Courses Of Intensive Chemotherapy Research Articles

Risk stratification in the clinical application of minimal residual disease assessment in acute myeloid leukemia.

In acute myeloid leukemia (AML), further investigation is warranted to integrate measurable residual disease (MRD) with genetic characteristics for formulating a dynamic prognostic system for predicting response and selecting appropriate postremission therapeutic strategies. The authors incorporated MRD with genetic risk classification and assessed its impact on transplantation decision making within different risk cohorts, comprising 769 patients with newly diagnosed AML across three clinical trials. Only patients who achieved complete remission (CR) within two courses of chemotherapy were selected. In the favorable-risk and intermediate-risk groups, patients who underwent transplantation according to the protocol experienced significant 3-year overall survival (OS) benefits compared with those who did not (favorable-risk group: hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20-0.73l p=.004; intermediate-risk group: HR, 0.53; 95% CI, 0.33-0.85; p=.008). In the intermediate-risk group, early detection of MRD positivity, even after the initial course of chemotherapy, was associated with a significantly elevated cumulative incidence of relapse (47.2% vs. 36.0%; p=.009) and a notable extension of OS with allogeneic hematopoietic stem cell transplantation (HR, 0.47; 95% CI, 0.28-0.79; p=.004). Conversely, patients who achieved MRD negativity at either of the two time points had comparable OS in the favorable-risk and intermediate-risk groups, regardless of whether they underwent transplant or not. In the adverse-risk group, allogeneic hematopoietic stem cell transplantation led to improvements in OS irrespective of MRD status (HR, 0.51; 95% CI, 0.38-0.69; p<.001). Early clearance of MRD demonstrated significant prognostic value, particularly for patients in the favorable-risk and intermediate-risk groups. Positive MRD status after two courses of intensive chemotherapy were associated with a higher relapse rate and inferior OS, necessitating allogeneic hematopoietic stem cell transplantation.

A Multicenter Clinical Study with Reduced Intensive Chemotherapy for Induction Remission of Pediatric Acute Megakaryoblastic Leukemia

Bcakground: Pediatric acute megakaryoblastic leukemia (AMKL) without Down syndrome (DS) is a genetically heterogenous myeloid malignancy and with dismal prognosis. Refractory and relapse remains a major challenge. Given to the young age distribution of AMKL and high frequency of abandonment in middle-income countries, we conducted a multicenter clinical trial (ChiCTR1800015875) in aims to lower the intensity of induction while without compromise the remission rate and survival. Methods: From June 2018 to December 2022, there were consecutively 43 cases with de novo non-DS AMKL, which accounted for 7.6% cases of acute myeloid leukemia (AML) during the same period, enrolled in this trial. All the patients received at least one cycle of low-dose induction with HAG regimen (homoharringtonine 1 mg/m 2, intravenous daily, days 1-7; cytarabine 10 mg/m 2, subcutaneously every 12 hours, 20 doses, and G-CSF 5µ/kg subcutaneous, daily, 10 doses) followed by 3 to 4 courses of intensive chemotherapy or HSCT as post-remission consolidation. Besides conventional molecule testing, RNA-sequencing and whole exon sequencing (WES) were performed as well to reveal underlying genetic landscape of this type of disease. Results: The median age of the 43 patients at diagnosis was 18.5 (range 4-114) months. The median while blood cell (WBC) counts and platelet at diagnosis were 17.2×10 9/L (range 1.8-105.7 ×10 9/L) and 36.5×10 9/L (range 4-472 ×10 9/L), respectively. Among them, 39.5% of cases exhibited hepatosplenomegaly. A diversity of genetic fusions and mutations were uncovered. The recurrent fusions in this cohort include CBFA2T3-GLIS2 (16.3%), MLLr (11.6%), NUP98-(9.3%), RBM15-MKL1 (7.0%), HOX fusions (7.0%) and PICALM-MLLT10 (4.7%). Other non-recurrent fusions accounted for 18.6% (Figure 1A). The common mutations detected in our pediatric AMKL were JAK2, NRAS, MPL, BCOR, CTCF, KRAS and PTPN11. Regarding treatment response, 20 of 43 cases (46.5%) attained complete remission (CR) or complete remission with incomplete blood cell recovery (CRi) after one cycle of induction. Among the 20 cases, 9 of them got minimal residual disease (MRD) negative by flow cytometry. Ten patients (23.2%) achieved partial remission (PR) while 13 patients (30.2%) showed no response (NR) to treatment. Thirty-one patients continued with another cycle of the same regimen and 21 of the 28 cases who were available for evaluation (75.0%) attained CR/CRi. Disease relapse was observed in 16/43 (37.2%) cases, with 7/43 (16.2%) patients relapsed after transplantation. The 3-year overall survival (OS) and event-free survival (EFS) were 49.6±8.2% and 29.5±7.1%, respectively (Figure 1B). In total, more than half of patients (22/43, 51.5%) underwent HSCT. The 3-year OS of transplant group and chemotherapy group were 57.9±11.7% versus 39.5±11.2%, P=0.036. As genetic characteristics often predict treatment response and prognosis, we wonder which subgroup could benefit from the reduced intensive induction. We further compared the features of patients who got CR/CRi after induction I with those achieved PR/NR. Interestingly, we found more patients with adverse fusions in PR/NR group, such as CBFA2T3-GLIS2 (26.0% vs. 5.0%), NUP98- (17.4% vs. 0%), MLLs (13.0% vs. 10.0%), and RBM15-MKL1 (8.7% vs. 5.0%); while other non-recurrent fusions were more common in CR/CRi group (4.3% vs. 35.0%). Two thirds of patients (67.4%) experienced refractory or relapse and almost half of them harbored adverse fusions or mutations such as CBFA2T3-GLIS2, MLLr, NUP98- fusions, NRAS and PTPN11. On the other hand, 14 patients without refractory or relapse had genetic features with more JAK2 and MPL mutations. No treatment-related mortality (TRM) occurred during induction. Only one patient with KRAS mutation died of infection after consolidation III. Conclusion: Insight into the genetic and molecular landscape improved our understanding of pediatric AMKL. Distinct molecular features can serve as a tool to tailor the therapy. Though treatment still lags behind and novel therapy is urgent for the adverse subgroups, our low-dose induction with HAG regimen could benefit for a subgroup with non-recurrent fusions, which showed efficiency while is tolerable for the young age group. Based on our results, we provide an induction option for these AMKL patients, especially for those in the middle-income countries.

