Hematopoietic Cell Transplantation In CR1 Research Articles

Early Allogeneic Transplantation Favorably Influences the Outcome of Pediatric Acute Myeloid Leukemia—A Retrospective Study in a Single Center Over 2 Decades

Transplantation advancements offer the potential for improving the prognosis of patients with acute myeloid leukemia (AML). Controversies surrounding indications and timing persist. We focused on identifying prognostic factors and exploring the advantages of early transplantation. We studied 102 pediatric patients with AML (February 1999-August 2022), using Cox regression to analyze survival and hematopoietic cell transplantation (HCT) outcomes and Kaplan-Meier curves to assess HCT timing's impact on prognosis. "Treatment in First Complete Remission [CR1]: Chemotherapy" showed increased risk in multivariate and univariate Cox regression analyses, whereas "HCT during the study period" displayed divergent outcomes. Focusing on transplanted patients, "Treatment in CR1: Chemotherapy" still correlated with higher mortality risk. These findings emphasize the pivotal role of the treatment strategy adopted in CR1 on overall survival rather than HCT alone. Donor cytomegalovirus (CMV) positivity is also related to reduced mortality risk. Kaplan-Meier analysis supported superior 5-year survival rates with "HCT" compared with "chemotherapy" in CR1. In the 3-arm analysis, "HCT in CR1" demonstrated better 5-year overall survival (OS) and 5-year disease-free survival (DFS) compared with "Never HCT," whereas "HCT in CR2" had the least favorable prognosis (5-year OS: 79.2% vs 57.1% vs 50%, P = .056; 5-year DFS: 73.6% vs 55.2% vs 0%, P = .000). Our study highlights the benefits of transplantation during CR1 on prognosis. However, when contemplating CR1 transplantation recommendations, evaluation of various factors, such as the patient's clinical state, relapse risk, transplant-related mortality, CMV status, and other pertinent considerations, is vital. Comprehensive case discussions with patients and families are demanded in optimizing treatment.

A Multicenter Analysis of Allogeneic Transplant Outcomes in Patients with Philadelphia-like (Ph-like) Acute Lymphoblastic Leukemia (ALL)

Background: Ph-like ALL is a high-risk subset of B-lineage ALL that responds poorly to standard chemotherapy regimens. While allogeneic hematopoietic cell transplantation (HCT) is routinely recommended for patients with Ph-like ALL, large multicenter data addressing its role is limited. Here, we conducted a multicenter study to evaluate the role of HCT in adolescent and young adult (AYA) and adult patients (pts) with Ph-like ALL and compare their outcomes to pts with Ph-pos and Ph-neg (non-Ph-like) ALL. Methods: The study included pts (age ≥18) with B-lineage ALL who received HCT in first complete remission (CR1) at 3 academic centers (MD Anderson Cancer Center, City of Hope and Mayo Clinic) between 2006 and 2021. Pts were divided into 3 main subgroups: Ph-like, Ph-pos and Ph-neg ALL. Ph-like ALL cases were identified using cumulative data obtained by targeted RNA sequencing, conventional cytogenetics, FISH studies, whole genome chromosomal microarray and flow cytometry. Measurable residual disease (MRD) prior to HCT was measured using flow cytometry with a sensitivity of 0.01% for Ph-neg and Ph-like ALL, and with a PCR assay for BCR::ABL1 for Ph-pos ALL. MRD-negativity was defined as <0.01%. Predictors of relapse were evaluated in univariate and multivariate analysis using Fine-Gray sub-distribution hazard models considering non-relapse mortality (NRM) as a competing risk. Results: 673 patients were identified, 83 (12.3%) had Ph-like ALL, of which 73% had CRLF2-alterations. The remaining patients were classified either as Ph-pos (N=271, 40.3%) or Ph-neg ALL (N=319, 47.4%). Patients with Ph-like ALL were younger (median age 40 years vs 48 and 46 years for Ph-pos and Ph-neg ALL, respectively, p=0.01), more likely to be of Hispanic ethnicity (69% vs 32% and 48% for Ph-pos and Ph-neg ALL respectively, p<0.001). Patients with Ph-like ALL were also more likely to have induction failure (24% vs 2% and 11% for Ph-pos and Ph-neg ALL, respectively, p=0.001). A summary of pts characteristics for each subgroup can be found in Table 1. The median follow-up was 30, 52 and 48 months for patients with Ph-like, Ph-pos and Ph-neg ALL, respectively. In univariate analysis, 3-yr OS and PFS did not differ significantly (66% and 59% vs 59% and 54%, p=0.1) between patients with Ph-like and Ph-neg ALL, respectively. Similarly, the cumulative incidence of relapse was comparable between patients with Ph-like and Ph-neg ALL (22% vs 20%, respectively, p=0.7). In contrast, the 3-yr OS (75%, p<0.001) and PFS (70%, p=0.001) were significantly higher and relapse rate significantly lower (12%, p=0.003) in pts with Ph-pos ALL compared with Ph-like or Ph-neg ALL (Figure 1). The inferior survival in patients with Ph-like and Ph-neg ALL was likely attributable to higher relapse rates (22% and 20% vs 12%, respectively, p=0.003) compared to Ph-pos ALL. Finally, the 3-yr NRM rate in patients with Ph-like ALL was comparable (20% vs 18% and 23%, respectively, p>0.1) to Ph-pos and Ph-neg ALL. We confirmed that the relapse rate in patients with Ph-like ALL was comparable to the rate in pts with Ph-neg ALL (HR=1.02, 95% CI 0.6-1.8, p=0.9) on multivariate analysis (MVA). Ph-pos ALL was associated with a significantly lower relapse rate compared with Ph-neg ALL (HR=0.4, 95% CI 0.3-0.7, p<0.001). MRD positivity prior to allo-HCT was the only additional significant predictor for relapse on MVA (HR=2.9, 95% CI 1.8-4.7, p<0.001). Conclusions: HCT appears to overcome the poor prognosis of patients with Ph-like ALL. Despite higher induction failure rates, patients with Ph-like ALL undergoing HCT in CR1 had similar outcomes to other Ph-neg ALL subsets. The impact of effective salvage therapy leading to MRD-negativity in CR1 in this group is under investigation and will be reported. Further studies are needed to assess the impact of different Ph-like alterations on HCT outcomes. Outcomes for patients with Ph-pos ALL are significantly better than other groups, likely due to the use of TKIs pre- and post-HCT.

