Refractory Acute Myelogenous Leukemia Research Articles

NKT-Licensed In Vivo Dendritic Cell-Based Immunotherapy as Cellular Immunodrugs for Cancer Treatment.

With the advent of new therapies, immunotherapy has gained attention as a critical modality. After the discovery of the natural killer T (NKT) cells ligand, ex vivo cultured dendritic cells (DCs) loaded with NKT ligand (especially α-galactosylceramide (α-GalCer) (DC/Gal) or ex vivo expanded NKT transfer studies were clinically examined in several institutes. To prevent tumoral immune escape, the link between innate and adaptive immunity, in situ selective targeting of DCs has been attempted; however, protocol optimization was required. As a type of DC targeting therapy that combines the benefits of invariant natural killer T (iNKT) cells, we established an all-in-one, off-the-shelf drug, named the artificial adjuvant vector cell (aAVC), which consists of the tumor antigen and the CD1d-iNKT ligand complex. Here, to our knowledge, we first demonstrate the DC/GalCer therapy and NKT transfer therapy. Next, we introduce and discuss the use of aAVC therapy not only for efficient innate and adaptive immunity induction using fully matured DC in situ but also the characterization necessary for locally reprogramming the tumor microenvironment and systemically inducing long-term memory in T cells. We also discuss how the immune network mechanism is controlled by DCs. Next, we performed the first human clinical trial using WT1 antigen-expressing aAVC against relapse and refractory acute myelogenous leukemia. Thus, we highlight the challenges of using aAVCs as prodrugs for actively energizing DCs in vivo, underpinning immunological networks, and developing strategies for providing maximal benefits for patients.

Treatment of relapsed or refractory FLT-3 acute myelogenous leukemia with a triplet regimen of hypomethylating agent, venetoclax, and gilteritinib

Relapsed or refractory (R/R) acute myeloid leukemia (AML) with FMS-like tyrosine kinase 3 (FLT3) mutations remains a difficult and hard to treat entity. Gilteritinib is a potent oral FLT-3 inhibitor that improves overall survival in R/R AML, but studies are limited in combining gilteritinib with a hypomethylating agent and venetoclax treatment backbone (HMA-VEN-GILT). Here we report our experience with HMA-VEN-GILT for 22 R/R FLT3 AML patients. HMA-VEN-GILT yielded an ORR of 77.3% (17/22), CR 4.5% (1/22), CRi 13.6% (3/22), MLFS 59.1% (13/22). Median follow-up was 10.4 months with a relapse rate of 29.4% (5/17), median time to relapse of 69 days (range 35–298 days), 6-month overall survival of 84%, and median OS of 10.1 months. Additionally, 36.4% (8/22) of patients proceeded to hematopoietic stem cell transplant. In conclusion, HMA-VEN-GILT for the treatment of R/R FLT3 AML is feasible and can be used as a bridge to allogeneic transplantation.

The guidelines for diagnosis and treatment of relapse /refractory acute myelogenous leukemia in China (2023)

The guidelines for diagnosis and treatment of relapse /refractory acute myelogenous leukemia in China (2023)

Abstract #1393925: An Interesting Case of Bisphosphonate Resistant Hypercalcemia in Acute Myelogenous Leukemia (AML)

Hypercalcemia of malignancy (HCM), a PTH-independent process, usually occurs in solid tumors, multiple myeloma, and occasionally lymphomas. It generally results from excess secretion of parathyroid hormone related protein (PTHrP) by the tumor, osteolytic metastases, or rarely, tumor production of 1,25-(OH)2 vitamin D. We present an unusual case of HCM in a patient with refractory acute myelogenous leukemia (AML) without a defined mechanism that was resistant to bisphosphonate therapy. A 49-year-old woman with refractory AML presented acutely with altered mental status, decreased appetite, nausea, and fatigue. She was found to have HCM with a low intact parathyroid hormone (PTH) level. Her PTHrP and 25-(OH) vitamin D levels were normal, and her 1,25-(OH)2 vitamin D level was suppressed. Other labs were unrevealing, and imaging showed no new osseous lesions. Her hypercalcemia was treated with normal saline, intravenous furosemide, calcitonin, and two doses of pamidronate. Her calcium level normalized but then rebounded and remained elevated despite pamidronate therapy. Denosumab was considered, but due to rapid clinical deterioration, the patient’s family pursued comfort care. AML is an extremely rare cause of HCM. This is the eighth reported case of AML-related HCM since 2000 and the first known case with bisphosphonate resistance. Our patient’s HCM was not explained by typical mechanisms. Based on similar cases, one plausible mechanism for our patient's hypercalcemia was upregulation of receptor activator of nuclear factor κB ligand (RANKL) on osteoblasts due to elevated proinflammatory cytokines. RANKL binds to receptor activator of nuclear factor κB (RANK) on osteoclasts to promote their maturation and thus bone resorption. Regarding treatment, several case reports have demonstrated that denosumab can successfully treat bisphosphonate resistant HCM and is a potential therapeutic option.

Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients.

Effects of LSD1 Inhibition with Img-7289 on the Leukemia Initiating Cell Population with Induction of Differentiation and Cell Death in Pediatric Relapsed/Refractory AML

Background: Outcomes for pediatric patients with relapsed or refractory acute myelogenous leukemia (AML) are poor, with <30% overall survival in recurrent settings. Additionally, patients harboring high-risk molecular features, including KMT2A/MLL-rearrangements or GLIS2 fusion genes, experience poor outcomes. LSD1 inhibition has been evaluated as a potential therapeutic approach in adult patients with AML, but its role in pediatric AML remains limited. In this study, we characterize the anti-leukemic effect of an LSD1 inhibitor, IMG-7289, across a panel of pediatric AML models in vitro and in vivo and evaluate its effect on leukemia initiating cells (LICs). Methods: Dose-response effect of IMG-7289 on cell viability was assessed across 11 pediatric leukemia cell lines. Induction of apoptosis and cell cycle arrest was assessed by flow cytometric analysis of Annexin V and 7-AAD respectively. Flow cytometry was also used to analyze a panel of cell surface markers to assess for differentiation effect. Pediatric AML patient-derived xenograft (PDX) mouse models, including an acute megakaryoblastic leukemia (AMKL) model and a KMT2A-rearranged (KMT2A-r) AML model, established by implanting AML cells into NSG-S mice, were used for in vivo validation studies and limiting dilution secondary transplantation studies. PDX models were treated with IMG-7289 (25 mg/kg PO) or Vehicle daily for 21 days (n=6/arm). Engraftment was determined using flow cytometry to assess expression of human CD45 (hCD45) in the bone marrow. Leukemia initiating cell (LIC) frequency was evaluated by transplanting serial dilutions (2x105, 105, 104, 103, and 102 cells) of bone marrow cells derived from Vehicle- or IMG-7289-treated PDX models into untreated donor mice. The LIC frequency was estimated using the Extreme Limiting Dilution Analysis (ELDA) software (Walter and Eliza Hall Bioinformatics Institute of Medical Research), and log-rank analysis was used to compare event-free survival (EFS), defined as time from secondary transplant to engraftment. Results: Seven pediatric AML cell lines demonstrated sensitivity to IMG-7289, including 2 AMKL cell lines, M07e (IC50: 0.03 μM ± 0.01) and CMK (IC50: 0.065 μM ± 0.003), and 2 KMT2A-r AML cell lines, MV4;11 (IC50: 0.007 μM ± 0.001) and MOLM14. Treatment with IMG-7289 leads to induction of apoptosis (DMSO 8.8% vs IMG-7289 30.3%, P=0.0005) and cell-cycle arrest (G0/G1 phase populations: DMSO 65.5% vs IMG-7289 74.7%, P<0.0001) in MV4;11 cells. To investigate the effect of IMG-7289 on induction of cell differentiation, cell surface marker changes were evaluated over time in IMG-7289-treated AML. MV4;11 and M07e cells treated over 25 days showed increased expression of the monocytic cell surface markers CD14 and CD86 compared to DMSO control. Additionally, decreased expression of megakaryocytic markers CD41 and CD42b were observed in IMG-7289-treated M07e cells. To evaluate the in vivo activity of IMG-7289, a KMT2A-r AML PDX model was treated with IMG-7289 for 21 days. We observed a significant reduction in hCD45+ cells in IMG-7289-treated mice (27.5% hCD45+) vs Vehicle-treated mice (76% hCD45+, P=0.0012). To evaluate effects of IMG-7289 on the LIC population, serial transplantation of cells derived from Vehicle-treated or IMG-7289-treated AMKL PDX model was performed. Assessment of leukemia engraftment (flow cytometric analysis for hCD45+ cells in mouse bone marrow) at 20 weeks post-secondary transplant demonstrated an LIC frequency of 1 in 4.9x104 in IMG-7289-treated mice representing a ~500-fold reduction in LIC number compared to Vehicle control. Furthermore, a significant improvement in EFS was observed in IMG-7289-treated mice (median survival = 33 days) compared to Vehicle control (median survival = 76 days, P=0.0009, log-rank). Conclusions: In conclusion, treatment with IMG-7289 results in decreased viability, as demonstrated by induction of apoptosis and cell cycle arrest, as well as differentiation induction in pediatric AML cell lines. The in vitro and in vivo activity observed in pediatric AML is also observed in models with high-risk phenotypes (KMT2A-r AML and AMKL). Activity of LSD1 inhibition on the LIC population may represent a promising strategy to mitigate relapse or refractory disease.