Dynamic changes in physical function during intensive chemotherapy affect transplant outcomes in older adults with AML.

Intensive chemotherapy (IC) can affect all geriatric assessment (GA) domains in older adults with acute myeloid leukemia (AML), but data on the effects of these changes on transplant outcomes are lacking. Therefore, we prospectively assessed the prognostic role of GA domains at diagnosis and allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 51 patients with AML aged ≥60 years who achieved complete remission after IC. We performed both baseline and pre-allo-HSCT GA; moreover, physical function, including a short physical performance battery (SPPB), cognitive function, psychological function, nutritional status, and social support were examined. All GA domains showed dynamic changes between the two time points. The directions of change were statistically significant for social support, self-reported physical and psychological functions, and distress, but not for nutritional status, cognitive function, or physical function. Among all GA domains at each time point, only poor physical function and its submaneuvers at diagnosis but not at allo-HSCT were significantly associated with inferior survival. In particular, since the direction of change varied between patients, we found that patients whose physical function improved before allo-HSCT were more likely to survive longer than those with persistently impaired SPPB (55.6% vs. 28.6%, p=0.268). Finally, persistent impairment in SPPB (28.6% vs. 65.9%, p=0.006), tandem stand (0% vs. 63.3%, p=0.012), sit-and-stand (41.2% vs. 70.6%, p=0.009), and gait speed (38.5% vs. 68.4%, p=0.027) further strongly predicted inferior survival. This study showed that IC courses can induce dynamic changes in different directions in the GA domains of each patient and that changes in objectively measured physical function can predict transplant outcomes.

Advancing Diagnostics and Therapy to Reach Universal Cure in Childhood ALL.

Systemic combination chemotherapy and intrathecal chemotherapy markedly increased the survival rate of children with ALL. In the past two decades, the use of minimal (measurable) residual disease (MRD) measurements early in therapy improved risk group stratification with subsequent treatment intensifications for patients at high risk of relapse, and enabled a reduction of treatment for low-risk patients. The recent development of more sensitive MRD technologies may further affect risk stratification. Molecular genetic profiling has led to the discovery of many new subtypes and their driver genetic alterations. This increased our understanding of the biological basis of ALL, improved risk classification, and enabled implementation of precision medicine. In the past decade, immunotherapies, including bispecific antibodies, antibody-drug conjugates, and cellular therapies directed against surface proteins, led to more effective and less toxic therapies, replacing intensive chemotherapy courses and allogeneic stem-cell transplantation in patients with relapsed and refractory ALL, and are now being tested in newly diagnosed patients. It has taken 50-60 years to increase the cure rate in childhood ALL from 0% to 90% by stepwise improvements in chemotherapy. This review provides an overview of how the developments over the past 10-15 years mentioned above have significantly changed the diagnostic and treatment approach in ALL, and discusses how the integrated use of molecular and immunotherapeutic insights will very likely direct efforts to cure those children with ALL who are not cured today, and improve the quality of life for survivors who should have decades of life ahead. Future efforts must focus on making effective, yet very expensive, new technologies and therapies available to children with ALL worldwide.

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18–60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4–78.5%) and 57.1% (95%CI: 39.5–82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

Invasive Fungal Disease in Patients with Myeloid Malignancies: A Retrospective Cohort Study of a Diagnostic-Driven Care Pathway Withholding Mould-Active Prophylaxis

Objectives: Patients receiving remission induction therapy for acute myeloid leukaemia (AML) are at high risk of developing invasive fungal disease (IFD). Newer therapies with targeted antileukemic agents and the emergence of azole resistance pose a challenge to the strategy of primary antifungal prophylaxis. We report the experience of a diagnostic-driven care pathway (DCP) for the management of IFD in these patients, using only culture-directed mould inactive prophylaxis. Methods: Retrospectively, we used a single-centre study of consecutive patients receiving intensive chemotherapy for myeloid malignancies between 2014 and 2021. DCP consisted of serial cultures and serum galactomannan (sGM) screening, CT imaging, and bronchoscopy to direct targeted antifungal treatment. IFD was classified according to the 2020 EORTC/MSGERC criteria. Results: A total of 192 patients with myeloid malignancies received 300 courses of intensive chemotherapy. There were 14 cases of invasive yeast infections and 18 of probable/proven invasive mould disease (IMD). The incidence of probable/proven IMD during the first cycle of remission-induction chemotherapy was 4.6% (n = 9). sGM remained negative in all cases of invasive aspergillosis (IA), with positive mycology findings in bronchoalveolar lavage. All-cause mortality was 9.4% (n = 18) 100 days after starting chemotherapy and was comparable between patients with or without IFD. The fungal-related mortality was 1% (n = 2). Conclusion: Diagnostic-driven based management without universal mould active prophylaxis is a feasible strategy in the management of IFD and limits unnecessary antimould treatment during intensive chemotherapy. The poor performance of serial serum galactomannan screening in detecting IA warrants further investigation.

Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia

Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management. To evaluate outpatient vs inpatient neutropenia management for pediatric AML. This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020. Discharge to outpatient vs inpatient neutropenia management. The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome. Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management. This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.

CombiFlow: combinatorial AML-specific plasma membrane expression profiles allow longitudinal tracking of clones

AbstractAcute myeloid leukemia (AML) often presents as an oligoclonal disease whereby multiple genetically distinct subclones can coexist within patients. Differences in signaling and drug sensitivity of such subclones complicate treatment and warrant tools to identify them and track disease progression. We previously identified >50 AML-specific plasma membrane (PM) proteins, and 7 of these (CD82, CD97, FLT3, IL1RAP, TIM3, CD25, and CD123) were implemented in routine diagnostics in patients with AML (n = 256) and myelodysplastic syndrome (n = 33). We developed a pipeline termed CombiFlow in which expression data of multiple PM markers is merged, allowing a principal component–based analysis to identify distinctive marker expression profiles and to generate single-cell t-distributed stochastic neighbor embedding landscapes to longitudinally track clonal evolution. Positivity for one or more of the markers after 2 courses of intensive chemotherapy predicted a shorter relapse-free survival, supporting a role for these markers in measurable residual disease (MRD) detection. CombiFlow also allowed the tracking of clonal evolution in paired diagnosis and relapse samples. Extending the panel to 36 AML-specific markers further refined the CombiFlow pipeline. In conclusion, CombiFlow provides a valuable tool in the diagnosis, MRD detection, clonal tracking, and understanding of clonal heterogeneity in AML.

Effectiveness of Supportive Care Measurements to Reduce Infections during Induction for Children with Acute Myeloid Leukemia: A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

BACKGROUNDCurrent intensive chemotherapy for pediatric acute myeloid leukemia (AML) in conjunction with supportive care has increased survival rate up to 70%, and yet infections are still responsible for considerable morbidity and most treatment-related deaths. These factors have led to much interest in supportive care measurements to reduce infections and infectious mortality. The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) trial AML-05 was a phase 2 study that included children with de novo AML treated with intensive chemotherapy. We surveyed participating JPLSG sites to assess the effect of each supportive care measurements on Induction I infection risk and non-relapse mortality for children in AML-05 study. METHODSBetween November 2006 and December 2010, JPLSG AML-05, registered at http://www.umin.ac.jp/ctr/ as UMIN000000511, recruited 447 eligible children (age <18 years) with de novo AML. AML-05 used 5 courses of intensive chemotherapy with Induction I consisting of etoposide 150mg/m2/dose intravenous (IV) every 24 h on day 1-5; cytarabine 200 mg/m2/dose intravenous (IV) every 12 h on days 6-12; mitoxantrone 5 mg/m2/dose IV on days 6-10; triple intrathecal treatment (methotrexate/ cytarabine/ hydrocortisone) (ECM 5+7+5). Data of Infectious complications were collected prospectively and monitored in real-time to optimize reporting accuracy. In this analysis, infectious events were limited to Induction I. Non-relapse mortality was defined as any induction death within 40 days of being taken off study due to non-disease related causes. The survey included questions on implementations in each patient participated in AML-05 study for antibacterial prophylaxis, antifungal prophylaxis, intestinal sterilization, use of HEPA-filter, surveillance culture, and use of G-CSF until count recovery. RESULTSThe survey response rate from the JPLSG sites was 359/447 (80.3%). In multiple regression, anti-bacterial prophylaxis reduced the development of febrile neutropenia during induction chemotherapy (Odds ratio [OR] 0.56, 95% confidence interval [CI] 0.39-0.88; p = 0.013). Sterile site bacterial infections increased in younger age group (OR 2.0, 95% CI, 1.09-3.66; p = 0.025) but decreased in patients who were routinely carried out surveillance culture (OR 0.5, 95% CI, 0.27-0.96; p = 0.038). Fungal infection during induction chemotherapy was associated with intestinal sterilization (OR 0.21, 95% CI, 0.61-0.70; p = 0.011) and the use of G-CSF (OR 3.83, 95% CI, 1.10-13.32; p = 0.035). Prophylactic antifungal agent had a tendency to reduce the frequency and duration of pyrexia, and the peak value of CRP. Nonetheless, routine prophylaxis with these agents did not impact non-relapse mortality. CONCLUSIONSProphylactic use of antibiotics was associated with less development of febrile neutropenia. Routine prophylaxis with these agents may be associated with incidence and severity of infectious complications, but did not impact non-relapse mortality during induction chemotherapy in childhood AML. DisclosuresNo relevant conflicts of interest to declare.

