Transplantation In Complete Remission Research Articles

Olverembatinib (HQP1351) Combined with Chemotherapy Is an Effective and Safe Treatment in Patients with Philadelphia Chromosome-Positive (Ph +) Acute Lymphoblastic Leukemia (ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CML-LBP) That Failed TKI-Based Regimens

Background The prognosis of relapsed or refractory (R/R) Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL) and TKI-resistant chronic myeloid leukemia in lymphoid blast phase (CML-LBP) remains poor, with lower rates of complete remission (CR) and shorter durations of response. Olverembatinib is a novel third-generation tyrosine kinase inhibitor (TKI) that has been demonstrated to effectively target a wide range of BCR::ABL1 kinase mutations, especially T315I, in patients with CML in the chronic or accelerated phase resistant to either imatinib or second-generation TKIs. However, data on olverembatinib-based regimens in R/R Ph+ ALL and CML-LBP are limited. Here, we report the efficacy and safety of olverembatinib, combined with chemotherapy, in patients with Ph+ ALL or CML-LBP that failed prior TKI-based therapies. Methods A retrospective study was conducted in adults with Ph + ALL or CML-LBP who failed imatinib- or second-generation TKI-based chemotherapy and subsequently received olverembatinib-based chemotherapy. Per NCCN 2023 guidelines: refractory disease was defined as CR not achieved at the end of induction; relapsed disease, reappearance of blasts in the blood or bone marrow (> 5%) or any extramedullary site after CR; molecular resistance, persistent or rising BCR::ABL1 transcript (> 1-log) by real-time quantitative polymerase chain reaction (RT-qPCR); and complete molecular response (CMR), BCR::ABL1 transcript < 0.01% by RT-qPCR. The primary endpoints of this study were CR rates in R/R patients and CMR rates in molecular-resistant patients. Results From February 2022 to May 2023, 31 patients were included in this study, including 24 (77%) with TKI-based chemotherapy-failed Ph + ALL; 7 (23%) with TKI-resistant CML-LBP; 15 (48%) with R/R disease; and 16 (52%) with molecular-resistant disease. A total of 17 (57%) patients were male, and the median (range; IQR) age was 46 (20-72; 30-64) years. Among 30 patients screened for BCR::ABL1 kinase domain mutations before administration of olverembatinib, 6 (19%) had no mutations; 15 (48%) had T315I; and 9 (29%) had other mutations, including E255K (n = 2), G250E(n = 2), D241E (n = 1), Y253H (n = 1), F317L (n = 1), F359C(n = 1), and Y253Fplus M351T (n = 1). The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth). A total of 13 (86%) patients achieved CR after 4-week induction therapy. At a median (IQR) follow-up of 8 (4-13) months, 5 patients received allogeneic transplantation in CR, and were alive in CMR. A total of 8 patients received olverembatinib-based consolidation chemotherapy of either VP (n = 4) or hyper-CVAD (n = 4) after achieving CR. Six patients relapsed, of whom 4 died, and 1 remained in CMR. The 1-year relapse-free survival (RFS) and 1-year survival rates were 52% (95% CI, 21-83) and 68% (95% CI, 37-98), respectively. Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation. At a median (IQR) follow-up of 9 (5-11) months, 1 of the patients receiving olverembatinib monotherapy progressed to hematologic relapse and was switched to CAR T-cell therapy; the other patient did not achieve CMR and underwent transplantation. Of the 14 patients receiving olverembatinib plus chemotherapy, 7 (50%) achieved CMR and 3 (21.4%) progressed to relapse, of whom 1 had hematological relapse and 2 developed central nervous system leukemia (CNSL) with bone marrow remission. A total of 7 patients received allogeneic transplantation, of whom 3 achieved and 4 did not achieve CMR before transplantation. After transplantation, all the 7 patients were in CMR except one who developed CNSL. The 1-year RFS and survival rates were 67% (95% CI, 42-91) and 93% (95% CI, 79-100), respectively. Among all patients, hematologic adverse events were readily manageable. Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

Heterogeneous Gene Fusion Transcripts Found in t(7;12)(q36;p13) Acute Myeloid Leukemia but with Similar Gene Expression Profile