Outcomes in Mantle Cell Lymphoma with Central Nervous System Involvement - a Dual Center Study

Background Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

Feasibility and efficacy of salvage allogeneic stem cell transplantation in AML patients relapsing after autologous stem cell transplantation

Autologous hematopoietic cell transplantation (HCT) is suitable for consolidation of favorable-/intermediate-risk AML patients in CR1. However, ~50% of AML patients relapse after autologous HCT, and efficacy of subsequent salvage strategies including allogeneic HCT remains unclear. We studied 123 consecutive patients with newly diagnosed AML undergoing high-dose chemotherapy (HDCT)/autologous HCT in CR1. In relapsing patients afterwards, we analyzed salvage treatments and outcomes focusing particularly on salvage allogeneic HCT. Of 123 patients, 64 (52%) relapsed after autologous HCT. Subsequently, 13 (21%) received palliative therapy, whereas 51 (79%) proceeded to salvage therapy with a curative intent. Of the 47 patients with a curative intent and who did not proceed directly to allogeneic HCT, 23 (49%) achieved CR2 or had ongoing hematologic CR1 despite molecular relapse. Finally, 30 patients (47%) received allogeneic HCT with estimated 3-year leukemia-free and overall survival rates of 33% and 43%. Hematologic remission at allogeneic HCT and lack of acute GvHD had a positive impact on OS and LFS (p < 0.05). Our study suggests that almost 80% of AML patients can undergo salvage therapy following relapse after front-line HDCT/autologous HCT. Allogeneic HCT can provide cure in one third of patients relapsing after front-line HDCT/autologous HCT.

Primary Central Nervous System Involvement at Initial Diagnosis Remains an Independent Risk Factor for Relapse in Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Cell Transplantation in CR1