Is there an impact of measurable residual disease as assessed by multiparameter flow cytometry on survival of AML patients treated in clinical practice? A population-based study

The Swedish national guidelines for treatment of acute myeloid leukemia (AML) recommend analysis of measurable residual disease (MRD) by multiparameter flow cytometry (MFC) in bone marrow in the routine clinical setting. The Swedish AML registry contains such MRD data in AML patients diagnosed 2011–2019. Of 327 patients with AML (non-APL) with MRD-results reported in complete remission after two courses of intensive chemotherapy 229 were MRD-negative (70%), as defined by <0.1% cells with leukemia-associated immunophenotype in the bone marrow. MRD-results were reported to clinicians in real time. Multivariate statistical analysis adjusted for known established risk factors did not indicate an association between MFC-MRD and overall survival (HR: 1.00 [95% CI 0.61, 1.63]) with a median follow-up of 2.7 years. Knowledge of the importance of MRD status by clinicians and individualized decisions could have ameliorated the effects of MRD as an independent prognostic factor of overall survival.

Newly Diagnosed Childhood AML Patients Treated with Bortezomib Show Superior Survival If CD74 Is Expressed: A Report of 991 Patients from the Children's Oncology Group AAML1031 Protocol

Introduction: CD74 is a type II transmembrane protein expressed on antigen-presenting cells and an MHC class II chaperone. It has been associated with tumor progression and metastasis in solid tumors, and its expression has been suggested to serve as a prognostic factor in many cancers, with higher relative expression associated with oncogenesis. As the expression of CD74 has been associated with response to bortezomib in multiple myeloma, we inquired whether such correlation might be seen in pediatric AML. We prospectively evaluated CD74 expression by difference from normal (ΔN) flow cytometry and correlated expression with clinical characteristics and outcome as part of Children's Oncology Group protocol AAML1031 that randomized patients younger than 30 years of age with de novo AML to standard treatment with (Arm B) or without (Arm A) bortezomib. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. Given the association of CD74 with B-lymphoid neoplasms and bortezomib's known efficacy in B-cell neoplasms and multiple myeloma, we hypothesized that within Arm B, the patients with CD74 expression would have a more favorable outcome. Methods: In total, 1,139 newly diagnosed pediatric patients with de novo AML were randomized to standard chemotherapy (n=561, Arm A) or standard chemotherapy with bortezomib (n=578, Arm B). All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. To qualify for this correlative study, 991 patients satisfied 2 criteria: (1) submitting a bone marrow aspirate for ΔN at diagnosis and (2) providing consent for correlative biology studies. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD74 by ΔN. AML was considered to be CD74-positive if the MFI was more than two times above background autofluorescence and more than 40% of the leukemia was above background autofluorescence. Results: Among 991 patients, 263 were CD74-positive (26.5%) by ΔN, with similar prevalence in Arm A (27.9%) and Arm B (25.2%). Correlation of CD74 expression with clinical characteristics showed that those with CD74 expression had higher median age (p&amp;lt;0.001), lower median WBC (p&amp;lt;0.001), higher prevalence of low risk protocol status (p=0.039), lower frequency of CEBPA mutation (p=0.039), inv(16) (p=0.001), and KMT2A rearrangements (p=0.002), and were enriched for t(8;21) (p&amp;lt;0.001) and t(6;9) (p=0.014) fusions. All these features retained significance when patients were sub analyzed by respective treatment arms. CD74-positive patients had a higher morphologic CR rate (p=0.016), however, measurable residual disease by flow cytometry was not significant in the entire cohort or in the sub analysis of treatment arms (p=0.155). CD74-positive patients showed superior 5-year OS (70.6% vs 61.8%, p=0.003) and EFS survival (51.2% vs 43.1%, p=0.007) compared to those who were CD74-negative. For patients in Arm A (no bortezomib), the differences in OS (66.1% vs 61.0%, p=0.138) and EFS (48.9% vs 41.7% p=0.088) were not significant between those that were CD74-positive and those that were CD74-negative (Figure 1). However, patients in Arm B receiving bortezomib that were CD74-positive showed a significant improvement in OS (75.3% vs 62.5%, p=0.006) and EFS (53.6% vs 44.3%, p=0.028) compared to those who were CD74-negative (Figure 1). Comparison of the outcomes for CD74-positive patients with and without bortezomib exposure showed a difference in OS of 66.1% vs. 75.3% for those in Arm A vs. Arm B but did not reach significance (p=0.155). Multivariable analysis for OS yielded a hazard ratio of 0.67 (95% CI: 0.44 - 1.02) and p=0.061, approaching, but not reaching, statistical significance. Conclusions: These data demonstrate that CD74 expression is associated with more favorable disease characteristics and survival. Patients receiving bortezomib that were CD74-positive showed a superior response to therapy compared to patients who did not express CD74, by both OS and EFS, suggesting that CD74-positive childhood AML patients stand to benefit from bortezomib therapy. Bortezomib may induce a mechanistic response in CD74-positive AMLs similar to that in bortezomib-treated B-cell neoplasms and/or multiple myeloma, where bortezomib has proven to be beneficial. Disclosures Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019). Pollard:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group.