Cytogenetic aberrations are often involved in acute myeloid leukemia (AML) and can serve as diagnostic markers, prognosis predictors and impact the choice of therapy. A translocation t(7;12)(q36;p13) is reported in up to 20-30% of AML patients typically diagnosed before 24 months of age (Beverloo, Panagopoulos et al. 2001, Cancer Res 61(14): 5374-5377). However, in a retrospective survey of the Nordic Organization of Pediatric Hematology and Oncology (NOPHO) registry, only 4% of reported AML diagnosed before 24 months of age had t(7;12) (Espersen, Noren-Nystrom et al. 2018, Genes Chromosomes Cancer 57(7): 359-365). The t(7;12) is difficult to identify with conventional karyotyping, why the true frequency of t(7;12) may be underestimated. Similarly, the reported prognosis for t(7;12) patients has varied ranging from good (Espersen, Noren-Nystrom et al. 2018) to dismal (von Bergh, van Drunen et al. 2006, Genes Chromosomes Cancer 45(8): 731-739). The translocation has been reported to give rise to an in-frame fusion transcript, MNX1::ETV6. However, detection of this fusion is reported only in 50% of cases in contrast to high expression of MNX1 in 100% (von Bergh, van Drunen et al. 2006). The aim of this study was to determine the frequency of the t(7;12) in pediatric AML patients in the NOPHO AML-2004/2012 protocols, their event-free and overall survival and to investigate the presence of additional genetic alterations. Patients in Sweden, Denmark, or Iceland between 2004 to 2020 diagnosed with AML before 2 years of age that had not been reported with a recurrent genetic aberration plus all patients diagnosed with t(7;12) AML were identified. Bone marrow, or peripheral blood samples from patients were retrieved from the NOPHO biobank. This cohort constituted 86% (31 out of 36) of all patients that fulfilled these criteria. In total 89 AML patients were diagnosed before 2 years of age. The t(7;12) AML cases were identified by screening for high expression of MNX1 and presence of fusion transcripts using whole transcriptome sequencing (WTS). Whole genome sequencing (WGS) was done to identify chromosomal rearrangements, and translocation breakpoints. At diagnosis, four patients were diagnosed with t(7;12). A central karyotype review of all patients reported two additional cases. No further cases were identified using WTS. Thus, the frequency of t(7;12) AML was 7% (6 out of 89) and for patients diagnosed before 12 months of age 11% (5 out of 47). In total 12 cases with t(7;12) were identified in the complete NOPHO registry but only 11 patients received treatment according to NOPHO protocol. The relapse rate was 54% (6 out of 11). All relapse cases underwent allogeneic hematopoietic stem cell (HSC) transplantation in complete remission two (CR2), and their overall survival (OS) was 83% (5 out of 6). Hence OS for all t(7;12) patients treated according to the NOPHO2004 and NOPHO2012 protocols was 91% (10 out of 11). Analysis of WTS data showed similar gene expression profile between our t(7;12) cases and t(7;12) cases retrieved from the TARGET database. Genes that were typically overexpressed in all t(7;12) AML were, MNX1, MNX1-AS1, MNX1-AS2, LIN28B, BAMBI, MAF, CRISP3, EDIL3, CTTNBP2, KRT72, and AGR2, where MNX1 seems to be uniquely expressed in this type of leukemia (Nilsson et al. 2022, Int J Cancer 151(5): 770-782). Analysis of fusion transcripts showed presence of MNX1::ETV6 in just one case. The remaining cases instead showed presence of other fusion transcripts involving ETV6, NOM1::ETV6, ETV6::NOM1, ETV6::LMBR1 and ETV6::BMAL2. WGS verified a fusion between NOM1 and ETV6 in 3 cases. The patient with ETV6::BMAL2 showed that 16 Mb of chromosome 12 was inserted into chromosome 7 placing a large part of ETV6 near MNX1. The fusion transcript ETV6::BMAL2 is the product of what remains on chromosome 12. In conclusion, frequency of t(7;12) AML in the NOPHO treatment cohort was approximately 7%, with 54% relapse rate, but most patients were salvaged by HSCT in CR2. Heterogeneous gene fusion transcripts were identified in this subgroup of AML where ETV6::NOM1 was most frequent. However, all cases showed similar gene expression signatures which underlines that the leukemia driving event is ectopic expression of MNX1 (Waraky, A., 2023, Haematologica, DOI: 10.3324/haematol.2022.282255) and should therefore be the defining classifying criteria of this type of AML.

Impact of Inotuzumb Ozogamicin on Outcome in Relapsed or Refractory Acute B-Lymphoblastic Leukemia Patients Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Background: The outcome of patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) is poor. At present, allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative option for patients with r/r B-ALL with best outcomes achieved after effective salvage re-induction therapy and transplantation in complete remission (CR). Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allo-HCT. Inotuzumab ozogamicin (INO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, developed as a targeted therapy for B-cell malignancies. Rate of VOD/SOS is increased after therapy with INO. Aims: To characterize a series of relapsed/refractory (r/r) ALL patients (pts) and evaluate outcome after treatment with INO prior to allo-HCT, particularly with respect to risk of VOD/SOS. Methods: We studied 25 r/r pts (median age, 34 years; range, 16-64 years), who were treated with INO between 2016 and 2022 within a compassionate use program (n=7) or in-label after EMA approval (n=18) One of the 25 pts were previously treated with tyrosine kinase inhibitors for chronic myeloid leukemia and progressed to blast crisis of B-lymphoid lineage. All 25 pts were CD22 positive at relapse/progressive disease. Up to 4 INO cycles (≤2 cycles, n=22; 3-4 cycles, n=3) were administered according to the previously approved regimen. Results: At the time of r/r B-ALL median white blood cell and platelet counts were 47.1/nl (range, 1.3-300/nl) and 33.5/nl (range, 5-313/nl), respectively. Five pts (20%) were female; ECOG was ≤ 2 in all pts. Cytogenetic analysis at the time of r/r EM-ALL was available in 14 pts. Six pts displayed a t(9;22), 6 had a normal karyotype, 1 was complex and 1 had a deletion 6q as well as trisomy 13. Seventeen (68%) patients achieved CR after the first INO cycle. Prior to allo-HCT, 17 (68%) pts achieved CR, 3 (12%) a partial remission, 4 (16%) were refractory and one (4%) relapsed after CR achievement. Median follow-up was 41.6 months (95%-CI, 31.1-NR) and median overall survival (OS) was 9.0 months (95%-CI, 5.78-RD months; Figure 1). One- and two-years OS rates were 45.2% (95%-CI, 28.8-70.8%) and 40.7% (95%-CI, 24.8-66.7%), respectively. VOD/SOS after allo-HCT occurred in 7 (28%) pts. Of those, 5 pts died due to VOD and multi-organ failure, all had received ≤2 INO cycles. Risk factor for VOD/SOS was allo-HCT during first-line therapy (p=0.05), whereas age, gender, donor, dose intensity of conditioning or remission status before allo-HCT had no impact. Relapse/progressive disease occurred in eight (32%) pts and all pts succumbed of their disease. Cumulative incidences of relapse/progression or death after 12 months were 20.7% (standard error,E 8.5%) and 32.7% (standard error, 9.8%). Eight (32%) pts died in remission and nine (36%) pts are in ongoing CR. Conclusions: This outcome analysis demonstrates that treatment with INO is an effective approach with successful bridge-to-transplant. However, risk of VOD/SOS is high, necessitating continuous monitoring and recognition of VOD/SOS risk factors.

Myeloablative conditioning regimens in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation in complete remission: a systematic review and network meta-analysis.

