Reinduction Chemotherapy Research Articles

Homoharringtonine combined with cladribine and aclarubicin (HCA) in acute myeloid leukemia: A new regimen of conventional drugs and its mechanism.

Objective The prognosis of children with refractory acute myeloid leukemia (AML) is poor. Complete remission (CR) is not always achieved with current salvage chemotherapy regimens before transplantation, and some patients have no chance of transplantation. Here, we aimed to describe a new regimen of conventional chemotherapy drugs (homoharringtonine, cladribine , and aclarubicin (HCA)) for refractory AML and its mechanism in vitro. Methods We retrospectively collected the clinical data of 5 children with primary refractory AML using HCA as reinduction chemotherapy, and CR rates, adverse reactions, and disease-free survival (DFS) were analyzed. The effects of homoharringtonine, cladribine, and aclarubicin alone or in combination on the proliferation of HL60 and THP1 cells were analyzed by CCK-8 assay. Furthermore, CCK-8 was used to determine the effects of HCA, alone or in combination with apoptosis inhibitors, necroptosis inhibitors, ferroptosis inhibitors, or autophagy inhibitors, on the proliferation of HL60 and THP1 cells and to screen for possible HCA-mediated death pathways in AML cells. The pathway of HCA-mediated AML cell death was further verified by Hoechst/PI staining, flow cytometry, and Western blotting. Results After 2 cycles of conventional chemotherapy, none of the 5 children with AML achieved CR and were then treated with the HCA regimen for two cycles, 4 of 5 achieved CR, and another child achieved CR with incomplete hematological recovery (CRi). After CR, 3 children underwent hematopoietic stem cell transplantation (HSCT), and only 2 of them received consolidation therapy. As of the last follow-up, all 5 patients had been in DFS for a range of 23 to 28 months. The inhibition rate of homoharringtonine, cladribine, and aclarubicin in combination on HL60 and THP1 cells was significantly greater than that of a single drug or a combination of two drugs. We found that inhibitors of apoptosis and necroptosis were able to inhibit HCA-mediated cell death but not ferroptosis or autophagy inhibitors. Compared with the control group, the number of apoptotic cells in the HCA group was significantly increased and could be reduced by an apoptosis inhibitor. Western blot results showed that PARP, caspase-3, and caspase-8 proteins were activated and cleaved in the HCA group, the expression of Bax was upregulated and that of Bcl-2 was downregulated. The expression of apoptosis-related proteins could be reversed by apoptosis inhibition. Compared with the control group, the expression levels of the necroptosis-related proteins RIP1, RIP3, and MLKL were downregulated in the HCA group but were not phosphorylated. The necroptosis inhibitor increased the expression of RIP1 but caused no significant changes in RIP3 and MLKL, and none were phosphorylated. Conclusions HCA, as a new regimen of conventional drugs, was a safe and efficacious reinduction salvage strategy in children with refractory AML before HSCT. HCA exhibits the synergistic growth inhibition of AML cells and induces cell death mainly through apoptosis.

Incidence of invasive fungal infection in acute lymphoblastic and acute myelogenous leukemia in the era of antimold prophylaxis

The incidence of invasive fungal infection (IFI) in patients with acute myeloid leukemia (AML) has decreased with the introduction of antimold prophylaxis. Although acute lymphoblastic leukemia (ALL) has a lower risk of IFI than does AML, the incidences of IFI in both AML and ALL in the era of antimold prophylaxis should be re-evaluated. We analyzed adults with AML or ALL who had undergone induction, re-induction, or consolidation chemotherapy from January 2017 to December 2019 at Seoul National University Hospital. Their clinical characteristics during each chemotherapy episode were reviewed, and cases with proven or probable diagnoses were regarded as positive for IFI. Of 552 episodes (393 in AML and 159 in ALL), 40 (7.2%) were IFI events. Of the IFI episodes, 8.1% (12/148) and 5.9% (13/220) (P = 0.856) occurred in cases of ALL without antimold prophylaxis and AML with antimold prophylaxis, respectively. After adjusting for clinical factors, a lack of antimold prophylaxis (adjusted odds ratio [aOR], 3.52; 95% confidence interval [CI], 1.35–9.22; P = 0.010) and a longer duration of neutropenia (per one day, aOR, 1.02; 95% CI, 1.01–1.04; P = 0.001) were independently associated with IFI. In conclusion, the incidence of IFI in ALL without antimold prophylaxis was not lower than that in AML. A lack of antimold prophylaxis and prolonged neutropenia were independent risk factors for IFI. Clinicians should be on guard for detecting IFI in patients with ALL, especially those with risk factors.

A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in Low Risk (LR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs): A Report from Children's Oncology Group Study AALL1331

A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in Low Risk (LR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs): A Report from Children's Oncology Group Study AALL1331

Immediate Allogeneic Hematopietic Stem Cell Transplantation for Patients with NPM1-Mutated AML in Molecular Relapse

BackgroundAccording to ELN 2017 classification NPM1-mutated AML is characterized as favorable or intermediate risk depending on the coexistence of FLT3 mutations. For pts with favorable risk profile allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) is not recommended. Because NPM1 mutations are stable, and persisting or increasing levels are a strong predictor of relapse, regular monitoring of measurable residual disease (MRD) by quantitative PCR (qPCR) is recommended. Early HSCT in molecular relapse can be an effective treatment strategy and avoid possible complications of reinduction chemotherapy. From 2014 we started to search for a donor immediately after molecular relapse and proceed to HSCT without reinduction chemotherapy.MethodsMRD was monitored at least every 3 months (mos) in all pts with NPM1-mutated AML in CR by qPCR in bone marrow or peripheral blood. Molecular relapse was defined as an increase of MRD above a cut-off of 1% NPM1/ABL1. The conditioning regimen consisted of Treosulfan (Treo, 30g/m 2) and Fludarabin (Flu, 120mg/m 2). In pts with hematological relapse or a very high NPM1 ratio at the time of HSCT Melphalan (Mel, 100mg/m 2) was added before Treo/Flu to induce aplasia. Donors were HLA-compatible unrelated donors in 10/13 pts, HLA identical sibling in 1 pt and haploidentical related donors in 2 pts. All pts were transplanted with G-CSF stimulated peripheral blood stem cells. Immunosuppression consisted of ATG and Ciclosporin in combination with MTX or MMF and posttransplant Cyclophosphamide for haploidentical HSCT (2 pts).Results17/37 pts fit for allogeneic transplantation relapsed after initial induction and consolidation therapy. 4 pts showed a hematological relapse. In 13/15 pts (median age 52 (37-72) years) a molecular relapse was detected at a median of 9 (6-42) mos after diagnosis, these pts are analyzed here. 10/13 relapses occurred within 12 mos after CR. 11/13 pts relapsed after achieving MRD negative remission, 2 pts progressed from MRD positive hematological remission. Median time from increase in MRD to HSCT was 2 (2-4) mos. Even after this short time period, 6/13 pts developed a hematological relapse before start of conditioning therapy. Together with 3 pts with a high molekular NPM1 level, these 6 pts received melphalan for induction of aplasia before starting Treo/Flu. Although hematological regeneration took longer for these pts compared to pts without melphalan, there were not more infectious or bleeding complications. All 13 pts reached complete hematological and molecular remission after HSCT. After a median follow-up of 20 (4-47) mos all pts are in CR. 2 pt relapsed 6 and 13 mos after HSCT, but reached CR again after DLI (1 pt.) and venetoclax(1pt). In all pts the duration of second CR after HSCT lasted longer than the first CR.ConclusionThis analysis shows the efficacy and feasibility of early allogeneic HSCT without reinduction chemotherapy in molecular or early hematological relapse for NPM1- mutated AML pts. For this strategy pts have to be monitored strictly at regular intervals after end of chemotherapy consolidation, because most relapses can be detected at molecular level. DisclosuresNo relevant conflicts of interest to declare.