New therapeutic strategies are needed for pediatric acute myeloid leukemia (AML) to reduce disease recurrence and treatment-related morbidity. The Children’s Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed AML. AAML1031 randomized patients younger than 30 years of age with de novo AML to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. In total, 1,097 patients were randomized to standard chemotherapy (n=542) or standard chemotherapy with bortezomib (n=555). There was no difference in remission induction rate between the bortezomib and control treatment arms (89% vs. 91%, P=0.531). Bortezomib failed to improve 3-year event-free survival (44.8±4.5% vs. 47.0±4.5%, P=0.236) or overall survival (63.6±4.5 vs. 67.2±4.3, P=0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (P=0.006) and intensive care unit admissions (P=0.025) during the first course. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. These data do not support the addition of bortezomib to standard chemotherapy in children with de novo AML. (Trial registered at clinicaltrials.gov NCT01371981; https://www.cancer.gov/clinicaltrials/ NCT01371981).

Outcome and Genomic Characteristics of Non-Down Syndrome Acute Megakaryoblastic Leukemia in Children Treated with Low-Dose Chemotherapy for Induction Remission

Background: Acute megakaryocytic leukemia (AMKL) is a rare subtype of acute myeloid leukemia (AML) with a dismal outcome in children without Down syndrome. Refractory or relapsed disease accounts for treatment failure in most cases. Hematopoietic stem cell transplantation (HSCT) is recommended as post-remission therapy, although some patients have been cured with intensive chemotherapy alone. Genetic and genomic abnormalities are common in AMKL, but their prognostic significance is not known. In this study, we analyzed AMKL using high-throughput sequencing in addition to conventional morphology, immunophenotype, cytogenetic, and molecular (MICM) approaches. Methods: From February 2015 to April 2019, 19 cases of AMKL in non-Down syndrome patients were diagnosed according to conventional methods in our center. All patients, except one, were treated using a low-dose chemotherapy (LDC) regimen (cytarabine 10 mg/m2, subcutaneously every 12 h, 20 doses; mitoxantrone 5 mg/m2 days 1, 3 and 5, and G-CSF 5µ/kg subcutaneous, daily, 10 doses) for induction remission followed by four courses of intensive chemotherapy or hematopoietic stem cell transplantation (HSCT) as post-remission consolidation[1]. Patients were treated with consolidation chemotherapy if parents refused HSCT. High-throughput mutational sequencing of leukemia cells obtained at diagnosis was performed. The average sequencing depth was 500-1000× and analyses were performed using mGATK, SAMTools, SIFT, PolyPhen2, LRT, and MutatioinTaster methods. Results: The average age at diagnosis of AMKL of the nine boys and 10 girls was 19.7 months (7-53 months). Eighty-four percent of the cases were younger than 2 years of age. The 19 patients with AMKL represent 10% of cases diagnosed with AML during the study period. The median initial white blood cell (WBC) count was 13×109/L(2.38-126×109/L)and the average blasts at initial bone marrow (BM) was 54.5% (13-85%). In all cases of AMKL, more than 25% of cells were positive for CD41. Sixty-three percent of patients had recurrent fusion genes, including NUP98-KDM5A, HOXA11-AS/ANGPT1, CBFA2T3-GLIS2, KMT2A-MLLT3, RBM15-MKL1. Also, we identified PICALM-MLL10, TNIP1-CSF1R, NUP98-TAF3, and CBFA2T3-GLIS1 fusion genes which had not been previously reported in AMKL. EVI-1 expression was evaluated in all cases and was overexpressed in two cases. Forty-seven percent of patients showed at least single-gene mutations, including JAK2, MPL, KRAS, NRAS, TP53, NTRK3, MYO16, PDGFB, FLT3, and others. The response rate after remission induction I (IND-I) were 84.2% with 63.1% (12/19) attaining complete remission (CR) and 21.1% (4/19) partial remission (PR). After IND-II, the CR, PR, and no response (NR) rates was 68.4%, 10.5%, and 21.1%, respectively. Four patients (21.1%) were refractory to induction chemotherapy. Seven patients (36.8%) relapsed, three during consolidation chemotherapy courses, and four after transplantation (Table 1). Currently, 75% (6/8) patients who received chemotherapy only for consolidation were alive (median follow-up time 27 months). Eleven patients underwent allo-HSCT, and 8 patients are alive, including 6 cases living without evidence of disease. Four patients relapsed after allo-HSCT, and two of them have died. One additional patient died of transplantation related mortality. The 4-year OS, RFS, and EFS in this cohort were 62.4%±13.9%, 54.1±13.0% and 40.5±11.5%, respectively (Figure 1).Conclusion: Non-Down syndrome AMKL is genetically heterogeneous with recurrent and new fusion genes. Patients treated with LDC for induction followed by intensive chemotherapy or HSCT for consolidation have outcome comparable to those treated with intensive induction regimens. New treatment strategies are needed to improve the outcome of pediatric AMKL. Figure 1 Disclosures No relevant conflicts of interest to declare.