Background: A recent study from the Acute Leukemia Working Party of EBMT demonstrated that outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adults with acute lymphoblastic leukemia (ALL) have improved significantly over time and that total body irradiation (TBI) should be considered as the preferable type of myeloablative conditioning (MAC). This study, however, did not compare outcomes of allo-HCT in patients with CNS involvement (CNS-pos) vs. those without CNS disease (CNS-neg).Study population: Here, we evaluate post allo-HCT outcomes of 547 patients (CNS-pos at initial presentation=96, CNS-neg=451) who underwent the procedure in first complete remission (CR1) between 2009 and 2019 at an EBMT participating transplant center. The distribution of ALL subtypes were as follows: CNS-pos (Ph-neg B ALL=28%, Ph-pos B ALL=27%, and T-cell ALL=45%) and for CNS-neg (Ph-neg B ALL=21%, Ph-pos B ALL=44%, and T-cell ALL=35%), p=0.01. The primary endpoint was leukemia-free survival (LFS).Results: The median follow up was not statistically different between the CNS-pos (78.7 months) and the CNS-neg group (67.2 months), p=0.58. Patients in the CNS-pos group were younger (median age 31.3 vs. 39.7 years, p=0.004), received the procedure more recently (median year 2012 vs. 2010, p=0.003), were less likely to have a Karnofsky score of equal or higher than 90 (70.8% vs. 81.9%, p=0.017), or to have received peripheral blood stem cells (PBSC) (61.5% vs. 72.7%, p=0.028). The groups did not differ in regards to donor source (URD, 50% vs. 56.5%, p=0.24) or the intensity of the preparative regimen (MAC, 82.3% vs. 85.6%, p=0.41). In multivariate analysis, CNS-pos were associated with higher cumulative incidence of relapse (HR=1.58 (95%CI=1.06-2.35), P=0.025) and a trend for an inferior leukemia-free survival (LFS) (HR=1.38 (95%CI=0.99-1.92), p=0.057), but did not adversely impact overall survival (OS) (HR=1.28 (95%CI=0.89-1.85), p=0.18). A subgroup multivariate analysis limited to patients with CNS-pos showed that prescribing a TBI MAC regimen (vs. others) results in a lower cumulative incidence of relapse (HR=0.35 (95%CI=0.15-0.79), p=0.012) and 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). Use of PBSC (vs. BM) was also independently associated with better OS (HR=0.53 (95%CI=0.29-0.99), p=0.046).Conclusion: Notwithstanding the inherent limitations of registry data, particularly ascertaining the absence of CNS involvement in the CNS-neg group, our results show CNS involvement as an independent risk factor for relapse following allo-HCT. Our data support, nonetheless, the choice of a TBI-based MAC regimen in this group of patients but stresses the need for close monitoring of relapse after allo-HCT. DisclosuresLabopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Socie: Alexion: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Allogeneic Hematopoietic Cell Transplantation in Patients ≤ 60 Years with Intermediate-Risk Acute Myeloid Leukemia in First Remission - Results of the Randomized Etal-1 Trial-

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Allogeneic Hematopoietic Stem Cell Transplant Versus No Transplant in Adult Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia in First Complete Remission and Complete Molecular Remission

Role of Allogeneic HCT as Postremission Therapy for Transplant-Eligible Adult Lymphoblastic Leukemia/Lymphoma After Frontline Hyper-CVAD

BackgroundHyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with cytarabine and methotrexate (hyper-CVAD) is a commonly used regimen in adults with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Adult patients fit for pediatric-inspired protocols have an excellent outcome with chemotherapy alone. However, it is unclear whether patients receiving hyper-CVAD should undergo allogeneic hematopoietic cell transplantation (HCT) as postremission therapy. Our aim was to examine the role of HCT at first complete remission (CR1) in adult ALL/LBL after hyper-CVAD. Patients and MethodsAdult patients with newly diagnosed ALL/LBL receiving frontline hyper-CVAD from 2008 to 2018 were identified and records retrospectively extracted. ResultsA total of 85 patients were identified and included for further analysis. The median (range) age was 23 (14-68) years, and 56 (66%) were male. A total of 24 (28%) had adverse cytogenetics, and 48 (56%) had at least one risk factor. All patients received hyper-CVAD as induction; induction failure was seen in 10 (12%). A total of 38 patients continued the hyper-CVAD course, while the remaining 47 received HCT in CR1. Three-year event-free survival (EFS) and overall survival for the entire cohort were 51.4% and 61.6%, respectively. Median follow-up of alive patients was 39.9 (3.8-123.8) months. At multivariable analysis for EFS, induction failure was associated with worse outcome (hazard ratio [HR], 4.8; 95% confidence interval [CI] 1.7-13.7; P = .003), whereas HCT in CR1 improved outcome (HR, 0.42; 95% CI 0.18-0.97; P = .044). Furthermore, HCT in CR1 was the only prognostic factor for overall survival (HR, 0.3; 95% CI 0.11-0.85; P = .023). ConclusionHCT at CR1 resulted in a favorable EFS and overall survival in ALL/LBL patients after hyper-CVAD frontline therapy. Given that hyper-CVAD is a widely used protocol for adult patients, further examination of this observation is warranted.

Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.

Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT. We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1. Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 (P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months). Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.

Allogeneic Hematopoietic Cell Transplantation for Adult Acute Lymphoblastic Leukemia: Significant Increase in Survival in the Post-Targeted Immunotherapy Era