Blinatumomab Is Cost-Effective Compared to Standard Chemotherapy for Children with High Risk Relapses of Acute Lymphoblastic Leukemia: A Cost-Effectiveness Analysis Using Population-Based Healthcare Data

▪Introduction: Though cure rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly, outcomes for children with relapsed ALL remain poor. Novel immunotherapies have proved effective in relapsed disease. Blinatumomab, a bispecific T-cell engager targeting CD19, was recently shown to improve disease-free and overall survival among children with high-risk relapsed disease (Brown et al, 2021) prior to proceeding to stem cell transplant. Blinatumomab however also represents a significant cost burden to institutions and healthcare systems. Our objective was thus to determine the cost-effectiveness of blinatumomab vs. standard of care therapy among children with high-risk relapsed ALL.Methods: We used a childhood ALL-specific policy simulation model previously developed using real world clinical, healthcare utilization, and cost population-based data from Ontario, Canada, and restricted it to children with B-lineage ALL who relapsed with 18 months of their original diagnosis to capture a population of patients with high-risk relapse who survived their original month of re-induction chemotherapy. This model was combined with published data from the Children's Oncology Group randomized control study AALL1331 to estimate the long-term survival, healthcare costs and quality adjusted life years associated with two courses of blinatumomab vs. two courses of standard intensive chemotherapy, followed by stem cell transplant. Combining these two sources allowed for the creation of a multi-state survival model and the estimation of the impact of blinatumomab upon relapse and survival. Healthcare costs for the administration of blinatumomab or chemotherapy were sourced from administrative data, provincial formularies, and published sources. Lifetime costs and quality-adjusted life years were calculated while Monte Carlo simulation was used to propagate parameter uncertainty in the cost-effectiveness outcomes. All costs were calculated in Canadian dollars (CAD).Results: Blinatumomab was associated with on average higher life expectancy (43.4 years vs. 36.8 years) and a higher number of quality adjust life years [2.75 QALYs gained, 95 th confidence interval (95CI) -0.44 to 5.99] but higher costs (60,420 CAD, 95CI 26,794 - 94,047) compared to standard intensive chemotherapy. The incremental cost effectiveness ratio (ICER) associated with blinatumomab was 21,970 CAD/QALY gained. However, substantial uncertainty around model parameters resulted in wide confidence intervals around cost-effectiveness outcomes.Discussion: Initial evidence indicates that the use of blinatumomab in high-risk relapse of childhood ALL as compared to standard chemotherapy is associated with a cost-effectiveness ratio that is comparable to or lower than that associated with other interventions recently introduced in pediatric ALL, and represents a cost-effective intervention for this population. However, estimates are based on limited evidence; further research is necessary to better inform several model parameters and thereby decrease uncertainty in cost-effectiveness outcomes. DisclosuresGupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Combination with UK ALL-R3 Induction Chemotherapy for Children, Adolescents and Young Adults with Relapsed Acute Lymphoblastic Leukemia (ALL): A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial

Introduction: Vincristine intensification has the potential to improve outcomes in ALL, but severe neurotoxicity has prohibited escalation beyond standard capped doses. Vincristine sulfate liposome injection, VSLI (Marqibo®) is a liposomal formulation of aqueous vincristine that optimizes pharmacokinetics, prolongs circulating half-life, increases tissue penetration, and may be better tolerated than standard vincristine. VSLI received accelerated FDA approval for adults with relapsed/refractory (r/r) ALL, at a dose of 2.25 mg/m 2/dose without a dose cap. A phase I trial of VSLI in children and young adults with r/r ALL demonstrated safety, tolerability, and evidence for single-agent activity (Shah NN, et al. Pediatric Blood Cancer, 2016). Studies of VSLI with combination chemotherapy in children have not been conducted. With emerging data supporting improved outcomes for patients (pts) with r/r ALL who proceed to immunotherapy with low-burden disease, identifying safe and effective reinduction regimens to reduce disease burden remains a priority.Methods: This multicenter pilot study conducted through the TACL consortium was designed to assess safety and feasibility of VSLI as replacement for standard vincristine with combination chemotherapy for individuals between the ages of 2-21 years with r/r ALL. Two dose levels of VSLI were utilized without a dose cap: Dose level 1 (DL1) 1.5 mg/m 2/dose; and Dose level 2 (DL2) 2.0 mg/m 2/dose. Treatment success was determined by both 1) the absence of a dose-limiting toxicity (DLT) (as defined by any > Grade 3 regimen related non-hematologic toxicity which precluded completion of the pre-specified treatment course or from proceeding to subsequent therapy within 7 weeks) and 2) completion of the prescribed treatment regimen. Adverse event grading was based on CTCAE v4.03. Bone marrow aspirate was used for standard morphologic assessment of response with central flow cytometric analysis for minimal residual disease (MRD) determination with a cut-off of <0.01% of mononuclear cells considered as MRD negative. This analysis reports the toxicities and feasibilities for Cohort A which constituted the 4-drug UK ALL-R3 induction regimen consisting of VSLI, dexamethasone, mitoxantrone, and asparaginase (pegaspargase or Erwinia).Results: A total of 10 pts with r/r B-ALL, median age 13.4 (range 5.0-17.3 years) were treated on Cohort A. Pts were heavily pre-treated, with 3 having relapsed after prior allogeneic stem cell transplantation; 8 of 10 had an M3 marrow (>/= 25% blasts). The first 4 pts were treated at DL1. All 4 were evaluable for toxicity and response and met the criteria for treatment success, facilitating dose escalation to DL2. At DL2, 4 pts were treated, with 2 experiencing DLT, including one grade (Gr) 5 event (Table 1). Two additional pts were subsequently treated at DL1 and achieved treatment success, confirming safety and feasibility of DL1 with a VSLI dose of 1.5 mg/m 2 in combination with UK ALL-R3 4-drug induction. Nine of 10 (90%) pts achieved a morphologic complete remission (CR), 5 of which were MRD negative. The median VSLI dose administered at DL1 was 2.3 mg (range, 1.8-3.2 mg) and at DL2 was 2.2 mg (range, 1.5-3.3 mg) demonstrating the feasibility of dosing beyond the standard vincristine dose-cap of 2 mg. Transient aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were seen in 8 pts, 6 of whom had a grade 1-2 toxicity. Gr 3 hepatic toxicities were seen in 3 pts: 1 each with ALT elevation and hyperbilirubinemia; ALT and AST elevation; gamma-glutamyl transferase elevation. Toxicities were generally consistent with the UK ALL-R3 regimen.Conclusions: In children with r/r ALL, the combination of UK ALL-R3 with VSLI was highly effective with an acceptable safety profile. DL1 (1.5 mg/m 2/dose) was found to be the maximum tolerated dose in combination with this intensive re-induction regimen. The trial continues to enroll at DL1 in the expansion phase to obtain additional safety and response data with this 4-drug regimen. Additionally, 2 cohorts have been added to gain further experience with VSLI in combination with 3-drug induction (Cohort B: UK ALL-R3 without mitoxantrone) and with ALL maintenance chemotherapy (Cohort C: dexamethasone, methotrexate, mercaptopurine). VSLI has potential as a vincristine dose-intensification strategy in combination with reinduction chemotherapy for r/r ALL in pediatric patients. [Display omitted] DisclosuresHermiston: Novartis: Consultancy; Sobi: Consultancy. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Wayne: Spectrum/Acrotech: Research Funding; KITE/Gilead: Research Funding.