Comparison of Outcomes after Early Hospital Discharge (EHD) Following Intensive Induction Vs. Post-Remission Chemotherapy for Adults with Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

Comparison of Outcomes after Early Hospital Discharge (EHD) Following Intensive Induction Vs. Post-Remission Chemotherapy for Adults with Acute Myeloid Leukemia (AML) and Other High-Grade Myeloid Neoplasms

PS964 COMPARISON OF CONDITIONING REGIMEN CONTAINING TOTAL BODY IRRADIATION OR NOT FOR AUTOLOGOUS TRANSPLANTATION IN ADOLESCENTS AND YOUNG ADULTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Background:Autologous stem cell transplantation (ASCT) still plays an role in treatment of acute lymphoblastic leukemia (ALL). A myeloablative conditioning therapy should be done before ASCT. Many trials comparing regimens with total body irradiation (TBI) and non‐TBI in allogeneic stem cell tansplantation have been reported. However, very limited analysis focused on patients with ALL undergoing ASCT.Aims:The present study was undertaken to analyse retrospectively the outcome following conditioning with TBI regimens versus non‐TBI regimens in ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL patient cohorts.Methods:We defined 14–29 years of age as AYAs. Seventy four AYAs of all 95 patients with ALL undergoing consecutive ASCT between January 2007 and December 2016 were included in the study at Lymphoma Center at Blood Disease Hospital of Chinese Academy of Medical Sciences. Patients were chose based on the following criteria: (1) CR1 before ASCT; (2) first ASCT; (3) peripheral blood stem cell; (4) Philadelphia chromosome‐negative; (5) no definite central nervous system disease. According to the conditioning regimens administered, patients were divided into the following two groups: TBI group (consisting of TBI and chemotherapy, n = 38) and non‐TBI group (consisting of only chemotherapy, n = 36). The details of TBI‐based conditioning were TBI plus melphalan ± etoposide(n = 21), TBI plus cyclophosphamide ± cytosine arabinoside or etoposide (n = 14), others (n = 3). The details of non‐TBI conditioning were busulfan plus melphalan (n = 6), busulfan plus cyclophosphamide and etoposide (n = 16), busulfan plus cyclophosphamide and cytosine arabinoside (n = 3), busulfan plus cyclophosphamide and idarubicin (n = 6), others (n = 5). All of patients were received with VDCP ± L induction regimen for 28 days, then patients were administered with four courses of intensive chemotherapy. All of patients received 8–10 intrathecal injections for preventing central nervous system disease. After ASCT, maintenance chemotherapy based on VP regimen was continued for 1–1.5 years.Results:The main features at the time of diagnosis and transplant characteristics (sex, age, number of leukocytes, phenotype, karyotype and molecular biology, interval from treatment to MRD negative, interval between CR1 to patients transplanted) are parallel between the two groups. The median follow‐up for the survivors was 56 months (range, 30 ‐ 130 months) for TBI group and 65 months (range, 27 ‐ 126 months) for non‐TBI group after ASCT, respectively (P = 0.563). The median neutrophil engraftment days were 11days (range, 8–19 days) and 12 days (range, 9–30 days) for TBI group and non‐TBI group (P = 0.432), respectively. The median days to platelet engraftment were 15days (range, 10–95 days) and 14.5 days (range, 9–90 days) (P = 0.656), respectively. Hepatic vein occlusion syndrome occurred in 1 patients administered by busulfan plus melphalan conditioning at the day of 32 from transplantation. Cataract occurred in TBI plus melphalan (n = 1) conditioning group and TBI plus melphalan and etoposide conditioning group (n = 1).Non TRM occurred. The 5‐year disease‐free survival (DFS) was 68.1 ± 7.6% in TBI cohort and 62.3 ± 8.4% in non‐TBI cohort (P = 0.906). The 5‐year overall survival (OS) was 67.5 ± 7.8% and 63.8 ± 8.6% (P = 0.694). The DFS and OS results were no differences between the two regimens in univariate analysis.Summary/Conclusion:These data indicate similar survival with non‐TBI conditioning, compared with TBI‐based conditioning, for ASCT in adolescents and young adults with Philadelphia chromosome‐negative ALL.image

PS948 EXCELLENT RESPONSE TO BLINATUMOMAB IN REFRACTORY B LINEAGE ACUTE LYMPHOBLASTIC LEUKAEMIA IN CHILDREN AND YOUNG ADULTS AFTER DEBULKING CHEMOTHERAPY TO ACHIEVE PARTIAL REMISSION