Background The management of adult acute lymphoblastic leukemia (ALL) has evolved over the last five years with the FDA approval of targeted immunotherapies, routine incorporation of minimal residual disease, and uptake of the pediatric regimen in young adults. However, allogeneic hematopoietic cell transplantation (HCT) remains an important treatment modality for this population and progress has concomitantly occurred in the field of HCT. We hypothesized that a combination of these advancements would translate into significant improvements in post-HCT survival in adult ALL. Methods Successive patients >= 18 years who had undergone first allogeneic HCT for ALL at Stanford University between January 1, 2005 and January 30, 2019 were included and were categorized as Cohort 1 or Cohort 2 based upon time period of HCT: 2005-2013 vs 2014-2019, respectively. For survival analyses, patient post-HCT follow-up times in Cohort 1 were truncated to the maximum follow-up time in Cohort 2 (approximately 5 years) in order to account for differences in long-term follow-up between the cohorts. Results 308 adults (163 in Cohort 1; 145 in Cohort 2) with ALL underwent HCT. The median follow-up from HCT was 738 and 588 days in Cohorts 1 and 2, respectively. Median age was 39 years (range, 19-70) and did not differ between groups; 50-55% were men and 30-35% were Hispanic across time periods. Most patients (79-85% across time periods) received myeloablative conditioning (MAC) with a TBI-based regimen; a slight increase in non-TBI based MAC was observed in Cohort 2. Relative to Cohort 1, patients transplanted in Cohort 2 received cord blood units more frequently and were also more likely to enter HCT in CR1. The estimated six month, one, and two-year HCT outcomes are depicted in Table 1. The 2-year cumulative incidence of relapse (31% vs 25%) and TRM (23% vs 17%) were not significantly different between the two time cohorts but trended in favor of Cohort 2. Significant improvement in OS following HCT was observed in Cohort 2 (Figure 1) with estimated 2-year OS of 51% vs 70% in Cohorts 1 and 2, respectively. Conclusions In this large single center analysis of adult ALL outcomes following HCT over time, we demonstrate that OS following HCT has substantially improved since 2014, coinciding with a number of advancements in the fields of ALL and HCT. These data, if confirmed in a multi-center analysis, should provide new benchmarks for outcomes following HCT in adult ALL.

Conditioning Intensity for Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients with Poor-Prognosis Cytogenetics in First Complete Remission

The optimal intensity of conditioning regimen may be dependent on not only age and comorbidities but also disease characteristics and risk of relapse after allogeneic hematopoietic cell transplantation (HCT). We, therefore, analyzed the transplant outcomes of 840 adult patients with cytogenetically poor-risk acute myeloid leukemia (AML) in first complete remission (CR1) who received first allogeneic HCT with either myeloablative conditioning (MAC; n = 652) or reduced-intensity conditioning (RIC; n = 188) between 2006 and 2017.The median age at HCT was 50.5 years (range: 16 to 77 years). The multivariate analysis showed that patients receiving MAC had a significantly higher overall survival and lower leukemia-related mortality than those receiving RIC (P = .011 and P = .025, respectively). In the subgroup analysis, these results applied to patients aged 16 to 59 years, with HCT-comorbidity index scores ≥3, and with cytogenetic remission. Among MAC regimens, there was a trend for worse survival and nonrelapse mortality with the busulfan/fludarabine-based regimen compared with the total body irradiation (TBI) ≥8 Gy-based regimen (P = .082 and P = .062, respectively), whereas the busulfan/cyclophosphamide-based regimen and the fludarabine/melphalan-based regimen had similar outcomes with the TBI-based regimen. These data suggest that MAC is preferable to RIC for patients with cytogenetically poor-risk AML undergoing allogeneic HCT in CR1.

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Hematopoietic Cell Transplantation in Young Adult Acute Lymphoblastic Leukemia: A United States Population-Level Analysis.

In this population-based evaluation of adolescents and young adults (AYA) acute lymphoblastic leukemia (ALL), we describe patterns of care (POC) and outcomes regarding hematopoietic cell transplantation (HCT) in first complete remission (CR1). Data were abstracted from the 2013 United States Surveillance, Epidemiology, and End Results POC study; newly diagnosed AYA ALL were included. Multivariable logistic regression evaluated associations with HCT in CR1; Cox proportional hazards regression evaluated survival associations. Of 399 AYAs with ALL included, 102 (28.5%) underwent HCT in CR1. High-risk cytogenetics (odds ratio [OR] = 4.86, 95% confidence interval [CI] = 3.02-7.83) and hyper-cyclophosphamide, vincristine, adriamycin, and dexamethasone (CVAD) induction (OR = 1.84, 95% CI = 1.07-3.16) were associated with HCT in CR1. Two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI = 23.4-33.4), 69.3% (95% CI = 63.6-74.3%), and 84.1% (95% CI = 79.7-87.5), respectively. Two-year RFS was significantly higher in patients receiving CR1 HCT relative to chemotherapy (83.6%, 95% CI = 72.6-90.5% vs. 64.3%, 95% CI = 57.5-70.3), but no difference was seen in 2-year OS (88.9%, 95% CI = 80.8-93.7 vs. 82.5%, 95% CI = 77.2-86.7). Treatment at a nonteaching hospital was independently associated with inferior OS (hazard ratio = 2.15, 95% CI = 1.23-3.76). Although the ALL landscape is changing, these data provide a snapshot of the use and outcomes of HCT for AYA ALL across the United States.