Genetic Diversity within Leukemia-Associated Immunophenotype-Defined Subclones in AML

Acute myeloid leukemia (AML) is a heterogeneous clonal disease and in different patients, different combinations of mutations may be found that drive the disease. Also within patients, various leukemic clones with a different combination of mutations may co-exist, reflecting various evolutionary stages of the disease. At present, flowcytometry and mutational analyses are used to keep track of the malignant cells during and after treatment. Using panels of antibodies, abnormal cells can be identified when lineage markers are over- or underexpressed, or when abnormal differentiation leads to the co-expression of markers that normally are not expressed together on hematopoietic cells. These patient-specific leukemia-associated immunophenptypes (LAIPs) can be followed during and after treatment, and enable the early detection of resistant and recurring disease. Often, several LAIPs are present simultaneously within a patient, but their clonal relationship is not always clear. In addition, next-generation sequencing and mutation-specific PCR can be used to follow the leukemic cells. As the clinical consequences of MRD-positivity may consist of high-dose re-induction chemotherapy or stem cell transplantation, accurate results are of the highest importance. Although it has already been shown that flowcytometry and mutational analysis may have added value, in-depth information on the genetic make-up of immunophenotypically defined normal and leukemic subclones and their clonal relationship in AML is still scarce. To study the genetic similarities and differences between various normal and leukemic subclones defined by immunophenotyping, we performed an in-depth analysis of the genetic makeup of FACS-sorted immunophenotypically normal and aberrant subclones in 10 cases of AML. In total, 86 LAIPs and normal cell fractions were sorted and fully genotyped using error-corrected sequencing with a panel genes that are recurrently mutated in AML. In some cases, different aberrant populations from the same patient carried identical mutations, indicating that the leukemia was highly homogeneous, and that the phenotypically different LAIPs all were part of the same genetic clone. In these cases, monitoring the disease by following one of the present LAIPs would be sufficient, or, alternatively, following disease dynamics by molecularly monitoring one of the mutations would accurately show the dynamics of the disease. In other cases, different subclones harbored a different set of mutations. In addition, immunophenotypically normal populations frequently carried mutations, or, inversely, no mutations were found in immunophenotypically clearly aberrant clones. In these cases, following the disease by LAIPs or molecular markers would carry the risk that several subclones would be missed. In case these clones would be relevant for resistance or relapse, using either technique would be at risk to fail to detect MRD positivity. This work underscores that currently available, state-of-the-art immunophotyping and gene panels have added value and should be used simultaneously. We conclude that currently, MRD detection by molecular and immunophenotypic techniques are complementary, and should be used in parallel in order to obtain the most complete view on resistant disease and early detection of relapse. At the same time, both techniques can be further optimized with more monoclonal antibodies and genes that are screened for mutations, in order to increase their resolution. DisclosuresNo relevant conflicts of interest to declare.

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Phase 2 Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Capecitabine in Combination with Endocrine Therapy as Maintenance Therapy after Bevacizumab Plus Paclitaxel Induction Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: KBCSG-TR1214

Simple SummaryTo investigate a possible treatment strategy for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC), we investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab–paclitaxel induction therapy and did not have progressive disease were randomized to receive maintenance therapy with endocrine therapy alone (group E; n = 46) or endocrine therapy plus capecitabine (group EC; n = 44). The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC than in group E (11.1 vs. 4.3 months; hazard ratio, 0.53; p < 0.01). At 24 months from the induction therapy start, the overall survival (OS) rate was significantly higher in group EC than in group E (83.5% vs. 62.3%; p = 0.02). Therefore, the addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.Optimal treatment strategies for hormone receptor (HR)-positive, HER2-negative advanced and/or metastatic breast cancer (AMBC) remain uncertain. We investigated the clinical usefulness of adding capecitabine to maintenance endocrine therapy after induction chemotherapy and the efficacy of reinduction chemotherapy. Patients who had received bevacizumab–paclitaxel induction therapy and did not have progressive disease (PD) were randomized to maintenance therapy with endocrine therapy alone (group E) or endocrine plus capecitabine (1657 mg/m2/day on days 1–21, q4w) (group EC). In case of PD after maintenance therapy, patients received bevacizumab–paclitaxel reinduction therapy. Ninety patients were randomized. The median progression-free survival (PFS) under maintenance therapy (primary endpoint) was significantly longer in group EC (11.1 {95% CI, 8.0–11.8} months) than in group E (4.3 {3.6–6.0} months) (hazard ratio, 0.53; p < 0.01). At 24 months from the induction therapy start, the overall survival (OS) was significantly longer in group EC than in group E (hazard ratio, 0.41; p = 0.046). No difference was found in the time to failure of strategy (13.9 and 16.6 months in groups E and EC, respectively). Increased capecitabine-associated toxicities in group EC were tolerable. Addition of capecitabine to maintenance endocrine therapy may be a beneficial option after induction chemotherapy for HR-positive, HER2-negative AMBC patients.

Feasibility and benefits of a structured prehabilitation programme prior to autologous stem cell transplantation (ASCT) in patients with myeloma; a prospective feasibility study

Evidence supports the benefits of exercise-based rehabilitation in promoting recovery in myeloma patients following autologous stem-cell transplantation (ASCT). However, ‘prehabilitation’ has never been evaluated prior to ASCT, despite evidence of effectiveness in other cancers. Utilising a mixed method approach the authors investigated the feasibility of a mixed strength and cardiovascular exercise intervention pre-ASCT. Quantitative data were collected to determine feasibility targets; rates of recruitment, adherence and adverse events, including 6minute walking distance (6MWD) test and patient reported outcome measures (PROMs). Qualitative interviews were undertaken with a purposive sample of patients to capture their experiences of the study and the intervention. The authors recruited 23 patients who attended a mean percentage of 75% scheduled exercise sessions. However, retention rates were limited, with only 14/23 (62%) completing the programme. In these patients, the 6MWD increased from a mean of 346 to 451m (i.e. by 105m, 95% CI 62 to 148m) with no serious adverse events. Whist participants found the exercise programme acceptable and reported improvement in their physical fitness and overall mental health and wellbeing prior to ASCT, the study identified challenges in hospital attendance for the prehabilitation schedule whilst receiving induction or re-induction chemotherapy. Evaluation of digitally-enhanced directed but remote prehabilitation models for this patient group is warranted.Trial registration number NCT03135925

Improved outcome in AML relapse after allogeneic transplant with high-intensity chemotherapy followed by 2nd allogeneic stem cell transplant or donor lymphocyte infusion.

Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2ndalloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60years; range, 10-75). Of these, 4 patients underwent 2ndalloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6months, the statistical significance was preserved. Factors including age, donor source at 1stalloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible.

The Degree and Effect Of Weight Loss In Acute Myeloid Leukemia Patients Receiving Induction and Post-Remission Chemotherapy

▪ IntroductionInduction and post-remission chemotherapy for acute myeloid leukemia (AML) is an intensive regimen with significant toxicities performed almost exclusively in inpatient or closely monitored outpatient settings. Extreme weight loss is associated with poor outcomes in cancer. We studied whether treated AML patients (pts) lose a substantial amount of weight and whether weight loss affects overall survival (OS). MethodsAdult pts diagnosed with AML at the Cleveland Clinic from 08/08 - 11/12 were included. All pts completed intensive induction chemotherapy with 7+3 (cytarabine and anthracycline – daunorubicin, idarubicin, or mitoxantrone) as first-line therapy. Pts must have achieved complete remission (CR) by first-line induction or day 14 re-induction chemotherapy. Previously treated pts or those with relapsed or refractory disease were excluded. Co-morbidities and AML disease characteristics were assessed, in addition to weight and body-mass index (BMI) at baseline and throughout AML treatment course until disease relapse, stem cell transplantation (SCT), or loss-to-follow-up/death. The primary endpoints were change in BMI relative to completion of post-remission therapy (PRT), OS, and event-free survival (EFS). OS and EFS were measured from completion of PRT to the date of death (OS) and relapse or need for SCT (EFS). To assess impact of weight recovery on OS and EFS separate linear regression models were fit to each pt to determine rate and direction of change during the first 3 months following the completion of PRT. Pts whose fitted regression lines had slopes>0 were considered to have positive weight trajectories; pts with slopes<0, negative trajectories. Group comparisons were made using the Wilcoxon signed-rank test, logrank test, and proportional hazards models. ResultsOf 126 AML pts who met the inclusion criteria, 43% (n=54) were male and the median age at treatment start was 54 years (range 18-77). Disease characteristics were: acute promyelocytic leukemia 11% (n=14), other AML 89% (n=112); de novo 75% (n=94), secondary 24% (n=31); cytogenetic risk group - favorable 23% (n=29), intermediate 47% (n=59), unfavorable 21% (n=27), unknown 9% (n=11). Co-morbidities potentially impacting BMI and outcome included diabetes (11%), hypertension (42%), hyperlipidemia (28%), alcohol use (65%), use of steroids (13%) or oral contraceptives (16%). Median weight at the start of therapy was 84.9kg (range 37-159.5) and BMI was 29.6 (range 17.6-57.8). BMI groups included normal (18.5-24.9, 26%), overweight-moderately obese (>25-35, 54%), severely obese (>35, 20%). From the start of treatment, median weight loss was: 2% (range -21-53%, p=0.0001) at day 14; 6% (range -19-22%, p<0.0001) at time of CR determination; 4% (range -23-38%, p<0.0001) at end of PRT. With the exception of diabetes (time of CR, p=0.06) and alcohol use (time of CR and end of PRT, p=0.05 in both cases), none of the clinical or demographic factors examined impacted weight loss. In total, 29% of pts (n=37) had >10% weight loss at the completion of PRT, representing an absolute loss of 5.9-20.6kg; 40% of pts (n=50) had a loss<10%, and 31% of pts (n=39) had no change or weight gain. In the group with >10% loss, median time to recovery of >95% pre-treatment weight was 7 months; 11% of pts (n=4) exceeded their pre-treatment weight by >10%. Only age (p=0.06) was associated with weight recovery time, with younger pts recovering weight faster (Figure 1). 60% of pts (n=73) had disease progression and 36% of pts (n=44) had died; estimated EFS and OS are 10.1 (95% CI 6.6-14.7) and 28.2 months (95% CI 17.1-46.4), respectively. The degree of weight loss following completion of PRT was not associated with EFS (p=0.79) or OS (p=0.82). However, there was some indication that pts with positive weight trajectories had longer EFS than pts with negative trajectories, p=0.07 (Figure 2); OS was not impacted significantly (p=0.26). ConclusionAML pts achieving CR with induction therapy experience a median 6% weight loss from start of therapy, but recover by 7 months (median). Those with diabetes or alcohol use lose more weight. Weight changes were not associated with survival; however, there was some suggestion that pts who began to gain weight once PRT was completed had longer EFS than pts whose weight continued to decline. These data can be used to frame pt expectations about weight fluctuations going through AML treatment. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Patients Who Are Refractory to Ida-FLAG As Initial Induction Chemotherapy for AML Have Persistence of the Dominant Genetic Mutations and a Poor Clinical Outcome