Clofarabine and Busulfan Myeloablative Conditioning in Allogeneic Hematopoietic Cell Transplantation for Patients With Active Myeloid Malignancies

Patients with refractory or relapsed and refractory myeloid malignancies have a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) in patients with active, chemotherapy-refractory myeloid disease is historically associated with high rates of relapse and nonrelapse mortality (NRM). A MAC regimen combining clofarabine with busulfan (Clo/Bu4) has been reported to exhibit antileukemic activity with acceptable toxicity in patients age ≤70 years. Here we describe the clinical outcomes of a real-world population of patients with active myeloid malignancies undergoing allogeneic HCT with Clo/Bu4 MAC. In a single-center retrospective descriptive analysis, we identified patients who underwent HCT for myeloid malignancies not in remission using Clo/Bu4 MAC between 2012 and 2020. We report event-free survival (EFS) and overall survival (OS), cumulative incidences of relapse and NRM, and the incidence and severity of acute and chronic graft-versus-host disease (GVHD). We identified 69 patients with a median age of 60 years (range, 22 to 70 years). Most patients had relapsed/refractory or primary refractory acute myelogenous leukemia (AML; n=55) or refractory myelodysplastic syndrome (MDS; n=12); 1 patient had chronic myelogenous leukemia, and 1 patient had a blastic plasmacytoid dendritic cell neoplasm. Fifty patients (72.5%) had complete remission at day 100 post-transplantation. Two-year EFS and OS were 30% (95% confidence interval [CI], 20% to 44%) and 40% (95% CI, 29% to 54%), respectively. Patients with AML had a 2-year EFS and OS of 28% (95% CI, 18% to 44%) and 38% (95% CI, 27% to 54%), respectively; those with MDS had a 2-year EFS and OS of 47% (95% CI, 25% to 88%) and 56% (95% CI, 33% to 94%), respectively. The cumulative incidence of relapse at 2 years was 39% (95% CI, 27% to 51%) for all patients, including 45% (95% CI, 31% to 58%) in the patients with AML and 18% (95% CI, 2% to 45%) in those with MDS. NRM at 2 years was 31% (95% CI, 20% to 42%), including 27% (95% CI, 15% to 39%) in patients with AML and 35% (95% CI, 10% to 63%) in those with MDS. The total incidence of acute GVHD (aGVHD) of any severity was 80%, and the incidence of grade III-IV aGVHD was 22%. In patients who achieved remission, those who required systemic immunosuppression for aGVHD (58%) had poorer 2-year EFS (29% versus 54%; P=.05) and 2-year OS (39% versus 70%; P=.04) compared to those who did not. The 2-year cumulative incidence of chronic GVHD was 44% (95% CI, 28% to 58%). Clo/Bu4 MAC followed by allogeneic HCT for patients with active myeloid malignancies is an effective transplantation strategy for patients up to age 70, particularly those with advanced MDS. The high incidence of and poor outcomes associated with aGVHD highlight the importance of optimizing preventative strategies.

Reinvigoration of innate and adaptive immunity via therapeutic cellular vaccine for patients with AML

Strategies integrating activation of innate and adaptive immunity against cancer are desired. We established a novel platform, Wilms' tumor antigen 1 (WT1)-expressing artificial adjuvant vector cells (aAVC-WT1), linking invariant natural killer T (iNKT)-mediated dendritic cell activation to T cell immunity. Here, we report the first-in-human application of aAVC-WT1 in nine patients with relapsed and refractory acute myelogenous leukemia. No dose-limiting toxicities were observed, whereas activation of iNKT and/or NK cells was observed in all patients. Five patients experienced objective leukemic regression, which correlated with WT1-specific T cell responses. Paired single-cell RNA and T cell receptor (TCR) sequencing demonstrated effector CD8⁺ T cell clones in the bone marrow. Some bone marrow CD8⁺ T cells underwent transition from pre-existing precursor exhausted T cells to functional T cells or emerged as newly activated T cells, some of which were maintained long term. These demonstrate the feasibility and safety of aAVC-WT1 therapy and the capacity of this platform to activate both innate and adaptive immunity in humans.