Hematopoietic Cell Transplantation in First Remission Amongst Adolescent and Young Adult Acute Lymphoblastic Leukemia: A Population-Level Analysis across the United States

Background:The optimal role of allogeneic hematopoietic cell transplantation (HCT) for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) is an area of clinical debate. In this population-based evaluation of AYA ALL patients across the United States (US), we sought to describe recent patterns of care and outcomes regarding HCT in first complete remission (CR1) amongst AYAs with ALL.Methods:Data were abstracted from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Patterns of Care (POC) study focused on AYA cancers. AYAs (15-39 years) with ALL newly diagnosed between January 1, 2012 through December 31, 2013 and registered in the SEER program were included. Allogeneic HCT in CR1 was defined as occurrence of HCT without relapse/progression prior to the HCT date; HCT was considered a time-dependent variable in survival models. Multivariable logistic regression was used to evaluate associations with HCT in CR1; cox proportional hazards regression was used to evaluate associations with survival.Results:Three-hundred and ninety-nine AYAs (15-39 years) with newly diagnosed ALL between 2012-2013 were included; median follow-up for survival was 19 months (range, 0-35 months). The median age was 24 years; 85% had B-cell ALL, 27% had high risk ALL cytogenetics. One-third of AYA ALL patients received care from pediatric oncologists while two-thirds were treated by adult hematologist/oncologists; a majority (86%) received care at a teaching hospital. Fifty-eight percent received an asparaginase-containing ALL front-line regimen, 32% received hyperCVAD; 5.9% and 4.5% received another/unknown regimens, respectively. One-hundred and two (29%) AYAs underwent allogeneic HCT in CR1. Excluding patients with relapse/progression or death within three months of diagnosis (n=32), older age, high-risk ALL cytogenetics, treatment by an adult hematologist/oncologist, and front-line therapy with hyperCVAD were variables significantly associated (all P< 0.05) with increased odds of HCT in CR1 in univariate analysis, while Hispanic ethnicity and public or no/other insurance were associated with significantly lower odds of HCT in CR1. In multivariate adjusted analysis, only high-risk cytogenetics (odds ratio (OR) 4.84, 95% confidence interval (CI) 2.99-7.83) and receipt of hyperCVAD (OR 1.84, 95% CI 1.07-3.16) retained significant associations with HCT in CR1. The two-year cumulative incidence of relapse, relapse-free survival (RFS), and overall survival (OS) of the entire cohort were 28.3% (95% CI 23.4%-33.4%), 69.3% (95% CI, 63.6%-74.3%), and 84.1% (95% CI 79.7%-87.5%), respectively. Two-year cumulative incidence of relapse was significantly lower in patients receiving HCT in CR1 as opposed to those not receiving HCT in CR1 (15.1%, 95% CI 8.1%-24.1% vs 32.8%, 95% CI 26.9%-38.9%). This translated into a significant improvement in 2-year RFS (83.6%, 95% CI 72.6%-90.5% vs 64.3%, 95% CI 57.5%-70.3%), but no statistically significant differences in 2-year OS (88.9%, 95% CI 80.8%-93.7% vs 82.5%, 95% CI 77.2%-86.7%). Among all patients, receipt of care at a non-teaching hospital (hazard ratio (HR) 2.14, 95% CI 1.22-3.75) and use of another/unknown regimen (HR 9.08, 95% CI, 4.83-17.06) were significantly associated with inferior OS.Conclusions:In the US, allogeneic HCT in CR1 is most commonly administered to AYA ALL with high risk cytogenetics and as consolidation therapy for those who receive front-line hyperCVAD, as opposed to asparaginase-containing ALL regimens. Consistent with prior studies, AYA ALL patients treated at non-teaching hospitals have inferior survival. Although the landscape of ALL therapy is changing, these data provide an important snapshot of the modern state of HCT in CR1 for AYA ALL. DisclosuresMuffly:Shire Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding.

Hematopoietic Cell Transplantation for Children with Acute Megakaryoblastic Leukemia without Down Syndrome