The optimal myeloablative conditioning (MAC) regimens in adult patients with acute myeloid leukemia (AML) undergoing allogeneic hemopoietic stem cell transplantation (allo-HSCT) in complete remission (CR) remain unclear. We performed a systematic review and network meta-analysis to compare the effects of different MAC regimens. Bayesian network meta-analysis was performed using WinBUGS version 1.4.3. The commonly used MAC regimen Bu/Cy (4-day busulfan for toal 16 mg/kg orally or 12.8 mg/kg intravenously, plus 2-day cyclophosphamide for toal 120 mg/kg intravenously) is chosen as the common comparator. Pooled hazard ratios (HRs) with the associated 95% credibility interval (95% CrI) are obtained for all comparisons. We included 19 eligible studies, involving 8104 AML patients and 9 MAC regimens. Compared with Bu/Cy, 3-day busulfan plus fludarabine and thiotepa (Bu3/Flu/TT) is associated with significantly better overall survival (HR, 0.70; 95% CrI, 0.51 to 0.96) and lower risk of relapse (HR, 0.59; 95% CrI, 0.35 to 0.98). Bu3/Flu/TT is also associated with superior overall survival than Cy/TBI (cyclophosphamide plus total body irradiation), and lower risk of relapse than Bu4/Flu (4-day busulfan plus fludarabine). These results suggest that thiotepa-based new MAC regimen Bu3/Flu/TT is associated with improved outcomes in AML patients undergoing allo-HSCT in CR and worth further investigation.

Allogeneic Hematopoietic Cell Transplantation for Patients with Relapsed Acute Promyelocytic Leukemia

Although autologous hematopoietic cell transplantation (HCT) is an established therapy for patients with relapsed acute promyelocytic leukemia (APL) after returning to complete remission (CR), the role of allogeneic HCT remains unclear for treating relapsed APL. This study aimed to investigate allogeneic HCT outcomes in patients with relapsed APL, focusing particularly on those who underwent transplantation in non-CR and those who had relapsed after prior autologous HCT. We retrospectively analyzed Japanese nationwide transplantation registry data of patients with relapsed APL age ≥16 years who underwent allogeneic HCT between 2006 and 2020. A total of 195 patients were eligible for this analysis, including 69 who underwent transplantation in non-CR and 55 who relapsed after prior autologous HCT. The median duration of follow-up for survivors was 5.4 years. Multivariate analysis revealed that both non-CR at transplantation (hazard ratio [HR], 1.74; 95% confidence interval [CI], 1.12 to 2.71; P=.014) and prior autologous HCT (HR, 2.10; 95% CI, 1.28 to 3.44; P=.013) were associated with higher risks of overall mortality. The 5-year overall survival (OS) rates for patients who underwent transplantation in CR and non-CR were 58% and 39%, respectively (P=.085), if they did not have a history of prior autologous HCT. In the patients who had relapsed after prior autologous HCT, the 5-year OS rate was 47% for those who underwent allogeneic HCT in CR and 6% for those who did so in non-CR (P=.001). Allogeneic HCT still provides an opportunity for long-term survival for certain patients with relapsed APL for whom autologous HCT is unlikely to be effective. The dismal outcome of those with prior autologous HCT who underwent allogeneic HCT in non-CR poses a significant therapeutic challenge.

Should anti-thymocyte globulin be added in post-transplant cyclophosphamide based matched unrelated donor peripheral blood stem cell transplantation for acute myeloid leukemia? A study on behalf of the Acute Leukemia Working Party of the EBMT.

In this registry-based study which includes acute myeloid leukemia patients who underwent a matched unrelated donor allogeneic peripheral-blood stem cell transplantation in complete remission and received post-transplant cyclophosphamide (PTCY) as graft-versus-host disease (GvHD) prophylaxis, we compared 421 recipients without anti-thymocyte globulin (ATG) with 151 patients with ATG. The only significant differences between PTCY and PTCY + ATG cohorts were the median year of transplant and the follow-up period (2017 vs 2015 and 19.6 vs 31.1 months, respectively, p < 0.0001). Overall, 2-year survival was 69.9% vs 67.1% in PTCY and PTCY + ATG, respectively, with deaths related to relapse (39% vs 43.5%), infection (21.9% vs 23.9%) or GvHD (17.1% vs 17.4%) not differing between groups. On univariate comparison, a significantly lower rate of extensive chronic GvHD was found when ATG was added (9.9% vs 21%, p = 0.029), a finding which was not confirmed in the multivariate analysis. The Cox-model showed no difference between PTCY + ATG and PTCY alone with respect to acute and chronic GvHD of all grades, non-relapse mortality, relapse, leukemia-free survival, overall survival, and GvHD-free-relapse-free survival between study cohorts. Our results highlight that the addition of ATG in PTCY does not provide any extra benefit in terms of further GvHD reduction, better GRFS or better survival.

Haploidentical Stem Cell Transplantation in Patients with Myelodysplastic Syndrome: Case Report First Experience

&#x0D; BACKGROUND: Allogeneic stem cell transplantation (ASCT) is a potentially curative therapeutic approach in patients with intermediate and high-risk myelodysplastic syndrome (MDS). If a family sibling or unrelated donor is not available mismatched donors are viable option for young patients with no comorbidities. The aim of this case presentation was to evaluate our first experience with haploidentical transplantation for this indication.&#x0D; CASE PRESENTATION: We present a case of 50 years male patient with myelodysplastic syndrome (MDS) diagnosed at University Clinic for hematology, Skopje, North Macedonia. Patient was scored in IPSS -R as high risk patient. He was referred for HLA DNA typing of family siblings and since he didn’t have identical sibling and unrelated donor, he was referred to continue treatment with haploidentical stem cell transplantation. He received Flu Bu conditioning and PTCY, cyclosporine and MMF for GVHD prophylaxis. Peripheral blood stem cells (PBSC) from his mismatched brother were infused in the amount of CD34=5.8x106/kg. He experienced prolonged engraftment, severe infective bacterial infections and CMV reactivation with clinical manifestation of CMV colitis. He was successfully treated with antiviral drug and completely resolved. His bone marrow analysis showed complete remission and chimerism evaluation revealed high donor engraftment. Patient is now +34 months post transplant in complete remission.&#x0D; CONCLUSION: The use of a mismatched donor increases the risk of NRM, but there is also evidence to suggest that an haploidentical donor is a valid choice, as general outcome appears to be at least similar to MUD.