Background:A recent phase I/II study of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukaemia (B‐ALL), found 39–51% achieved complete, often MRD negative, remission after two cycles of therapy. Higher responses were observed in patients with less than 50% bone marrow blasts, compared to greater than 50% (55.6% vs 32.7% (95% CI 30.8–78.5 and 20.3–47.1 respectively). Furthermore, an adult study showed complete minimal residual disease (MRD) response rates of 78% when blinatumomab was used to treat MRD‐positive ALL in haematological remission. Hence response rates (and toxicity) to blinatumomab are highly correlated with pre‐treatment disease burden.Aims:We aimed to determine the outcome of children and young adults who received blinatumomab for primary refractory or relapsed B‐ALL, who had persistent MRD, or after debulking chemotherapy to achieve a partial remission.Methods:Eighteen patients were identified through a national survey. The mean age of patients was 8 years (range 0.5‐ 22), 4 infants and 1 Down syndrome ALL). All patients had B‐lineage ALL which was CD19 positive. None had active CNS disease at the point of receiving blinatumomab. Prior to administration of blinatumomab, all patients either had persistent MRD following several courses of intensive chemotherapy or received debulking chemotherapy for heavier marrow infiltrates. Pre‐blinatumomab chemotherapy to which the patients had failed to obtain an adequate MRD response included UKALL 2011 Regimens A or C, UKALL R3, Interfant 06, FLA‐IDA or NOPHO high risk blocks. Patients received 5–15 μg/m2 of blinatumomab for 1–2 cycles prior to definitive therapy.Results:Pre‐blinatumomab, all patients except two were in morphological remission with MRD measurable by PCR (0.003–6%), the remaining patient had 15 and 32% marrow disease by morphology. After 1–2 cycles of blinatumomab all patients had negative MRD when measured by flow cytometry and/or by PCR, giving a 100% response rate. This was followed by haemopoietic stem cell transplant (HSCT) in 17 patients, and of these, 11 are currently alive and disease‐free. Three patients died from transplant‐related complications, without evidence of disease recurrence. One patient had a lineage switch relapse post‐transplant and 2 with CD19 positive relapse 3–7 months post‐transplant have received CART cells. One patient is awaiting CART cells having relapsed 2 weeks after 1 cycle of blinatumomab.Minimal toxicity was observed; 6 patients had grade 1–2 CRS, which resolved spontaneously without interruption of therapy or treatment with corticosteroids or Tocilizumab. Two patients reported grade neurotoxicity (grade 1+3).Summary/Conclusion:This preliminary UK experience demonstrates that excellent MRD response is observed with minimal toxicity in children and young adults who receive blinatumomab for persistent MRD or after debulking chemotherapy which provides an opportunity for transplant in otherwise ineligible patients.

Proton Beam Therapy for Adolescent Primary Central Nervous System Lymphoma With Residual Tumor After Intensive Chemotherapy: A Case Report

Abstract Primary central nervous system lymphoma (PCNSL) is a very rare type of non-Hodgkin lymphoma. Although pediatric and adolescent PCNSL patients generally respond well to intensive chemotherapy, the salvage treatment for this condition remains uncertain for patients exhibiting a poor/suboptimal response to primary therapy. Proton beam therapy (PBT) is being increasingly employed especially for pediatric oncology cases. However, the safety and feasibility of PBT for PCNSL patients have not been addressed. We encountered an adolescent patient with PCNSL exhibiting 4 of 5 adverse prognostic factors at diagnosis and a residual tumor adjacent to the pituitary gland with gadolinium enhancement on brain magnetic resonance imaging after 7 courses of intensive chemotherapy. We selected local PBT at a dose of 30.6 Gy (relative biological effectiveness) as a salvage treatment for the residual tumor. After PBT, gadolinium enhancement of the residual lesion rapidly disappeared with no acute adverse effects. Moreover, during 30 months of follow-up, no neurological or endocrinological adverse effects have been observed despite the location of the tumor. The patient is now healthy and has shown no evidence of relapse. PBT deserves further investigation as a salvage treatment option for PCNSL patients exhibiting a suboptimal response to primary chemotherapy.

Primary Chest Wall MYC/BCL6 Double-hit Lymphoma with t (3;7) (q27;p12) and t (8;14) (q24;q32) Translocations

Primary chest wall lymphoma is rare and typically associated with chronic pleural inflammation. Double-hit lymphoma (DHL), which is defined as aggressive mature B-cell lymphoma with MYC and BCL2 or BCL6 rearrangements, is a highly aggressive malignancy that tends to have extranodal involvement and is resistant to standard immunochemotherapy. We herein report a 55-year-old man with no history of chronic pleural inflammation, diagnosed with primary chest wall DHL with MYC/BCL6 rearrangement, and harboring a unique BCL6 translocation, t(3;7)(q27;p12). After six courses of intensive chemotherapy, he has achieved complete remission. To our knowledge, this is the first case report of primary chest wall DHL.

Excellent Response to Blinatumomab in Children and Young Adults with Refractory B Lineage Acute Lymphoblastic Leukaemia for Persistent MRD or after Debulking Chemotherapy for Higher Disease Burden

Introduction: A recent phase I/II study of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukaemia (B-ALL), found 39-51% achieved complete, often MRD negative, remission after two cycles of therapy. Higher responses were observed in patients with less than 50% bone marrow blasts, compared to greater than 50% (55.6% vs 32.7% (95% CI 30.8-78.5 and 20.3-47.1 respectively)1. Furthermore, an adult study showed complete minimal residual disease (MRD) response rates of 78% when blinatumomab was used to treat MRD-positive ALL in haematological remission 2. Hence response rates (and toxicity) to blinatumomab are highly correlated with pre-treatment disease burden. We present preliminary data showing an excellent response to blinatumomab in children and young adults with resistant B-ALL who had persistent MRD, or after debulking chemotherapy to achieve a partial remission.Methods: Eleven patients were identified through a national survey. The mean age of patients was 10 years (range 0.7-22 years, 3 infants and 1 Down syndrome ALL). All patients had B-lineage ALL which was CD19 positive. None had active CNS disease at the point of receiving blinatumomab. Prior to administration of blinatumomab, all patients either had persistent MRD following several courses of intensive chemotherapy or received debulking chemotherapy for heavier marrow infiltrates. Pre-blinatumomab chemotherapy to which the patients had failed to obtain an adequate MRD response included UKALL 2011 Regimens A or C, UKALL R3, Interfant 06 or NOPHO high risk blocks. Patients received 5-15 µg/m2 of blinatumomab for 1-2 cycles prior to definitive therapy.Results: Pre-blinatumomab, all patients except one were in morphological remission with MRD measurable by PCR (0.003-1%), the remaining patient had 9% marrow disease by morphology. After 1-2 cycles of blinatumomab all patients had negative MRD when measured by flow cytometry and/or by PCR, giving a 100% response rate. This was followed by Haemopoietic stem cell transplant (HSCT) in nine patients and the remaining two are awaiting transplant. Further data on patient characteristics, CNS status, relapse and survival outcome are being collected and will be presented at the meeting.Minimal toxicity was observed; of the seven patients in whom toxicity data were available, three had grade 1 CRS, which resolved spontaneously without interruption of therapy or treatment with corticosteroids or Tocilizumab. One patient reported grade 1 neurotoxicity.This preliminary UK experience demonstrates that excellent MRD response is observed with minimal toxicity in children and young adults who receive blinatumomab for persistent MRD or after debulking chemotherapy. This provided a bridge to transplant in patients who would otherwise not have benefited from the procedure because of persistent MRD. We are planning to extend these observations by undertaking a study of this strategy in first high-risk B-ALL relapse.Stackelberg Av, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. 2016;34(36):4381-4389.Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. DisclosuresGhorashian:Celgene: Other: travel support; Novartis: Honoraria. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Vora:Amgen: Other: Advisory board; Novartis: Other: Advisory board; Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board.