Abstract Acute megakaryoblastic leukemia (AMKL) accounts for 10% of childhood acute myeloid leukemia. Although AMKL patients with Down syndrome (DS-AMKL) have an excellent survival rate, patients with non-DS-AMKL experience poor outcomes. Despite therapeutic advances, including use of intensified treatment protocols, there is no consensus on the optimal treatment strategy for non-DS-AMKL. Some study groups recommend hematopoietic cell transplantation (HCT) for patients with non-DS-AMKL in the first complete remission (CR1); however, it is unclear whether HCT in CR1 improves outcomes of these patients. To assess outcomes and risk factors of HCT for patients with non-DS-AMKL, we retrospectively analyzed 203 patients with non-DS-AMKL (male, 95; female, 108) who underwent first HCT between 1986 and 2015 using data from the Japan Society for Hematopoietic Cell Transplantation. The median age at the time of HCT was 2 years (range, 0-16). Out of 203 patients, 12 had translocation t(1;22)(p13;q13), 18 had monosomy 7, 21 had complex karyotype, and 109 had other chromosomal abnormalities. Bone marrow transplantation (BMT) was performed for 114, cord blood transplantation (CBT) for 74, and peripheral blood stem cell transplantation (PBSCT) for 15 patients. Seventy-eight patients underwent HCT from related (HLA-matched, 43; HLA-mismatched, 35), 108 from unrelated (HLA-matched, 56; HLA-mismatched, 52), and 17 from autologous donors. Ninety-two patients underwent HCT in CR1, 21 in the second CR (CR2), and 90 in non-CR. Myeloablative conditioning (MAC) regimen was defined as the use of total body irradiation (TBI) ≥8 Gy, administration of busulfan &gt;8 mg/kg or melphalan &gt;140 mg/m2. All other regimens were included in reduced intensity conditioning (RIC) regimen. MAC regimen was used for 192 and RIC regimen for 11 patients. Median duration of follow-up after HCT was 713 days (range, 3-10008). Out of 203 patients, 183 (90%) exhibited engraftment. Sixteen out of 20 patients who did not exhibit engraftment underwent HCT in non-CR. In the entire cohort, 5-year overall survival (OS) and event free survival (EFS) rates were 43% and 38%, respectively. Seventy-two patients died of disease relapse and 42 died of transplantation-related complications. Five-year OS/EFS rates were not significantly different between BMT (48%/43%), CBT (35%/31%), and PBSCT (31%/27%) (p = 0.221/p = 0.087). In allogeneic HCT, 5-year OS/EFS rates were significantly lower in patients who underwent HCT from HLA-mismatched donors (27%/22%) than those from HLA-matched donors (52%/47%) (p &lt; 0.001/p &lt; 0.001). Five-year cumulative incidence (CI) of relapse after HLA-mismatched HCT (64%) was significantly higher than that after HLA-matched HCT (45%) (p = 0.006). Five-year OS/EFS rates were not significantly different between patients with translocation t(1;22)(p13;q13) (50%/42%), those with monosomy 7 (65%/59%), and those with complex karyotype (61%/52%) (p = 0.094/p = 0.111). Five-year OS/EFS rates of patients who underwent HCT in CR1 (72%/64%) were significantly higher than those of patients who underwent in CR2 (23%/13%) and non-CR (16%/16%) (p &lt; 0.001/p &lt; 0.001). Five-year CI of relapse was significantly lower in CR1 (28%) than in CR2 (73%) and non-CR (73%) (p &lt; 0.001). Five-year non-relapse mortality was significantly higher in non-CR (27%) than in CR1 (15%) and CR2 (14%) (p = 0.022). Among the 92 patients who underwent HCT in CR1, 3-year CI of relapse in patients who received RIC (67%) was significantly higher than that in patients who received MAC regimen (25%) (p = 0.021). Five-year OS/EFS rates associated with HCT from HLA-mismatched (70%/63%) and HLA-matched donors (77%/59%) were not significantly different (p = 0.609/p = 0.761). In the multivariate analysis for 5-year OS, HCT in CR2 and non-CR was found to be a significant risk factor (hazard ratio, 5.16; 95% CI, 3.36-7.92; p &lt; 0.001). In conclusion, multivariate analysis confirmed that HCT in CR1 was a good prognostic factor for 5-year OS. Risk stratification in patients with non-DS-AMKL should be established to determine the indication for HCT in CR1. Disclosures No relevant conflicts of interest to declare.

Genetic Characteristics and Long-Term Outcomes of Korean Adult Patients with Ph-like Acute Lymphoblastic Leukemia Versus Non-Ph-like Acute Lymphoblastic Leukemia