Prognostic Impact of Clonal Hematopoiesis in Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is defined as presence of hematologic malignancy-associated mutations, e.g. in the genes DNMT3A, TET2, ASXL1, but absence of hematologic neoplasms & is a frequent phenomenon in healthy individuals with increasing age. Some individuals with CHIP eventually develop acute myeloid leukemia (AML) & persistent clonal hematopoiesis-associated mutations (CH-mutations) in complete remission (CR) may give rise to relapse. To date in AML little is known about the biological & clinical implications of the presence of CH-mutations in CR, especially in the context of allogeneic hematopoietic stem cell transplantation (HSCT).Patients & Methods: We analyzed peripheral blood samples of 113 AML patients (median age 63.6 years, range 31.9-75.8 years) in CR (CR1 61.9%, CR2 14.2%) or CR with incomplete peripheral recovery (CRi; 23.9%) for the presence of CH-mutations by targeted amplicon sequencing (mean amplicon coverage per sample 7205x) prior to HSCT. Genes evaluated for somatic CH-mutations based on database entries (dbSNP & COSMIC) & with a variant allele frequency (VAF) of ≥3% were DNMT3A, TET2, ASXL1, SRSF2, SF3B1, IDH1, IDH2, JAK2, PPM1D, &IKZF1 . Codon 646 ASXL1 mutations were validated using proof-reading polymerase Sanger sequencing. For 76 patients (67.3%) diagnostic bone marrow samples were available for applying a targeted amplicon panel comprising 54 recurrently mutated genes in myeloid malignancies (mean amplicon coverage per sample 8624x). At diagnosis, mutations in the genes NPM1, CEBPA, presence of FLT3 -ITD, & cytogenetics were determined using standard techniques. All patients received HSCT after non-myeloablative conditioning at our institution between 2001 & 2015. Samples were collected within 30 days before HSCT. Median follow-up for patients alive was 4.4 years after HSCT.Results: We identified 70 CH-mutations present in CR/CRi in 48 AML patients (42.5%) with a mean VAF of 19.1% (58.6% of mutations with VAF>10%). The genes DNMT3A (31.4%), TET2 (28.6%) &ASXL1 (14.3%) were found mutated most frequently. We observed no associations between present CH-mutations in CR/CRi & clinical characteristics, except that patients with ≥1 CH-mutation were more often transplanted in CR2 compared to patients without CH-mutation by trend (20.8% vs 9.2%, P=0.10). The presence of ≥1 CH-mutation in CR/CRi did not impact leukemia-free survival (LFS; P=0.95, Figure 1A) or OS (P=0.37, Figure 1B), whereas patients with ≥2 CH-mutations had longer LFS (P=0.02, Figure 1C) & OS (P=0.007, Figure 1D) compared to patients with no or 1 CH-mutation. In CR/CRi DNMT3A mutations did not impact LFS (P=0.73) or OS (P=0.71), the presence of TET2 mutations did not influence LFS (P=0.25) but associated with longer OS (P=0.06) &ASXL1 mutations associated with longer LFS (P=0.11) & OS (P=0.13) by trend. At diagnosis, we identified 83 CH-mutations in 56/76 AML patients (73.7%) of which 29 (34.9%) persisted in 19/76 patients (25.0%) in CR/CRi. Mutations in the genes JAK2 (80.0%), SRSF2 (57.1%) &DNMT3A (50.0%) were most likely to persist. We identified 9 CH-mutations (3 DNMT3A, 3 TET2, 2 ASXL1, 1 SF3B1 mutation) in CR/CRi in 8 patients (10.5%), which were not detectable at diagnosis, possibly following the expansion of subclones under chemotherapy selection pressure. Whether patients had persistent, newly detected or lost CH-mutation in CR/CRi did not impact LFS (P=0.22) or OS (P=0.83).Conclusion: In AML patients in CR/CRi CH-mutations are frequently present (42.5%) & show high VAFs (mean 19.1%) indicating presence of clonal hematopoiesis. Compared to diagnosis 34.9% of CH-mutations persisted in CR/CRi. 10.5% of patients had CH-mutations only detectable in CR/CRi prior to HSCT. While we did not observe a negative prognostic impact of presence of ≥1 CH-mutation in CR/CRi, the presence of distinct mutations (TET2, ASXL1) may positively influence outcome. Patients with ≥2 CH-mutations had longer LFS & OS. This finding may be explained by an increased immunogenic potential with higher number of CH-mutations leading to potent graft vs leukemia effects in the HSCT context. [Display omitted] DisclosuresLange:Novartis: Honoraria, Research Funding. Franke:Takeda: Consultancy; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. Schwind:Novartis: Consultancy.