Demographics, Treatment Outcomes and Resource Utilization Among Patients Hospitalized with Adult Onset Hemophagocytic Lymphohistiocytosis (HLH): A Nationwide Analysis

▪Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease in which impaired natural killer and cytotoxic T-cell function results in excessive immune activation. It is predominantly seen in children; most of the available data comes from the pediatric population so it cannot be generalized to adult HLH. Treatment of HLH usually involves either treating the underlying cause in the secondary form (i.e. malignancy with chemotherapy, rheumatologic with immune suppression) or chemotherapy and stem cell transplantation for primary, familial etiology, multiple courses of intensive chemotherapy, with stem cell transplantation for relapse and familial disease. Recently, increasing adult HLH cases have been reported. The goal of this study is to describe the association between patient factors, geography, hospital resource utilization, and mortality among adult HLH patients.Methods: We performed a retrospective cohort analysis of the National Inpatient Sample 2012, 2013 and 2014 Databases (HCUP-NIS). Patients were included in the study if they had a principal diagnosis of HLH and were older than 18 years. We used descriptive statistics to characterize the cohort in terms of personal demographic factors (age, race, sex, insurance type, community-level income level), hospital characteristics (size, region, teaching status, and urban or rural location), and admission timing (weekend or weekday). We performed univariate and multivariate regression to analyze the association of the following factors with length of stay and mortality: age, sex, Charlson index, hospital region (Northeast NE, Midwest MW, South, West), income, insurance, hospital size, weekend versus weekday, hospital location (rural versus urban), teaching status. All analyses applied the HCUP-NIS weights.Results: The cohort comprised 760 patients, the majority of whom were male (57.9%), aged 21-30 years (26.3%), white (56.3%), and treated in large (78.9%) and/or teaching (92.1%) hospitals, third quartile for median household income (30.4%), covered by private insurance (43.4%), and treated in the southern US (32.2%). Per hospitalization, the average total hospital charges were $210,526 (95% CI $176,251 to $244,801) and the average length of stay (ALOS) was 18 days (95% CI 16 to 20). On multivariate analysis, ALOS was significantly longer with patients at teaching hospitals (AMD 5.10 95% CI 0.57 to 9.64, p=0.03) or with self-pay status (AMD 29.05 95% CI 21.62 to 36.48, p <0.01). Coverage with private insurance was associated with reduced ALOS (AMD -5.04 95% CI -10.19 to 0.11, p=0.05). Hospital charges was lower with age (AMD -4434 95% CI -7786 to -1082, p=<0.01); however Charlson index increased hospital charges (AMD 33876 95% CI 6043 to 61708, p=0.02). For mortality, age (OR 1.03, 95% CI 1.01-1.05, p=0.002), Charlson index (OR 1.29, 95% CI 1.05-1.57, p=0.013), and Medicaid coverage (OR 0.19, 95% CI 0.049 to 0.698, p=0.013) were statistically significant on univariate analysis, however only age (OR 1.02 95% CI 1.00 to 1.04, p=0.045) was statistically significant on multivariate analysis.Discussion: HLH in adults remains a rare disease which requires prolonged hospitalization and high resource utilization. Receiving care in teaching hospitals increases the length of stay most likely reason is that sicker and more complex patients often end up at teaching hospitals. Private insurance coverage reduced ALOS and self pay increased it. We hypothesize that the shorter ALOS with private insurance is due to increased scrutiny by the insurance provider, while the longer ALOS with self pay is related to difficulties ensuring outpatient follow up. In addition, we hypothesize that the decrease in hospital charges with increasing age may be because of early mortality among these patients. However, further studies are required to investigate the above noted associations. DisclosuresBussel:Rigel: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Protalex: Consultancy; Momenta: Consultancy; Novartis: Consultancy, Research Funding; Uptodate: Honoraria; Prophylix: Consultancy, Research Funding. Marks:UPMC: Employment; Heron: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Equity Ownership; Lilly: Membership on an entity's Board of Directors or advisory committees; Odonate: Membership on an entity's Board of Directors or advisory committees.