Background: Recently, a high-risk subgroup of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) called Philadelphia chromosome (Ph)-like ALL was identified in adolescents and young adults. However, there are conflicting data regarding the incidence and prognosis of Ph-like ALL in adult patients, and no data have yet been introduced in Asian countries.Aim: We tried to identify the prevalence and genetic characteristics of Ph-like ALL in adult patients with newly diagnosed BCP-ALL. Furthermore, we analyzed the clinical characteristics, long-term outcomes, and prognostic impact of Ph-like ALL compared with non-Ph-like ALL (Ph-positive ALL or BCP-other ALL).Methods: Between December 2008 and March 2016, 334 adult patients with newly diagnosed BCP-ALL who received modified hyper-CVAD chemotherapy and had suitable material for genomic analysis were included in this analysis (median age, 43 years [range, 16-65 years]). Our post-remission therapy was based on allogeneic hematopoietic cell transplantation (HCT) if a donor is available. Ph-like ALL was determined by next generation sequencing using the Archer® FusionPlex® ALL Kit (ArcherDX Inc., CO) which can detect fusions, point mutations, and expression levels in 81 genes associated with ALL and additional FISH analysis was done.Results: Overall, 48 (14.4%) of the 334 patients were Ph-like ALL, and the cohort was divided into patients with ABL1-class rearrangements (n=4), CRLF2 rearrangements (n=11), JAK2 rearrangements (n=4), other JAK-STAT sequence mutations (n=12), and RAS mutations (n=17). The remaining 286 patients had Ph-positive ALL (n=197) and BCP-other ALL (n=89; including 19 patients with KMT2A [MLL] rearrangements). No significant differences in baseline characteristics were observed between the Ph-like ALL and BCP-other ALL subgroups, whereas patients with Ph-positive ALL were older (median age, 47 vs 37 years; p=0.003) and had higher presenting leukocyte counts (median, 33.1 vs 11.4´109/L; p=0.001) compared with Ph-like ALL. The complete remission rate was somewhat different between the 3 disease subgroups (Ph-like ALL, 97.9%; Ph-positive ALL, 95.9%; BCP-other ALL, 88.8%; p=0.027). A higher proportion of patients with Ph-like ALL actually received allogeneic HCT in CR1 than patients with non-Ph-like ALL (Ph-like ALL, 91.6%; Ph-positive ALL, 84.2%; BCP-other ALL, 71.9%; p=0.007). With a median follow-up of 58.1 months (range; 6.0-121.0), outcomes of patients with Ph-like ALL were not inferior compared with outcomes of patients with non-Ph-like ALL. Disease-free survival rates at 5 years were 56.0% for Ph-like ALL, 42.6% for Ph-positive ALL, and 40.6% for BCP-other ALL (p=0.138). The 5-year cumulative incidence of relapse were 19.2% for Ph-like ALL, 35.3% for Ph-positive ALL, and 33.5% for BCP-other ALL (p=0.076). These findings were maintained when only patients receiving HCT were considered. Within the Ph-like ALL subgroup, patients with ABL1-class and CRLF2-rearrangements had worse outcomes than patients with other JAK-STAT sequence and RAS mutations. Also, patients with higher CRLF2 expression had inferior outcomes.Conclusion: Within the limitation of sample size, our data showed a different frequency of subtypes (e.g., lower incidence of CRLF2 rearrangements, higher RAS mutations) and treatment outcomes of adult patients with Ph-like ALL compared with other Western reports. Racial and ethnic differences in the patient population studied may have contributed to these differences. We also suggest that HCT-based post-remission therapy may overcome the poor prognosis of Ph-like ALL. DisclosuresKim:BMS: Research Funding; Ilyang: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding.

Adults with Philadelphia Chromosome–Like Acute Lymphoblastic Leukemia: Considerations for Allogeneic Hematopoietic Cell Transplantation in First Complete Remission

Philadelphia chromosome–like (Ph-like) acute lymphoblastic leukemia (ALL) is a subset of high-risk B cell ALLs. A large proportion of Ph-like ALL cases carry activating kinase mutations that could potentially allow them to be targeted by tyrosine kinase inhibitors. Ph-like ALL is not an uncommon entity, especially among adults, with a frequency exceeding 20%, including in older patients (>60 years old) with ALL. Ph-like ALL is associated with inferior outcomes across all ages, and studies have consistently shown a higher incidence of persistent postinduction minimal residual disease in patients carrying Ph-like ALL compared with other subgroups of ALL, and this translates into inferior leukemia-related outcomes. The inferior outcome of conventional chemotherapy for Ph-like ALL in adults raises the fundamental question of whether all adults with Ph-like ALL require an allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) regardless of other presenting features and treatment response parameters. Here we present and discuss several scenarios in which adults with Ph-like ALL underwent or were considered for HCT in CR1 for various reasons. Although the decision to proceed with HCT was clear and indisputable in some of these situations, in others we struggled with the decision to transplant in CR1 because of the lack of published data regarding the efficacy of allogeneic HCT as consolidation for Ph-like ALL. We emphasize the urgent need for developing well-designed studies to address this important question.

Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1

Allogeneic Transplantation for Acute Myelogenous Leukemia in CR1

Outcomes of UCB transplantation are comparable in FLT3+ AML: results of CIBMTR, EUROCORD and EBMT collaborative analysis.

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FLT3+ acute myeloid leukemia (AML) that has poor prognosis due to high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126), (HR 0.86, p=0.54) and URD (n=91) (HR 0.81, p=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, p=0.02), but not vs. URD (HR 1.72, p=0.07). All three cohorts had statistically not significant 3-year LFS: 39% (95% CI 30–47) after UCB, 43% (95% CI 30–54) after sibling, and 50% (95% CI 40–60) after URD. Chronic GVHD rates were significantly lower after UCB compared with either sibling (HR 0.59, p=0.03) or URD (HR 0.49, p=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2. UCB is a suitable option for adults with FLT3+AML in the absence of an HLA-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common thus allowing HCT in CR1 when outcomes are best.