Prognostic Significance of Cytogenetic Abnormalities in Patients with Philadelphia-Negative ALL Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission: A CIBMTR Analysis

▪Background: Several cytogenetic risk stratifications have been developed and used as prognostic tools at diagnosis of acute lymphoblastic leukemia (ALL). However, most prior studies on the prognostic significance of ALL karyotyping were influenced by inclusion of Philadelphia-positive (Ph+) patients and those treated predominantly with conventional chemotherapies. The application of existing cytogenetic risk schemas to recipients of allogeneic hematopoietic cell transplantation (alloHCT) with Ph-negative (Ph-) ALL remains elusive because of the relatively low frequencies of individual Ph- abnormalities and modest population samples of prior studies.Patients and Methods: In this large international cohort (N=1731; 256 transplant centers from 38 countries) of adult Ph- ALL recipients of alloHCT (1995-2011), we examined the prognostic impact of individual cytogenetic abnormalities together with major established cytogenetic risk classifications (MRC-ECOG, modified MRC, SWOG, NILG-ALL, North UK, and GIMEMA 0496) on clinical outcomes after alloHCT. Abnormal cytogenetic profiles were validated via review of original reports (54%) from participating centers or from the CIBMTR database (46%); normal cytogenetics were reviewed and confirmed for 27% of reports (>95% accuracy). Leukemia-free survival (LFS) was the primary study endpoint. We included allograft recipients of both myeloablative (92.3%; 78% TBI-based) and reduced intensity/non-myeloablative (7.7%) conditioning using matched related (50%) and unrelated donor (27% 8/8 MUD; 21% mismatched UD), peripheral blood (46%) or bone marrow (54%) grafts.Results: A total of 632 patients (36.5%) had abnormal and 1099 (63.5%) had normal cytogenetics (Table). Young adults (<45 years) accounted for 82% of the entire cohort (63% males; 69% with B-cell ALL; 23% with high-risk hyperleukocytosis at diagnosis). Fifty-seven percent of patients underwent alloHCT in CR1 and 43% in CR2. Patients with abnormal cytogenetics had 40% LFS and 42% OS at 5-years post-transplant; which was similar to those with normal karyotype (both p>0.6). As opposed to all other cytogenetic schemas, only the modified MRC-ECOG stratification of patients into standard (n=24 with better outcomes) vs. intermediate (n=1447), high (n=160), and very high (n=78) groups was prognostic for LFS (overall p=0.03) in the multivariable analysis adjusted for recipient age, pre-HCT remission status, conditioning regimen, KPS, donor type, and GVHD prophylaxis (all co-variates were prognostic for LFS, p<0.01). Individual cytogenetic abnormalities that were consistent in their prognostic significance with modified MRC-ECOG but also associated independently with LFS in our cohort included unfavorable t(8;14) (HR=2.9; 95%CI, 1.4-6.0), del7q/-7 (HR=1.4; 95%CI, 1.0-2.1), and favorable high hyperdiploidy (HR=0.6; 95%CI, 0.4-1.0). Complex cytogenetics, monosomal karyotype, t(4;11), -17/i17q/del17p, +8, or t(1;19) were not associated with post-transplant LFS or OS in individual adjusted models.Conclusions: In this large analysis of adult Ph- ALL recipients of alloHCT with screened and validated cytogenetic profiles, we show that previously established high-risk ALL cytogenetics can be overcome by alloHCT. Although modified MRC-ECOG risk stratification appeared to be most prognostic for post-transplant LFS, its effect was largely driven by only few and relatively infrequent cytogenetic abnormalities. Our data argue that factors other than cytogenetic risk have greater impact on post-transplant survival of Ph- ALL. [Display omitted] DisclosuresBachanova:Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. De Lima:Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Characteristics and Outcomes of Pediatric Patients with t(16;16)-AML: Results of a Case Series By the International BFM Study Group

IntroductionCore binding factor (CBF) acute myeloid leukemia (AML) inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFβ-MYH11 [inv(16)/t(16;16)] is associated with a favorable outcome in children. Aberrations inv(16) and t(16;16) result in the same fusion of the CBFβ subunit at 16q22 and the myosin-11 heavy chain gene at 16p13, and are thought to share common biological features and outcomes. However, CBFβ-MYH11 fusion transcripts are heterogeneous and may vary in terms of biological activity. Therefore, in this cohort study by the International Berlin-Frankfurt-Munster (I-BFM) study group, we evaluated clinical characteristics, prognostic features and outcomes in pediatric patients with t(16;16)-AML.MethodsPatients (age 0‒19 years) with cytogenetically or molecularly confirmed t(16;16)-AML, diagnosed by members of the I-BFM study group between 1990 and 2015, were included in the study. Patients with previous malignancies, chemotherapy, or radiotherapy were excluded. Data on baseline characteristics, including cytogenetic and molecular information, fusion type, treatment details and follow up were collected using standardized case report forms. If data on the CBFβ fusion type were missing, real-time quantitative PCR for fusion types A, D, and E was performed on available biobank material. The molecular characterization part of the study is ongoing. Herein, we present descriptive statistics and estimated outcomes related to achieving complete remission (CR) and probabilities of event-free survival (pEFS) and overall survival (pOS).ResultsThe study included 46 patients with t(16;16)-AML. Median age was 9.8 [interquartile range (IQR) 1.7‒11.8] years, median white blood cell (WBC) count at diagnosis was 74 [IQR 35‒80] ×109/L and the predominant FAB-type was M4Eo (49%). Eleven patients (24%) had central nervous system involvement at diagnosis. Information on common additional molecular aberrations (e.g. cKIT and RAS mutations) was unavailable for more than 50% of patients and therefore not considered. Information on fusion types was available for 13 patients (28%). Biobank material was used to determine CBFβ fusion type in 2 patients for whom it had previously been unknown. Another 9 samples from international groups are available and pending analysis. Most patients for whom information was available on CBFβ fusion type had type A (n=7, 54%), followed by type D (n=3, 23%) and type E (n=3, 23%). No other fusion types were identified. Patients with type non-A (n=6, 46%) were predominantly male (67%) and had FAB-type M4Eo (83%). They were older than patients with type A (11.9 vs 8.8 years, respectively) and had a higher WBC count (69 vs 48 ×109/L, respectively), but these differences were not significant. Additional cytogenetic aberrations occurred in 38% of patients. Gain of chromosome 8, 21 or 22 were the most common additional chromosomal aberrations. Distribution of additional cytogenetic aberrations was comparable between patient with fusion type A and other types.Patient outcome was excellent with a 100% CR rate and a 5-year pEFS and pOS of 80% [standard error (SE), 6.4%] and 87% [SE, 5.6%], respectively (Figure 1). Five patients suffered a relapse. Of them, 4 had WBCs >50 ×109/L at diagnosis. None of the 5 patients had additional cytogenetic aberrations. Two patients had fusion type A and type was unknown for the other 3 patients. Of 46 patients, 2 died after relapse and 3 died from toxic complications in first CR. These complications included failure to recover bone marrow hypocellularity and subsequent multi-organ failure (n=1), and sepsis after stem cell transplantation in CR (n=2).ConclusionThis is the first report of a relatively large cohort of pediatric t(16;16)-AML patients. Patient outcomes were very good, especially compared with those reported for patients with non-CBF leukemias. However, these patients were at risk of toxic death in CR. Clinical characteristics and outcomes were comparable with those reported previously for patients with inv(16). Although this case series was large, patient numbers remained too small to identify significant prognostic factors associated with outcome. Prospective trials are needed to determine other biological features that may explain differences in outcomes among patients with either t(16;16) or inv(16)-AML. [Display omitted] DisclosuresKaspers:Janssen-Cilag: Research Funding.