Patients with AML who do not achieve remission with conventional 7+3 induction chemotherapy can frequently achieve CR with an intensive reinduction regimen such as Ida-FLAG. However, when Ida-FLAG is used as the initial induction regimen, the outcome of patients who do not achieve remission and the success of reinduction therapy is unknown.We identified 100 patients with newly diagnosed AML who received Ida-FLAG as their initial induction chemotherapy between November 2012 and September 2016. The median age was 59 (range 18-77); 49% were male. Twenty had therapy-related AML, 15 had AML following an MPN, 16 following MDS and 10 following an MDS/MPN overlap syndrome; 39 had de novo disease. One had low, 38 intermediate, 53 high risk and 8 unknown/inconclusive cytogenetics. Seventy-two achieved CR/CRi with FLAG-Ida induction. Nine died during induction prior to response assessment, and 19 were refractory. Survival, censored at the time of allogeneic transplantation, was longer for patients who achieved CR/CRi compared to those who did not (median OS 388 days vs 153 days, two-tailed log-rank p<0.001).Forty-four patients had DNA sequencing for mutations in 54 genes commonly mutated in AML using the TruSight Myeloid Sequencing Panel (TMSP; Illumina, San Diego, CA) on the Illumina MiSeq platform at the time of diagnosis. TP53 mutations were associated with disease refractoriness (p<0.05, corrected for multiple comparisons), as were high risk cytogenetics (p<0.05).Of the 19 patients whose disease was refractory to initial induction with Ida-FLAG, nine received intensive re-induction chemotherapy with NOVE-HiDAC (n=7), Ida-FLAG (n=1) and HiDAC, mitoxantrone, asparaginase, ATRA, vinblastine, valproate and imatinib (n=1). The remaining 10 patients received a low intensity experimental therapy on a clinical trial (n=1), low intensity/palliative therapy (n=2) or supportive care alone (n=7). Age, gender, presence of secondary AML and cytogenetic risk did not differ between those who did/did not receive reinduction.Of the 9 patients who received reinduction chemotherapy, only 1 achieved CR. This patient had secondary AML with high-risk cytogenetics and 70% blasts in the marrow at diagnosis. Following initial induction with Ida-FLAG, the patient had 6-7% marrow blasts with no recovery of their peripheral blood counts. The patient received a second course of Ida-FLAG as reinduction and achieved CR 51 days after the start of reinduction chemotherapy. The patient received an allotransplant but died of GVHD 69 days post-transplant. No other patient receiving reinduction chemotherapy responded and none achieved a PR/prolonged aplasia. No patients died during reinduction. No patients receiving experimental agents or low intensity therapy achieved CR or PR. Median OS for those receiving reinduction was similar to patients treated with palliative chemotherapy or clinical trial (182 v 153 days, p=0.2).We next assessed how Ida-FLAG and the reinduction regimens affected the genetic clones and subclones in the patients who did not achieve remission with Ida-FLAG. Paired blood or marrow samples from diagnosis and post-treatment were available for 4 consenting patients who did not achieve remission with Ida-FLAG or reinduction. For 2 patients, the second sample was available after Ida-FLAG induction and for 2 patients the second sample was available after reinduction. DNA was extracted and sequenced using the TMSP. All 4 patients had variants identified at diagnosis; 3 patients had recognized relevant somatic variants. All the predominant variants found at diagnosis were detected at follow-up. The variant allele fraction (VAF) of the predominant variants from diagnosis was similar or higher at the time of followup as shown in the figure. In one sample, variants found at low level in the diagnostic sample were reduced following reinduction but the dominant variant remained. No new variants were detected in follow-up samples.Thus, patients who do not achieve remission with Ida-FLAG as an initial induction regimen have a poor outcome and very low probability of achieving remission with a conventional reinduction regimen. Inferring clonal architecture by using VAF, reinduction chemotherapy may eliminate minor genetic subclones but the dominant clone persists. New therapeutic agents are needed for these patients. [Display omitted] DisclosuresKamel-Reid:BMS: Research Funding. Gupta:Incyte: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Medivir: Research Funding; Takeda Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Honoraria.

Prospective Study of an Antifungal Program to Reduce Invasive Fungal Infections in Patients with Acute Myeloid Leukemia Receiving Induction and Re-Induction Chemotherapy

Background: Invasive fungal infections (IFI) can occur up to 40% of patients with hematologic malignancies and are most common in patients with acute myeloid leukemia (AML). National averages within the United States, per Infectious Diseases Society of America (IDSA), range approximately from 8-10% in this high risk population. IFIs are not only problematic for individual patient care, potentially resulting in increased antimicrobial usage and delay of future chemotherapy treatments or stem cell transplant, but IFI also negatively impact hospital resource utilization including increased days in hospital and the intensive care unit (ICU).Methods: In attempt to decrease IFIs in hematologic malignancy patients at the University of Virginia Health System (UVAHS), a multidisciplinary team of oncology and infectious diseases physicians, nurses, and pharmacists was formed to develop an Antifungal Program. Retrospective chart review was done of 79 patient encounters from 7/2011 to 9/2014 to establish our baseline cohort. For each of these encounters, extensive patient demographics, clinical, and inpatient event data were collected. Analysis of our baseline data showed a 19.7% proven or probable IFI rate in patients with acute myeloid leukemia undergoing induction chemotherapy. In concordance with IFI rates published by IDSA, we aimed to decrease the IFI in this patient population at UVAHS to less than 10%. With guidance from the American Society of Clinical Oncology's Quality Training Program, our team utilized multiple qualitative and quantitative tools to further understand factors contributing to an increased rate of IFIs. These tools included a process map and Ishikawa cause-and-effect diagram to depict all the steps from leukemia diagnosis to end of treatment and hospital discharge, a Pareto chart to quantify delays of individual steps, and a priority matrix categorizing potential interventions based on impact and ease of implementation. A statistical process control chart (p-chart) depicted rates of IFI in the baseline cohort and intervention groups.Results: Our baseline proven or probable IFI rate in patients with acute myeloid leukemia was 19.7%. Antifungal prophylaxis was not administered to baseline cohort patients. Per Pareto chart analysis, the team identified the most common problems contributing to IFI: inconsistent definition of IFI, no routine antifungal prophylaxis, and lack of education for the health care team. Two Plan-Do-Study-Act (PDSA) cycles of interventions were implemented; post-intervention data were collected and analyzed. From 9/2014 to 8/2016, the first PDSA cycle consisted of individual attending physicians ordering antifungal prophylaxis on an ad hoc basis; the first PDSA cycle resulted in a decreased IFI rate of 11.7% (n = 77). Though close to project aim of less than 10%, this process was burdensome and not sustainable, as it required individual physicians to remember to add antifungal prophylaxis and did not standardize which antifungal agent was used. During the second PDSA cycle from 8/2016 to 4/2017, a clinical practice guideline standardized the definition of IFI and recommended posaconazole as the prophylactic antifungal of choice. Team champions educated physicians, nurses, and pharmacists on the new standard work. This second PDSA cycle resulted in zero IFIs (n = 18), surpassing the team's goal of improving IFI to less than 10%. P-chart depicting IFI reduction is shown in Figure 1. Additionally, median ICU length of stay improved from 2.5 days to 1.5 days. Overall hospital length of stay decreased from 32.3 days to 29.9 days. As no proven or probable IFI were diagnosed during PDSA Cycle 2, no resistant fungal organisms were noted.Conclusions: This project illustrates the importance of forming a multidisciplinary team, whose collaborative effort developed an Antifungal Program that reduced IFI rates in a statistical significant method. When compared to historical controls, the Antifungal Program decreased both IFI rates and ICU length of stay. To ensure sustainability of the quality improvement study, monthly electronic medical record reports will capture guideline compliance, specifically the use of antifungal agents, and track future IFI. The Antifungal Program is an effective clinical tool to not only improve patient care, but likely represents increased patient quality of life, cost-savings, and decreased length of stay. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Timing and Epidemiology of Enterococcus Faecium and E. Faecalis Bloodstream Infections (BSI) in Patients with Acute Leukemia Receiving Chemotherapy

Enterococcal BSI occurs frequently in patients with acute leukemia and causes significant morbidity and mortality. Daptomycin non-susceptible Enterococcus (DNSE) infection has emerged as a threat that has limited treatment options. However, the timing of enterococcal BSI in relationship to chemotherapy is unknown. In addition, previous studies have focused on the epidemiology of vancomycin-resistant E. faecium (VRE) BSI. The present study investigates the timing of enterococcal BSI in relationship to chemotherapy and the epidemiology of both E. faecium and E. faecalis BSI in patients with acute leukemia. We hypothesize that most BSIs are gut derived, mucosal barrier injury infections that occur in patients who undergo intensive chemotherapy that causes prolonged neutropenia and chemotherapy-induced mucositis leading to febrile neutropenia and antimicrobial-induced gut dysbiosis.We conducted a retrospective cohort study of patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) admitted to Duke University for infusional chemotherapy from 2010-15. BSI was adjudicated by CDC criteria. Appropriate enterococcal therapy was defined as receipt of an antibiotic with in vitro activity against the BSI isolate. BSI clearance was defined by negative follow-up blood cultures obtained within 72 hours after positive blood cultures. Recurrent BSI was defined by positive blood cultures for Enterococcus after BSI clearance. Bivariate analysis was performed using chi-squared test.Three hundred twelve patients were evaluated for this study, 83 of whom had enterococcal BSI during the study period (27%; Table 1). Eight-seven percent had BSI due to E. faecium while 13% had BSI due to E. faecalis . Most were febrile (82%) and neutropenic (96%) on broad-spectrum antimicrobials at the time of BSI. All patients had an indwelling central line and had received intensive chemotherapy prior to BSI. Median time from acute leukemia diagnosis to BSI was 30 days. BSI occurred most frequently during the first cycle of induction chemotherapy (47%), but a combined 52% of BSIs occurred during the 2nd-5rd cycles of induction chemotherapy. Sixty-six percent of BSIs qualified as mucosal barrier injury infections. Only 2 patients had metastatic sites of infection: 1 with empyema and 1 with CNS infection, both due to VRE. In terms of clinical response to therapy, 61% of patients achieved cure, and 10% died with BSI. Twenty-eight percent suffered recurrent BSI, and 29% of these patients had DNSE BSI after previous daptomycin exposure. Fifty-one percent of patients underwent central line removal for BSI. Failure to remove the central line for BSI did not increase risk of recurrent BSI (p=0.38).Enterococcal BSI typically occurs as a mucosal barrier injury infection in febrile neutropenic patients with acute leukemia receiving intensive chemotherapy. Many cases take place during re-induction chemotherapy in patients with relapsed or refractory disease. VRE is the most common infecting pathogen, but E. faecalis is not an insignificant cause of BSI (13%). In addition, some E. faecium isolates maintain ampicillin or vancomycin susceptibility. These results support empiric anti-VRE therapy with daptomycin upon initial suspicion for enterococcal BSI, but this therapy could be switched to ampicillin or vancomycin depending on isolate susceptibility to conserve daptomycin susceptibility. The risk of recurrent enterococcal BSI is notable as is the emergence of DNSE following daptomycin therapy. However, failure to remove the central line does not appear to be associated with recurrent BSI. Future study of changes to the gut enterococcal microbiome over the course of chemotherapy for acute leukemia will be critical in ultimately preventing enterococcal BSI. [Display omitted] DisclosuresSung:Cellective: Research Funding; Novartis: Research Funding; Merck: Research Funding.

Incidence of Bleeding Events in Acute Myeloid Leukemia (AML) Patients Receiving Anticoagulation Therapy for Treatment of Deep Vein Thrombosis (DVT) or Pulmonary Embolism (PE) Who Are Also Undergoing Induction or Re-Induction Therapy

Background/Rationale:Venous thromboembolic events (VTE) remain a prevalent complication in cancer patients. Despite this increased risk, the decision on whether or not to treat and/or use prophylactic therapy remains highly debatable among clinicians. Induction and re-induction therapy, in combination with the pathophysiology of the disease can cause profound thrombocytopenia. Additionally, leukemic cells can cause an inappropriate release of procoagulants directly into the bloodstream, initiating the clotting cascade and causing simultaneous clot formation and hemorrhage leading to disseminated intravascular coagulation (DIC). Another major factor to consider in this patient population is central venous access. Although the National Comprehensive Cancer Network (NCCN) guidelines recommend ≥3 months of therapeutic anticoagulation for catheter-associated VTEs, clinicians use anticoagulation cautiously in the AML population due to severe thrombocytopenia and the increased risk of bleeding. Data that can be used to optimize treatment strategies for catheter-associated VTE in patients with acute leukemia are needed as the risk versus benefit for anticoagulation is currently unclear. A recent article by Rajasekhar and colleagues investigated this risk and noted that among patients with severe thrombocytopenia (platelets <50,000/μL) who received therapeutic anticoagulation, 27% experienced a significant bleeding event compared to only 2% of patients who did not receive therapeutic anticoagulation. In order to establish the bleeding complications associated with patients receiving induction or re-induction therapy for AML, we conducted a retrospective chart review evaluating the incidence of bleeding in patients receiving therapeutic anticoagulation for treatment of VTE.Objective:The primary outcome of this study is incidence of bleeding events in AML patients receiving anticoagulation therapy for treatment of DVT or PE who are also undergoing induction or re-induction therapy. Secondary outcomes include incidence of chemical and non-chemical DVT prophylaxis, as well as the difference in incidence of bleeding events among agents.Methods:This is a retrospective chart review evaluating the incidence of bleeding in AML patients receiving anticoagulation for treatment of VTE during induction or re-induction therapy at WFBH from October 2012 to October 2016. AML patients who were >18 years of age who had undergone induction or re-induction chemotherapy and developed a VTE were included in the study. Clinical diagnosis of VTE was confirmed by objective imaging procedures. The following induction or re-induction regimens were excluded: azacitidine or decitabine. Descriptive statistics were used for data analysis.Results: Out of 523 patients screened, 24 met eligibility criteria for a total VTE incidence of 4.6%. The age range for the patients included was 22 to 77, with 14 patients (58.3%) being female and 10 patients (41.7%) being male. Of the patients who developed a VTE, 18 (75%) received non-chemical DVT prophylaxis. Twenty (83.3%) of the 24 VTEs were catheter-associated DVTs. Twenty-two of 24 patients received therapeutic anticoagulation with either heparin (n=21) or enoxaparin (n=1). The 2 patients who did not receive anticoagulation did not have a bleeding event. Patients who developed a bleed were more likely to have supratherapeutic PTTs (defined as PTTs ≥ 90 seconds); however, supratherapeutic levels were isolated and not associated with the time of the bleed. Of the patients who received therapeutic anticoagulation, 8 (36.4%) had a major bleed and 9 (40.9%) had a minor bleed, for an overall bleeding rate of 77.3%. There were no deaths as a result of bleeding events. Of the 20 patients with catheter-associated VTEs, 7 (35%) had a major bleed; 4 of these patients required anticoagulation reversal with protamine.Conclusions:AML patients who received induction or re-induction therapy had a low incidence of VTE overall. However, when patients received anticoagulation for VTE treatment there was a high incidence of bleeding. The results found in this retrospective chart review showed that for patients with catheter-associated VTEs, the risk of bleeding outweighed the risk of VTE. We recommend a risk-adapted strategy where patients do not receive therapeutic anticoagulation until platelet recovery. DisclosuresPowell:Rafael Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ellis:Alexion: Speakers Bureau. Pardee:Rafael Pharmaceuticals: Employment, Research Funding.

CTL019 Therapy Appears Safe and Effective in Pediatric Patients with Down Syndrome with Relapsed/ Refractory (r/r) Acute Lymphoblastic Leukemia

Introduction: Children with Down syndrome have increased risk of developing leukemia. Pediatric patients with Down syndrome-associated acute lymphoblastic leukemia (DS-ALL) are known to have significant toxicities with reinduction chemotherapy and historically poor outcomes with stem cell transplant (SCT) compared to those without Down syndrome. Alternate therapies are urgently needed for this patient population. The anti-CD19 chimeric antigen receptor (CAR) T-cell therapy CTL019 has demonstrated high rates of durable complete remission and a manageable safety profile in children with r/r B-ALL treated in the multicenter ELIANA and ENSIGN trials.Methods: Pooled data from 2 single-arm, multicenter phase 2 trials of CTL019 in pediatric/young adult patients with r/r B-ALL (ELIANA, NCT02435849 and ENSIGN, NCT02228096) were used to characterize efficacy and safety of CTL019 therapy in children with DS-ALL.Results: Eight patients with DS-ALL were enrolled (data cutoff: ELIANA, 23 November 2016; ENSIGN, 1 February 2016). 7 DS-ALL patients were infused with CTL019; 1 patient died prior to infusion due to ALL progression and intracranial hemorrhage. No manufacturing issues occurred during the production of CTL019 for DS-ALL patients. 5/7 infused patients were male, 2/7 had prior SCT, and the patients' ages ranged from 6-16 years.Complete remission (CR) or CR with incomplete blood count recovery (CRi) occurred in 6/7 patients by day 28 (CR+CRi rate, 86%); the 7th patient died (cerebral hemorrhage) prior to day 28 and was not evaluable for response. Multiparameter flow cytometry was negative in bone marrow for minimal residual disease in all responding patients. Two patients have relapsed at 5 and 8 months after infusion (both CD19 negative relapses). Ongoing remissions in the 4 patients without relapse ranges from 2 to 11 months.The safety profile of CTL019 in DS-ALL (n=7) appears similar to that for patients without Down syndrome treated in the same trials (n=90). Grade 3 or 4 cytokine release syndrome occurred in 3/7 patients (43%) with Down syndrome and 44% of patients without Down syndrome. Rates of other grade 3 or 4 adverse events of special interest did not appear to favor a consistent trend between patients with and without Down syndrome (febrile neutropenia: 43% vs 36%; neurological events: 14% vs 11%; tumor lysis syndrome: 14% vs 2%). Importantly, grade 3 or 4 infections were not observed in patients with Down syndrome (0% vs 23%). One patient died after infusion due to intracranial parenchymal hemorrhage on day 15 associated with ongoing coagulopathy. Extent and timing of CTL019 expansion as well as long-term persistence of CTL019 was similar in patients with and without Down syndrome.Conclusions: This is the first analysis of CAR T-cell therapy in pediatric patients with r/r B-ALL and Down syndrome. Although experience in these patients is limited, these data suggest that toxicities appear similar to B-ALL patients without Down syndrome, rates of remission in DS-ALL are high and long-term outcomes of CTL019 therapy with sustained persistence appear promising. Further exploration of CTL019 therapy as an alternative to SCT in children with r/r DS-ALL is warranted. DisclosuresLaetsch:Novartis Pharmaceuticals Corporation: Consultancy. Maude:Novartis Pharmaceuticals: Consultancy, Other: Medical Advisory Boards. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties; Jazz Pharmaceuticals: Consultancy. Boyer:Novartis Pharmaceuticals Corporation: Honoraria. Phillips:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Pulsipher:Chimerix: Other: Advisory board Dec 2015; Jazz Pharmaceuticals: Other: advisory board, education; CSL Behring: Other: advisory board Feb 2017; Adaptive: Other: Advisory board 6/17; Novartis Pharmaceuticals Corporation: Consultancy, Other: Phase II steering committee. Bittencourt:Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Travel Grant; Amgen Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy. Wood:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Mueller:Novartis Pharmaceuticals Corporation: Employment. Weng:Novartis Pharmaceuticals Corporation: Employment. June:Immune Design: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celldex: Honoraria, Membership on an entity's Board of Directors or advisory committees; WIRB/Copernicus Group: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Levine:Tmunity Therapeutics: Equity Ownership, Research Funding; Novartis Pharmaceuticals Corporation: Patents & Royalties, Research Funding; Brammer Bio: Consultancy; GE Healthcare: Consultancy. Hiramatsu:Novartis Pharmaceuticals Corporation: Other: Clinical trials .

Phase I/II Study of Infusional Gemcitabine and High-Dose Melphalan Conditioning Prior to Autologous Stem Cell Transplantation for Patients with Relapsed/Refractory Lymphoma: Interim Safety Analysis

IntroductionThe optimal re-induction and high dose chemotherapy regimens for transplant-eligible patients with relapsed lymphoma are not known. Our centre has previously established the efficacy and tolerability of single-agent high-dose melphalan and ASCT in patients with relapsed/refractory Hodgkin's lymphoma (HL), and others have similarly demonstrated this with non-Hodgkin's lymphoma (NHL). The activity of alkylating agents such as melphalan is dependent on the extent of DNA damage, and combining melphalan with drugs known to inhibit DNA damage repair would be predicted to produce synergistic effects. Gemcitabine is a nucleoside analogue that has been shown to inhibit DNA damage repair caused by prior exposure to alkylating agents, and has clinical anti-tumour activity against lymphoma, and therefore presents a promising combination with alkylators in high-dose chemotherapy studies for lymphoma.ObjectiveTo evaluate the safety and efficacy of infusional gemcitabine prior to high-dose melphalan followed by autologous stem cell transplantation in patients with relapsed/refractory lymphoma. The data reported currently reflects a planned interim safety analysis after the first 40 patients enrolled on the study.MethodsThis is an investigator-initiated single centre study currently enrolling patients as of April 2015. Adult patients with relapsed or refractory HL, aggressive NHL, or indolent NHL after at least one prior systemic therapy are eligible for this study. Inclusion/exclusion criteria included ECOG performance status ≤2, no significant end-organ dysfunction, no prior history of stem cell transplantation, no CNS involvement, and chemo-sensitive disease (at least partial remission to salvage chemotherapy) at the time of transplantation. High dose therapy regimen was as follows: On Day -1, IV gemcitabine was administered as a loading bolus of 75 mg/m2, followed by a continuous infusion rate of 10 mg/m2/min, followed immediately by IV melphalan 200 mg/m2. In the phase I portion of the study, the starting dose of gemcitabine was 1.5 g/m2 in the first cohort, with dose escalation based on standard “3+3” design, increasing by 0.5 g/m2 increments at each dose level to maximum of 2.5 g/m2. Dose-limiting toxicity was defined as grade 3 mucositis >5 days, grade 3 skin toxicity >3 days, grade 3 diarrhea >7 days, or any grade 4 non-hematological toxicity.ResultsThe mean age of the study population was 52 (SD +/-14) with equal numbers of male and female patients. 12 (30%) patients had aggressive NHL (6 DLBCL, 1 PMBCL, 3 ALCL, 2 PTCL), 17 (42.5%) had indolent NHL (15 follicular, 1 lymphoplasmacytic, 1 marginal zone lymphoma), and 11 (27.5%) had HL. At time of relapse, 30% (12/40) of patients had refractory disease after first line therapy, 70% (28/40) had stage III/IV disease, and 6 patients (16%) had >1 prior line of systemic chemotherapy. The median time from relapse to transplant was 90 days (range 12 to 189 days). There were no dose limiting toxicities at 1.5 g/m2 dose of gemcitabine. 8 patients received 2.0 g/m2 and dose-limiting toxicity (grade 3 diarrhea >7 days) was noted in 2 patients, thus the remaining patients received 1.5 g/m2 gemcitabine. 18 patients experienced 24 grade 3-4 adverse non-hematological events: mucositis (7), infectious enterocolitis (5), pneumonia (4), sepsis (2), non-infectious diarrhea (1), esophagitis (1), emesis (1), transaminitis (1), pulmonary edema (1), and stroke (1). There were no treatment-related deaths associated with this regimen. Post-transplant complete remission and partial remission was attained in 25/40 and 9/40 patients, respectively. 6/40 (15%) patients have progressed after transplant, and 2 have died of lymphoma. At a median follow-up of 10 months (range 2-26 months), the progression-free survival is 59.3% and overall survival is 93.8% (Figure 1).ConclusionInfusional gemcitabine at a maximum tolerated dose of 1.5 g/m2 in combination with high dose melphalan as a conditioning regimen for autologous stem cell transplantation is tolerable and appears to be efficacious in patients with relapsed/refractory lymphoma. [Display omitted] DisclosuresStewart:BMS: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Seattle Genetics: Honoraria; Servier: Honoraria; Gilead: Honoraria; Merck: Honoraria; Lundbeck: Honoraria; Roche: Honoraria.

Clonal Progression during First Course of Chemotherapy in Acute Myeloid Leukemia Suboptimal Responders Heralds Reinduction Failure and Early Death

INTRODUCTIONOptimal response to induction chemotherapy for acute myeloid leukemia (AML) is achievement of complete remission (CR) and minimal residual disease (MRD) negativity. Suboptimal responses include achievement of CR but MRD positivity (CRMRD+ patients) as well as failure to achieve CR. The prospect is bleak, especially in the latter group, but intensified treatment can cure some of these. Careful deliberation of patient fitness, drug toxicities and level of residual disease is required prior to choice of reinduction therapy. HYPOTHESISWe hypothesized that by studying clonal architecture changes during AML treatment, subclonal development or progression would add another dimension to the chemotherapy response assessment beyond that of merely a quantitative reduction in blasts or a given MRD marker. PATIENTS AND METHODS25 uniformly treated (“3+7” like) AML patients were included, 7 CRMRD+ (flow cytometry-determined MRD levels between 0.02% and 1%), and 18 who did not achieve CR after the first course of chemotherapy, of whom 17 received reinduction chemotherapy. Median time from diagnosis to CR evaluation after first course of chemotherapy: 33 days (range: 20-74 days)For the CRMRD+ patients; MRD cells from bone marrow samples taken after 1st treatment course were isolated using a FACSAria III based on the appropriate leukemia associated phenotype determined at diagnosis.All samples were analyzed using a 26-gene panel (ASXL1, BCOR, CALR, CBL, CSNK1A1, DNMT3A, ETV6, EZH2, FLT3-TKD, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1 and ZRSR2) . Furthermore, CSFR3, GATA1, PTPN11 and WT1 were analyzed in the group who did not achieve CR. The TruSeq Custom Amplicon kit was used for library prep and samples were sequenced using the MiSeq instrument. RESULTSIn the CRMRD+ group clonal architecture in unsorted diagnosis samples were compared to clonal architecture in the FACS products. In 3 informative cases, a development in the clonal architecture was seen. In two cases, a subclone positive for TET2 only persisted even if the fully mutated clones of the patients (one TET2 +/ NRAS +, one TET2 +/ NPM1 +/ IDH2 +) disappeared. Both patients relapsed. In the third patient; a IDH2 + SRSF2 + clone persisted, a IDH2 + SRSF2 + BCOR + clone disappeared. In the remaining 4 patients no mutations were detected in the FACS product.For the group of patients not in CR clonal architecture development between diagnosis and regeneration after first course of chemotherapy could be studied in 16/18 cases. Two cases were negative for all aberrations tested. 9/16 cases were clonally stable, displaying a reduction in mutation load comparable to leukemic burden reduction. In the remaining 7 cases, clonal development was seen: In 4 cases, one or more subclones were selectively eradicated leaving the more resistant clones. NPM1 was the only marker that was eradicated in more than one clone (n=2) and TET2 was the only marker that persisted in more than one clone (n=2). In 3/7 cases subclones emerged during chemotherapy; a WT1 + NRAS + clone in a NRAS + background, a SETBP1 + TET2 + ASXL1 + RUNX1 + clone in an RUNX1 + background and a DNMT3A + NPM1 + clone in a NPM1 + background. The 2-year survival of patients who received further chemotherapy was significantly different in the three groups (Clonally stable (n=9): 0.58, clonal architecture development but no emerging subclones (n=4): 0.25, AMLs with emerging subclones (n=3): 0 (last patient died after 224 days), P = 0.01 (Log-rank test)). CONCLUSIONThis study provides proof of the concept of subclonal architecture changes even in patients with minute amounts of residual leukemia (CRMRD+ group) and we were able to study the subclonal architecture changes in three of these patients.In patients not reaching CR, clonal architecture development was a rather common occurrence (7/16 cases). In three patients we observed that not only did a subclone resist chemotherapy, it grew during treatment. Even in this small study, this finding proved to be a significant marker of ultimate treatment failure.If corroborated in larger studies, we envisage that an approach like the one applied here can assist physicians' decisions in the choice of further treatment in patients experiencing suboptimal response to induction chemotherapy. DisclosuresMeggendorfer:MLL Munich Leukemia Laboratory: Employment. Koch:Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Outcomes in Obese Patients Undergoing Induction Therapy for Acute Leukemia

Obesity continues to be a growing concern in the United States. According to the guidelines published by ASCO in 2012, chemotherapy doses in this patient population should be calculated based on actual body weight. However, the guidelines do not provide guidance for chemotherapy dosing in patients with hematologic malignancies. We conducted a single-center retrospective chart review (from November 2012 to August 2016) to evaluate clinical outcomes in obese versus nonobese patients undergoing induction chemotherapy for newly diagnosed acute leukemia. All chemotherapy doses were calculated based on actual body weight. The primary outcome was rate of complete remission (CR) following induction chemotherapy. Secondary outcomes included time to absolute neutrophil count (ANC) and platelet recovery, the incidence of febrile neutropenia and clinical or microbiological infections, rate of early (0-15 days) and in-hospital mortality, and overall survival at 6 months. The rate of CR was similar between obese patients and non-obese patients diagnosed with AML (60% vs 61.9%; p=0.86) and ALL (87.5% vs 92.8%; p=0.31). Obese patients with AML were more likely to receive re-induction chemotherapy following 14-day bone marrow biopsy (53.3% vs 23.2%; p=0.019). There were no significant differences in secondary outcomes in either group when comparing obese versus non-obese patients. Obese patients with acute leukemia had similar rates of CR compared to non-obese patients following induction chemotherapy. While chemotherapy dosing based on actual body weight did not lead to excessive toxicity in these patients, continued research is needed to determine optimal dosing and long-term outcomes in this patient population. DisclosuresNo relevant conflicts of interest to declare.