Phase I/II Study on Cytarabine and Idarubicin Combined with Escalating Doses of Clofarabine in Untreated Patients with Acute Myeloid Leukemia and High Risk for Induction Failure (AMLSG 17-10 CIARA)

Background: Clofarabine is a second-generation purine nucleoside analogue, which has shown synergistic activity with cytarabine. We determined the maximum tolerated dose (MTD, primary endpoint), safety and efficacy (secondary endpoints) of clofarabine in combination with cytarabine and idarubicin in newly diagnosed acute myeloid leukemia (AML) patients with high-risk for induction failure stratified in two age groups (< 60 years and ≥ 60 years).Methods: In this prospective, open-label, multicenter phase I/II study (EudraCT 2010-021719-18, CIARA trial), newly diagnosed AML patients with high risk of induction failure (NPM1 wildtype, FLT3-ITD negative), who were eligible for intensive chemotherapy, received two induction courses (cytarabine 750 mg/m2 d1-5, idarubicin 7.5 mg/m2 in patients <60 years or 6 mg/m2 in patients ≥60 years d1+3) with increasing doses of clofarabine (20-35 mg/m2 d1-5) following a 3+3 design with extension cohorts. Consolidation consisted of up to 3 courses of high-dose cytarabine or allogeneic hematopoietic cell transplantation (HCT).Results: Forty-two patients with de novo (n=32) or secondary (n=10) AML were included. Median age was 58.5 years (range 28-73, 24 patients < 60 years, 18 patients ≥ 60 years). Intermediate/adverse risk cytogenetics were found in 22 and 12 patients, respectively (karyotype missing in 8 patients). All patients received induction 1, 27 (64%) received induction 2; 4 (10%) patients died during induction courses 1 or 2. Eight patients developed a dose-limiting toxicity (6 patients with grade 3/4 non-hematologic toxicity and 3 patients with grade 4/5 hematologic toxicity) and the MTD was determined at 30 mg/m2 clofarabine for both age cohorts (younger patients: 2 of 6 patients with DLT at 35 mg/m2, no DLT at 30 mg/m2 (n=9); older patients: 4 of 6 patients with DLT at 35 mg/m2 in the extension phase, no DLT at 30 mg/m2 (n=3). The most frequent grade 3-5 non-hematologic adverse events were febrile neutropenia, sepsis, increased liver enzymes, pneumonia, decreased appetite and diarrhea occurring in 55, 24, 21, 21, 10 and 10% of patients. The median time to neutrophils ≥0.5/nl and platelets ≥50/nl after induction 1 was 25 and 24 days, respectively. Sixteen patients (38%) proceeded to allogeneic HCT in first CR and 8 (19%) received at least one course of high-dose cytarabine consolidation.Complete remission (CR) or CR with incomplete recovery (CRi) was achieved in 67%. After a median follow up of 2.2 years the 2-year overall survival (OS) was 56% and the 2-year event-free survival was 38% (median EFS 11.4 months). Compared to a matched historical control of 197 younger AML patients (SHG 0199 trial, Schlenk et al. NEJM 2008), the CR rate was 79% in the 24 younger CIARA patients compared to 66% in the control cohort (P=.18), and 2-year OS was higher for CIARA than for control patients (74% vs 49%, P=.021, Figure A). The allogeneic HCT rate in first CR (CR1) was higher in younger CIARA compared to younger control patients (58% vs 27%, P=.002). The CR rate in older CIARA patients was 50% compared to 36% in a historical control of 191 older patients, who were selected using the same genetic inclusion criteria as for CIARA patients (HD98B trial, Schlenk et al. Haematologica 2009, P=.23). Two-year OS in older patients was similar between CIARA and control patients (33% vs 17%, P=.31, Figure B). The allogeneic HCT rate in CR1 was 11% vs 2% in CIARA vs control patients (P=.029).Conclusion: Clofarabine can be safely administered at 30 mg/m2 in combination with cytarabine and idarubicin in younger and older newly diagnosed AML patients. Allogeneic HCT in CR1 was feasible in a high proportion of younger AML patients and likely contributed to the favorable outcome compared to historical control patients. [Display omitted] DisclosuresKrauter:Genzyme: Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding. Paschka:Novartis: Consultancy; Medupdate GmbH: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer Pharma GmbH: Honoraria; Celgene: Honoraria; ASTEX Pharmaceuticals: Consultancy. Lübbert:Ratiopharm: Other: Study drug valproic acid; Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding. Janning:Teva: Honoraria. Becker:BMS: Honoraria; Novartis: Honoraria. Heuser:Tetralogic: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Pfizer: Research Funding; Bayer Pharma AG: Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding.