86% (95% CI: 81-91%) and 57% (95% CI: 51-63%; P = 0.003), overall survivals (OS) was 88% (95% CI: 84-92%) and 58% (95% CI: 52-64%; P = 0.002), the 1-year NRM was 4% (95% CI: 1-7%) and 9% (95% CI: 4-14%; P = 0.40). Multivariate analysis showed that pediatric-type regimen was associated with lower CIR (Hazard Ratio [HR] = 0.31 [95% CI: 0.09-1.00]; P = 0.05), better LFS (HR = 0.34 [95% CI: 0.15-0.78]; P = 0.01) and OS (HR = 0.30 [95% CI: 0.13-0.72]; P = 0.01). Our results suggested that adult T-ALL patients undergoing allo-HSCT might benefit from pediatric-type chemotherapy.

Allogeneic hematopoietic stem cell transplantation for pediatric acute myeloid leukemia in first complete remission: a meta-analysis

Identification of pediatric patients with acute myeloid leukemia (AML) candidates to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first complete remission (CR1) is still a matter of debate. Currently, transplantation is reserved to patients considered at high risk of relapse based on cytogenetics, molecular biology, and minimal residual disease (MRD) assessment. However, no randomized clinical trial exists in the literature comparing transplantation with other types of consolidation therapy. Here, we provide an up-to-date meta-analysis of studies comparing allo-HSCT in CR1 with chemotherapy alone as a post-remission treatment in high-risk pediatric AML. The literature search strategy identified 10 cohorts from 9 studies performing as-treated analysis. The quantitative synthesis showed improved overall survival (OS) (relative risk, 1.15; 95% confidence interval [CI], 1.06–1.24; P = 0.0006) and disease-free survival (relative risk, 1.31; 95% CI, 1.17–1.47; P = 0.0001) in the allo-HSCT group, with increased relapse rate in the chemotherapy group (relative risk, 1.26; 95% CI, 1.07–1.49; P = 0.006). Sensitivity analysis including prospective studies alone and excluding studies that reported the comparison only on intermediate-risk patients confirmed the benefit of allo-HSCT on OS. Further research should focus on individualizing allo-HSCT indications based on molecular stratification and MRD monitoring.

Combination of KIT and FLT3-ITD mutation status with minimal residual disease levels guides treatment strategy for adult patients with inv(16) acute myeloid leukemia in first complete remission.

Although several studies have investigated the benefits of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with inv (16) acute myeloid leukemia (AML) in first complete remission (CR1) individually stratified by KIT or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation status or minimal residual disease (MRD) levels, evaluation based on the combination of mutation status and MRD levels remains absent. This study included 157 adult patients with inv (16) AML who were consecutively diagnosed and receiving treatment at our center. A total of 50 (31.6%) patients had KIT mutations (KITMU ), and the risk of relapse was significantly higher in patients with KITMU than in patients with KITWT (p<0.001). A total of 12 patients (7.6%) had FLT3-ITD, and FLT3-ITD+ tended to be related to a higher risk of relapse (p=0.14). KITMU , FLT3-ITD and MRD3-H (beta subunit of core binding factor-myosin heavy chain 11 levels >0.2% after course 2 of consolidation therapy) were independent adverse prognostic factors for relapse with patients who received allo-HSCT at CR1 were censored at the time of transplantation. After combination, patients were categorized into molecularly defined high-risk (M-HR; KITMU or FLT3-ITD+ with MRD3-H; n=30), low-risk (M-LR; KITWT and FLT3-ITD- with MRD3-L; n=45) and intermediate-risk (M-IR; others; n=70) groups. For the M-HR group, allo-HSCT significantly improved both cumulative incidence of relapse cumulative incidence of relapse (CIR) and overall survival (OS) (11.1% vs. 92.6%, p<0.001; 90.0% vs. 34.1%, p=0.019). For the M-IR group, allo-HSCT significantly improved CIR but did not affect OS (14.1% vs. 62.2%, p=0.0004; 73.3% vs. 68.3%, p=0.43). For the M-LR group, allo-HSCT had no significant effect on both CIR and OS (0% vs. 35.1%, p=0.31; 100% vs. 78.8%, p=0.22). Therefore, the combination of KIT and FLT3-ITD mutation status with MRD levels may identify inv (16) AML patients with high-risk who can benefit from allo-HSCT in CR1.

In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial

SummaryBackgroundThe outcome of chemotherapy in patients older than 40 years with acute lymphoblastic leukaemia is poor and myeloablative allogeneic haematopoietic stem-cell transplantation (HSCT) has a high transplant-related mortality (TRM) in this age cohort. The aim of this study was to assess the activity and safety of reduced-intensity conditioned allogeneic HSCT in this patient population.MethodsThis was a single-arm, prospective study within the UKALL14 trial done in 46 centres in the UK, which recruited patients to the transplantation substudy. Participants in UKALL14 had B-cell or T-cell acute lymphoblastic leukaemia, were aged 25–65 years (BCR-ABL1-negative) or 18–65 years (BCR-ABL1-positive), and for this subcohort had a fit, matched sibling donor or an 8 out of 8 allelic matched unrelated donor (HLA-A, HLA-B, HLA-C, and HLA-DR). On June 20, 2014, the protocol was amended to allow 7 out of 8 matched unrelated donors if the patient had high risk cytogenetics or was minimal residual disease (MRD)-positive after the second induction course. Patients were given fludarabine, melphalan, and alemtuzumab (FMA; intravenous fludarabine 30 mg/m2 on days –6 to –2, melphalan 140 mg/m2 on day –2, and alemtuzumab 30 mg on day –1 [sibling donor] and days –2 and –1 [unrelated donor]) before allogeneic HSCT (aged ≥41 years patient pathway). Donor lymphocyte infusions were given from 6 months for mixed chimerism or MRD. The primary endpoint was event-free survival and secondary and transplantation-specific endpoints included overall survival, relapse incidence, TRM, and acute and chronic graft-versus-host disease (GVHD). This study is registered with ClinicalTrials.gov, NCT01085617.FindingsFrom Feb 22, 2011, to July 26, 2018, 249 patients (236 aged ≥41 years and 13 younger than 41 years) considered unfit for a myeloablative allograft received an FMA reduced-intensity conditioned HSCT. 138 (55%) patients were male and 111 (45%) were female. 88 (35%) participants received transplantations from a sibling donor and 160 (64%) received transplantations from unrelated donors. 211 (85%) participants had B-precursor acute lymphoblastic leukaemia. High-risk cytogenetics were present in 43 (22%) and another 63 (25%) participants were BCR-ABL1-positive. At median follow-up of 49 months (IQR 36–70), 4-year event-free survival was 46·8% (95% CI 40·1–53·2) and 4-year overall survival was 54·8% (48·0–61·2). 4-year cumulative incidence of relapse was 33·6% (27·9–40·2) and 4-year TRM was 19·6% (15·1–25·3). 27 (56%) of 48 patients with TRM had infection as the named cause of death. Seven (15%) of 48 patients had fungal infections, 13 (27%) patients had bacterial infections (six gram-negative), and 11 (23%) had viral infections (three cytomegalovirus and two Epstein-Barr virus). Acute GVHD grade 2–4 occurred in 29 (12%) of 247 patients and grade 3–4 occurred in 12 (5%) patients. Chronic GVHD incidence was 84 (37%) of 228 patients (50 [22%] had extensive chronic GVHD). 49 (30%) of 162 patients had detectable end-of-induction MRD, which portended worse outcomes with event-free survival (HR 2·40 [95% CI 1·46–3·93]) and time-to-relapse (HR 2·41 [1·29–4·48]).InterpretationFMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes.FundingCancer Research UK.