Clinical risk score for predicting invasive fungal disease after allogeneic hematopoietic stem cell transplantation: Analysis of the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study.

Invasive fungal disease (IFD) is associated with a high mortality for patients with hematological malignancies undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). This study aimed not only to develop a proven/probable IFD risk-scoring model but to identify high-risk populations that would benefit from anti-fungal prophylaxis. Data from the China Assessment of Antifungal Therapy in Hematological Diseases (CAESAR) study were retrieved, and all patients (n=1053) undergoing allo-HSCT were randomly divided into the training set (n=685) for model development and the validation set (n=368) for model verification. A weighted risk score for proven or probable IFD was established through multivariate logistic regression analysis. The study population had a mean age of 28.95years and the majority underwent myeloablative transplantation in complete remission 1 (53.4%). Five risk factors of IFD were identified, namely neutropenia lasting longer than 14days, corticosteroid use, diabetes, haploidentical donor, and unrelated donor. Based on the risk score for IFD, the patients were categorized into three groups: low risk (score 0-4, 1.5%-4.0%), intermediate risk (score 5-8, 9.8%), and high risk (score>8, 24.7%-14.0%). Anti-fungal prophylaxis may provide benefits for patients with intermediate (8.5% vs. 18.5%, P=.0085) or high risk (19.4% vs. 30.8%, P=.4651) but not low risk (2.1% vs. 3.8%, P=.6136) of IFD. A practical weighted risk score for IFD in patients receiving allo-HSCT was established, which can aid decision-making regarding the administration of anti-fungal prophylaxis.

Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine Following Allogeneic Transplantation in a Phase 1 Clinical Trial

Viral Reactivation in Acute Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation in Complete Remission: Stimulation of the Immune System

Background: Many studies have evaluated the impact of cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (allo-HSCT) showing a significant association with reduced risk of relapse while other studies failed to show the same results. On the other hand, other frequent viral infections or reactivations like Epstein-Barr virus (EBV), Human Herpesvirus 6 (HHV6) and BK virus (BK-V) have not been evaluated in the same context and/or together with CMV. The aim of this study is to evaluate the impact of CMV, EBV, HHV6 and BK-V reactivation in acute leukemia (AL) patients receiving allo-HSCT in complete remission (CR) and evaluate their impact alone or associated on disease relapse. Patients and methods: We evaluated 158 consecutive AL patients who received allo-HSCT at our center between January 2008 and June 2015; 95 (60%) were males, median age was 46 years (range: 18-67), 101 (64%) had acute myeloid leukemia (AML) and 57 (36%) had acute lymphoblastic leukemia (ALL). At transplantation, 114 (72%) patients were in first complete response (CR1) and 44 (28%) were in second CR (CR2). Conditioning regimen was myeloablative for 97 (61%) patients and of reduced intensity in 61 (39%) patients. DNA levels of CMV, EBV, HHV6 and BK-V were detected by quantitative RQ-PCR after weekly monitoring up to 3 months after allo-HSCT. CMV-DNA, EBV-DNA, HHV6-DNA or BK-V-DNA was considered positive when the copies exceeded 1000 copies/ml. Results: Among 158 patients, 45 (28%) patients had CMV reactivation after a median time of 40 days (6-72) after allo-HSCT; 53 (34%) patients had EBV reactivation after a median time of 42 days (18-91) after allo-HSCT; 33 (21%) patients had HHV6 reactivation after a median time of 24 days (6-69) and 30 (19%) patients had BK-V reactivation after a median time of 32 days (6-60) after allo-HSCT. There was 61 (39%) patients who did not have any viral reactivation, 46 (29%) patients who had only one reactivation (no matter the type), and 51 (32%) patients who had at least two or more co-reactivations (group 1). When evaluating relapse incidence, we found that patients who had only one reactivation were not significantly different from those who did not have any reactivation, with a comparable relapse incidence, thus, we analyzed those patients as one group (group 2, n=107). The cumulative incidence of relapse at 6 months for group 1 and group 2 was 2% (95% CI: 0.2-9.4) and 15.9 % (95%CI: 9.7-23.5) respectively, this result remained significantly different when stratifying on the type of conditioning, in RIC: 15.8% (95%CI: 3.7-35.7) vs 21.4% (95%CI: 10.5-35) respectively; and in MAC: 0 % vs 15.4% (95%CI: 7.8-25.3) respectively, p=0.04. This finding was confirmed independently of the presence of GVHD or not. Conclusion: We demonstrate here for the first time, in this homogeneous population, that co-reactivation of multiple viruses after allo-HSCT could lead to a lower incidence of relapse in AL patients in CR; this can be explained as a stimulation of the immune system via both the functional activation and amplification of NK compartment. This could also explain some conflicting results in studies evaluating single viral reactivation alone without consideration of other reactivations. These encouraging results should be validated at a larger multicenter level. Disclosures No relevant conflicts of interest to declare.

Tolerability and toxicity of pegaspargase in adults 40 years and older with acute lymphoblastic leukemia

Pegaspargase is a modified version of asparaginase with prolonged asparagine depletion. It appears to be safe in adults <40 years old, but has a unique spectrum of toxicities, the risks of which appear to increase with age. The primary objective of this study was to evaluate pegaspargase tolerability and toxicity as assessed by evaluation of incidence and severity of adverse events. Secondary objectives included characterization of the reasons underlying pegaspargase discontinuation, when applicable. Grade 3/4 asparaginase-related toxicities with ≥10% incidence included: hyperbilirubinemia, hyperglycemia, hypertriglyceridemia, hypoalbuminemia, hypofibrinogenemia, and transaminitis. 63% of patients (38 of 60) received all intended doses of pegaspargase, with the most common reasons for discontinuation noted as hypersensitivity (12%), hyperbilirubinemia/transaminitis (8%), and hematopoietic transplantation in complete remission (10%). This study suggests that while hepatotoxicity and other known adverse effects are common, with careful monitoring, pegaspargase can safely be administered to adults with ALL age ≥40 years old.

Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report

AbstractThere is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

Is the Achievement of Pre-Autologous Transplant CR Necessary Indeed in Refractory/ Relapsed DLBCL Patients? a Retrospective Multicenter Study

Introduction - Salvage chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) is the standard-of-care for relapsed and refractory (R/R) diffuse large B cell lymphoma (DLBCL) patients. Eligibility is based on the presence of chemo-sensitive disease as defined by complete remission (CR) or partial remission (PR) according to FDG PET/CT study post salvage therapy. Patients achieving CR prior to auto-HCT have better prognosis than those undergoing it in PR. However, to this date, it is not clear whether one should struggle to achieve CR prior to auto-HCT or is PR after first salvage therapy good enough. Aim - To evaluate the role of additional salvage regimen prior to autologous HCT in R/R DLBCL patients who achieved PR per FDG PET/CT following first salvage regimen. Methods - We retrospectively reviewed the medical records of all patients who underwent auto-HCT for R/R DLBCL at three Israeli stem cell transplant centers between 2008 and 2018. Patients were identified based on the reports to the EBMT registry or according to the center's surveillance data. We recorded and compared outcomes between patients who achieved PR after first salvage therapy and proceeded immediately to auto-HCT vs. patients who continued with additional salvage treatment (either the same or a different regimen) before auto-HCT. Outcomes were compared between these groups and between patients who achieved CR after first salvage and patients with chemo-refractory disease who proceeded to transplant. Continuous variables were described as the mean, median, standard deviation and range of n observations. Categorical data were described with contingency tables including frequency and percent. Differences between the two groups of patients were examined by the Mann-Whitney test for continuous variables, and the two-tailed Fisher's exact test for categorical variables. Progression Free Survival (PFS) was defined as the time from autologous HCT to post transplant disease progression or to death from any cause, whichever occurred earlier. Overall survival (OS) was defined as the time from HCT until the date of subject death from any cause. The Kaplan-Meier method was used to estimate the distribution and median PFS and OS. Disease response and disease progression were assessed according to the Lugano criteria. Results - Between the years 2008 - 2018 149 patients underwent auto-HCT for R/R DLBCL. After first salvage chemotherapy 81 patients (54%) achieved CR, 50 patients (33%) achieved PR and 18 (12%) had progressive disease (PD). Among the 50 patients achieving PR after first salvage, 30 patients (60%) proceeded immediately to transplant and 20 patients (40%) were treated with additional salvage treatment. There were no differences between the two groups in the characteristics of the patients, the disease and regimens being given (Table). Median PFS was better for patients proceeding to HCT in PR compared to those who continued with additional salvage therapy in order to achieve CR (not reached vs. 12.5 months, p=.089). This was also true, with respect to OS (105 months vs. 35 months, p=.019). Interestingly, OS was comparable between patients who proceeded to transplant in CR or in PR after first salvage (Median not reached, vs. 105 months, p=0.245). Among patients who received further salvage chemotherapy (either the same or a different regimen) and obtained CR before HCT (n=8), overall survival was comparable to those who achieved CR after first salvage (mean 84 months vs. 99 months, p=.35). Patients who were still in PR after second salvage had a dismal prognosis which was comparable to that of patients proceeding to HCT in progressive disease after first salvage (mean OS of 11 vs. 22 months, p=.24). Conclusions - Albeit the small number of patients, our results do not support the administration of further salvage treatments in R/R DLBCL patients achieving PR after first salvage treatment in order to achieve pre-transplant CR. Table Disclosures Gurion: Roche: Consultancy.

Increasing Lengths of First Complete Remission with 7+3 Induction Chemotherapy for Acute Myeloid Leukemia over the Past Four Decades: Analysis of SWOG Trial Data

Background: We have previously shown that the survival of patients with AML who fail to achieve complete remission (CR) with 7+3 has improved since the 1980s. However, although CR rates with 7+3 have improved over the last four decades, we have not previously evaluated how outcomes for patients who achieve a CR1 with 7+3 has changed over time. Here we evaluate if either length of first CR (CR1) after 7+3 or of survival after relapse from CR1 has changed over the last four decades. Patients and Methods:We analyzed 1247 patients randomized to 7+3 arms from 5 SWOG studies and restricted to patients age 65 or younger: S8600 (n=530), S9031 (n=98), S9333 (n=57), S0106 (n=301), S1203 (n=261). S8600 enrolled patients in the 1980s, S9031 and S9333 in the 1990s, S0106 in the 2000s, and S1203 in the 2010s. S9031 and S9333 were analyzed together. All 5 protocols gave 7+3 per existing standard, which changed over time. In S8600, S9031, and S9033 the ara-C and daunorubicin doses were 200mg/m2and 45mg/m2, in S0106 100mg/m2and 60mg/m2, and in S1203 200mg/m2and 90mg/m2. CR was defined morphologically. To account for censoring in the dataset, we used landmark analyses. To evaluate patterns in length of CR1, among patients achieving CR1 and alive at 2 and 3 years, we calculated the proportion of 2 (or 3) years spent in CR1. To evaluate survival after relapse, among patients who achieved CR1 but who relapsed in next 2 (or 3) years we calculated the proportion of patients alive at least 1 year after relapse. To account for changing patient characteristics over time, multivariate linear and logistic regression models were fit. Results:Overall survival has improved dramatically over the last 4 decades (Figure 1). Additionally, among patients who achieved CR1 and were alive 2 years later, the proportion of those 2 years spent in CR1 has significantly improved over the last 4 decades (Figure 2) from a median of 58% to a median of 96% (p&amp;lt;0.001). This trend was maintained in multivariable modeling (Table 1) and similar trends were observed using a 3-year landmark time. Survival after relapse also improved over the 4 decades. Among patients who relapsed in the first 2 years after CR1, the proportion alive at least one year after relapse has significantly increased from 32% to 52% (Table 2, p&amp;lt;0.0001). This pattern was maintained in multivariable modeling adjusting for patient prognostic factors (Table 3) and similar trends were observed using a 3-year landmark time. Conclusion:Both length of CR1 and survival after relapse have increased over the last four decades in patients age 65 or younger even after accounting for differences in patient characteristics. Possible explanations for the longer survival after relapse include higher 2ndCR rates, more frequent use of hematopoietic cell transplant in CR, or better supportive care. Regardless, the longer survival after relapse suggests analyses of event-free survival should complement those of overall survival when evaluating new treatments in AML. Acknowledgement:The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. Disclosures Othus: Glycomimetics: Other: Data Safety and Monitoring Committee; Celgene: Other: Data Safety and Monitoring Committee. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding. Erba:Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau.

Underdiagnosed Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome(VOD/SOS) As a Major Cause of Multi-Organ Failure in Acute Leukemia Transplant Patients: An Analysis from the EBMT Acute Leukemia Working Party

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was &gt;90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p&lt;10-3) with the presence of hepatic risk factors (scoring from 0 to 5): history of liver disease, transaminases 2.5 times and bilirubin 2 times above normal limits at time of alloHCT, the presence of iron overload and the use of gemtuzumab. Of note, there was no significant detrimental impact of the use of total body irradiation or disease status. The median survival for patients with VOD/SOS-related MOF was 47 days (95%CI, 34-84) compared to 175 (95%CI, 121-234) days for patients with non-VOD/SOS related MOF. Conclusion: The above results suggest that VOD/SOS-related MOF is an under-reported cause of death. It is actually a relatively frequent cause of MOF, accounting for at least 28% of deaths that would otherwise been attributed to MOF of unknown origin. While the MOF concept is a widely used cause of death after alloHCT, having precise categories of cause-specific death from MOF should allow (whenever possible), for earlier specific therapeutic intervention (eg. defibrotide), thus contributing to improved patient outcome. Table Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Schaap:Celgene: Consultancy; Novartis: Consultancy. Snowden:Jazz: Honoraria; IDMC: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Therapeutic Dose Monitoring of Busulfan Is Associated with Reduced Risk of Relapse in Non-Hodgkin Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Optimal administration of busulfan (Bu) is hampered by variable and unpredictable drug metabolism in individual patients. At our institution, Bu was previously administered with fixed weight-based dosing (WBD) in combination with cyclophosphamide (Cy) and etoposide (E) for patients with non-Hodgkin lymphoma (NHL) undergoing autologous stem cell transplantation (ASCT). In 2014, we adopted real-time pharmacokinetic (PK)-guided therapeutic drug monitoring (TDM) of Bu for all NHL patients undergoing Bu-containing ASCT. Here we compare outcomes of NHL patients who underwent ASCT with Bu/Cy/E using WBD and those who did so using TDM of Bu. We studied 336 consecutive adult NHL patients who underwent ASCT with Bu/Cy/E using WBD from January 2007 to December 2013 (n = 258) or TDM from May 2014 to December 2017 (n = 78), excluding patients with mantle cell lymphoma. Clinical outcomes, including relapse, nonrelapse mortality (NRM), progression-free survival (PFS), and overall survival (OS), hepatotoxicity and pulmonary toxicity were compared in the 2 groups. To adjust for differences in baseline characteristics between the groups, propensity-matched cohorts of WBD and TDM patients were also studied. After the first dose of Bu, the dose was increased in 36% of the patients and decreased in 41%. Changes in pulmonary and liver function from baseline to transplantation were not different between the 2 groups, although these changes showed significantly less variability with TDM than with WBD. Relapse was significantly lower and PFS was improved with TDM; 2-year estimates were 19% for TDM and 38% for WBD for relapse (P = .004) and 69% and 55%, respectively, for PFS (P = .038). No significant between-group differences in NRM or OS were seen. In multivariable analysis, TDM remained prognostic for lower risk of relapse (hazard ratio [HR], .52; 95% confidence interval [CI], .30 to .89; P = .018), but did not remain prognostic for PFS (HR, .74; 95% CI, .48 to 1.16; P = .19). Propensity-matched cohorts displayed similar patterns of outcomes. In subset analysis based on disease status at ASCT, TDM was associated with less relapse and better PFS than WBD for patients who underwent transplantation in less than complete remission (CR) compared with those who underwent transplantation in CR. Compared with WBD, PK-directed TDM of Bu reduces the incidence of relapse when used in combination with Cy and E for patients with NHL undergoing ASCT, particularly for patients in less than CR. These data support the continued use of personalized PK-guided dosing for all NHL patients undergoing ASCT with Bu-containing preparative regimens.

Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia.

Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P= 0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.