Novel strategies in the treatment of acute lymphoblastic leukaemia

The outcome of paediatric acute lymphoblastic leukaemia is excellent, with a 90% overall survival rate. However, the overall survival of adults with acute lymphoblastic leukaemia with standard chemotherapy is only 40–50%. This outcome is typically worse with increasing age. Given this prognosis, novel therapies and strategies are needed to improve outcomes. In The Lancet Haematology, two different strategies are employed by the UKALL group: (1) the addition of the monoclonal anti-CD20 antibody, rituximab, to standard induction therapy in adults aged 25–65 years with precursor B-cell acute lymphoblastic leukaemia; 1 Marks DI Kirkwood AA Rowntree CJ et al. Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trial. Lancet Haematol. 2022; 9: e262-e275 Summary Full Text Full Text PDF PubMed Scopus (1) Google Scholar and (2) the use of in-vivo T-cell depleted reduced intensity allogeneic haematopoietic stem-cell transplantation (HSCT) in first remission for patients aged 41 years and older or for patients younger than 41 years considered unfit for a myeloablative allograft. 2 Marks DI Clifton-Hadley L Copland M et al. In-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trial. Lancet Haematol. 2022; 9: e276-e288 Summary Full Text Full Text PDF PubMed Google Scholar Addition of four doses of rituximab to standard induction chemotherapy in adult patients with precursor B-cell acute lymphoblastic leukaemia (UKALL14): a phase 3, multicentre, randomised controlled trialStandard of care plus four doses of rituximab did not significantly improve event-free survival over standard of care. Rituximab is beneficial in acute lymphoblastic leukaemia but four doses during induction is likely to be insufficient. Full-Text PDF Open AccessIn-vivo T-cell depleted reduced-intensity conditioned allogeneic haematopoietic stem-cell transplantation for patients with acute lymphoblastic leukaemia in first remission: results from the prospective, single-arm evaluation of the UKALL14 trialFMA reduced-intensity conditioned allogeneic HSCT in older patients with acute lymphoblastic leukaemia in first complete remission provided good disease control with moderate GVHD, resulting in better-than-expected event-free survival and overall survival in this high-risk population. Strategies to reduce infection-related TRM will further improve outcomes. Full-Text PDF Open Access

Haploidentical hematopoietic stem cell transplantation may improve long-term survival for children with high-risk T-cell acute lymphoblastic leukemia in first complete remission.

Background:The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with high-risk (HR) T-cell acute lymphoblastic leukemia (T-ALL) in first complete remission (CR1) is still under evaluation. Moreover, relapse is the main factor affecting survival. This study aimed to explore the effect of allo-HSCT (especially haploidentical HSCT [haplo-HSCT]) on improving survival and reducing relapse for HR childhood T-ALL in CR1 and the prognostic factors of childhood T-ALL in order to identify who could benefit from HSCT.Methods:A total of 74 newly diagnosed pediatric T-ALL patients between January 1, 2012 and June 30, 2018 were enrolled in this retrospective study. Patients were stratified into the low-risk chemotherapy cohort (n = 16), HR chemotherapy cohort (n = 31), and HR transplant cohort (n = 27). Characteristics, survival outcomes, and prognostic factors of all patients were then analyzed.Results:Patient prognosis in the HR chemotherapy cohort was significantly worse than that in the low-risk chemotherapy cohort (5year overall survival [OS]: 58.5% vs. 100%, P = 0.003; 5-year event-free survival [EFS]: 54.1% vs. 83.4%, P = 0.010; 5-year cumulative incidence of relapse [CIR]: 45.2% vs. 6.3%, P = 0.011). In HR patients, allo-HSCT improved the 5-year EFS and CIR compared to that of chemotherapy (5-year EFS: 80.1% vs. 54.1%, P = 0.041; 5-year CIR: 11.6% vs. 45.2%, P = 0.006). The 5-year OS was higher in the HR transplant cohort than that in the HR chemotherapy cohort (81.0% vs. 58.5%, P = 0.084). Minimal residual disease re-emergence was an independent risk factor for 5-year OS, EFS, and CIR; age ≥10 years was an independent risk factor for OS and EFS; and high white blood cell count was an independent risk factor for EFS and CIR.Conclusion:Allo-HSCT, especially haplo-HSCT, could effectively reduce relapse of children with HR T-ALL in CR1.