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Phase 1/2, Open-Label, Dose Escalation, Dose Expansion Study of Menin Inhibitor DSP-5336 in Adult Patients (pts) with Acute Leukemia with and without Mixed-Lineage Leukemia (MLL)-Rearrangement or Nucleophosmin 1 (NPM1) Mutation

Relapsed or refractory acute leukemia (AL) in adults, including acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL), still represents a significant unmet need. Once AML or ALL relapses after initial treatment, the prognosis is extremely limited, with median survival <6 mo for AML and <1 y for ALL. This is especially true of AML or ALL with MLL rearrangements (MLLr) or relapsed AML with NPM1 mutations. Translocations of the MLL gene, found in approximately 5% to 10% of adult patients with AL, result in an aggressive subtype of leukemia, with a median overall survival (OS) of approximately 9 months and a very high rate of relapse after standard induction therapy for AML or ALL. The NPM1 mutation (NPM1m) is seen in approximately 30-35% of adult AML cases, most commonly in de novo AML, and is associated with a more favorable prognosis in newly diagnosed AML. However, this favorable prognostic effect is lost in the presence of concomitant FLT3-internal tandem duplication (ITD) mutations, which are seen in 40% to 50% of AML with mutated NPM1.These genomic alterations have been the focus for the development of DSP-5336, a novel small-molecule oral therapy that prevents binding of the menin protein to MLL fusion proteins that drive leukemogenesis.In nonclinical studies, DSP-5336 showed selective cell growth inhibitory activity against humanAL cell lines with MLLr or NPM1m. In addition, evidence of antitumor activity and survival advantage was demonstrated in 3 AML xenograft models with MLLr and/or NPM1m. Treatment with DSP-5336 may result in the reduction of leukemic cells, offering therapeutic benefits that include achieving complete remission and prolonged survival in patients with relapsed or refractory AML with MLLr or NPM1m or pts with relapsed or refractory ALL with MLLr.An open-label, single-arm, phase 1/2 study (NCT04988555) of DSP-5336 is being started to evaluate the safety and efficacy of DSP-5336 and determine the recommended phase 2 dose (RP2D) in adults aged ≥18 y with relapsed/refractory AML or ALL after at least one line of standard therapy, including hematopoietic stem cell transplant. Key inclusion criteria are ECOG performance status 0-2 and adequate cardiac, renal, and hepatic function. Patients on the strong CYP3A4 inhibitors ketoconazole, itraconazole, or isavuconazole, are excluded unless they can be safely taken off these medications or switched to another antifungal medication at least 7 days prior to start of study treatment.Patients will be dosed twice daily for 28 days per cycle. The study design is depicted below in Figure 1. In phase 1, 21-30 pts will be enrolled into multiple ascending dose cohorts (1-6 pts per dose level), with dose escalation determined using a two-parameter Bayesian logistic regression model. Determination of the RP2D will be informed by the maximum biologic effect or maximum tolerated dose, whichever is lower. The phase 2 study will include arm A (relapsed or refractory AML with MLLr) and arm B (relapsed or refractory AML with NPM1m) (Figure 1). Patients will be treated at the RP2D to evaluate clinical activity and safety, which will be monitored using Bayesian posterior probability to optimize enrollment with Bayesian stopping rules. Bayesian monitoring of responses will be started after the first 10 enrolled patients are evaluable for efficacy. Study endpoints are summarized in Table 1. [Display omitted] DisclosuresDaver: Genentech: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Hanmi: Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novartis: Consultancy; ImmunoGen: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Abbvie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novimmune: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Affinito: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Cai: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Dobrowolska: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Dow: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Eguchi: Sumitomo Dainippon Pharma: Current Employment. Song: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Stoudemire: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Watanbe: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment. Komarnitsky: Sumitomo Dainippon Pharma Oncology, Inc: Current Employment.

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia

Programmed death 1 (PD-1) is an integral component of acute myelogenous leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. PD-1 inhibitors are being investigated as treatment for AML in combination with hypomethylating agents and cytotoxic chemotherapy with encouraging findings. Although allogeneic stem cell transplantation (alloSCT) remains the most established curative treatment for patients with relapsed and refractory AML in complete remission, there are limited data on the clinical outcomes and safety of immune checkpoint inhibitors (ICIs) prior to alloSCT in AML. In the present study, we compared clinical outcomes of 9 patients with AML receiving high-dose cytarabine followed by pembrolizumab in a phase II clinical trial (NCT02768792) prior to alloSCT versus a historical control group of 18 AML patients who underwent alloSCT without prior ICI exposure. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft-versus-host disease (GVHD) within 100 days of transplantation. Time-to-event estimates for overall survival and relapse-free survival were calculated using the Kaplan-Meier method and compared using a log-rank test. One-year survival was not significantly different between the treatment groups (67% versus 78%; P=.34). 100-day mortality was 0% in the ICI group versus 17% in the control group, and there was no increase in grade III-IV acute GVHD in patients treated with pembrolizumab prior to alloSCT. No chronic GVHD was seen in patients treated with pembrolizumab prior to alloSCT and who received post-transplantation cyclophosphamide (PTCy) as part of their conditioning regimen. These findings reinforce the safety and feasibility of ICI therapy prior to alloSCT in patients with AML, and suggest that PTCy may abrogate GVHD risk and severity in patients who receive ICI prior to undergoing alloSCT for AML.

Retrospective Analysis of Adult Relapsed and Refractory Acute Leukemia Patients Treated with FLAG at a Comprehensive Cancer Center

IntroductionRelapsed and Refractory (R/R) Acute Myelogenous Leukemia (AML) and Acute Lymphoblastic Leukemia (ALL) have poor outcomes. No uniform consensus has been made on a preferred treatment regimen for R/R AML & ALL. FLAG, comprised of fludarabine, cytarabine, granulocyte colony-stimulating factor (GCSF), with or without Idarubicin, is an induction and salvage chemotherapy regimen for these diseases. Studies reviewing FLAG-/+Ida are decades-old with small populations. CR rates in R/R-AML historically range from 52-63% and in R/R-ALL from 30-39%. Here, we retrospectively review the outcomes for R/R-AML/ALL patients recently treated with FLAG-/+Ida at the UC Davis Comprehensive Cancer Center (UCDCCC).MethodsAdult patients (≥18 years) with R/R-AML and R/R-ALL who received FLAG or FLAG-Ida from January 1, 2012 to October 31, 2016 were eligible. Patient charts were generated from a pharmacy electronic medical record report and retrospectively reviewed. Baseline data included demographics, performance status, number of prior therapies, disease status, and pre-treatment peripheral blood and marrow biopsy data, including cytogenetic and molecular studies. Disease status was defined as “relapsed” if patients experienced recurrence of disease after previously obtaining CR with another chemotherapy regimen and “refractory” if they failed to obtain CR with another regimen prior to receiving FLAG. Primary outcomes were complete remission (CR) and overall survival (OS). Secondary outcomes included overall response rate [ORR: defined as number of patients achieving CR plus CR with incomplete count recovery (CRi)], disease-free survival (DFS), and adverse events.ResultsOf the 57 patients identified, 42 had AML, 14 had B-Cell ALL and 1 had T-Cell ALL. The median age was 51 (range 22-74). Twenty-two (38.5%) patients were relapsed, 31 (54.4%) refractory, and 4 (7%) relapsed and refractory. The median number of chemotherapy regimens prior to FLAG was 2, with range from 1 to 5. Seventy-seven percent of patients had an ECOG score of 0 to 1 at treatment initiation. For AML patients, 4 (9.5%) were European Leukemia Network (ELN) Favorable Risk, 20 (47.6%) were ELN Intermediate-1, 15 (35.7%) were ELN Intermediate-2, and 3 (7.1%) were ELN Adverse Risk. No patients with ALL were Philadelphia chromosome positive, 10 (66%) were older than age 35, and 5 (33%) had a WBC count higher than 30k at start of therapy. For AML, responses were CR in 20 (47.6%), CRi in 5 (11.9%), and partial response in 1 (2.4%). In ALL, responses were CR in 7 (46.7%) and no patients achieved CRi or PR. ORR (CR+CRi) was 59.5% for AML and 46.7% for ALL. Ten (23.8%) patients with AML received FLAG within 100 days prior to allogeneic hematopoietic stem cell transplant (HSCT; n=3) or donor lymphocyte infusion (DLI, n=7). Two (4.8%) AML patients received FLAG within 100 days after HSCT. Two (13.3%) patients with ALL received FLAG within 100 days prior to HSCT(n=1) or DLI (n=1). Median OS in AML was 10 months and Median DFS was 8.8 months. When censored for HSCT, Median OS and DFS in AML were both 7.8 months. Median OS and DFS in ALL were both 4.7 months, and censoring for HSCT did not change this duration. Patients experienced the following notable adverse events: febrile neutropenia 40 (70.2%), culture-positive bacteremia 14 (24.6%), pneumonia 3 (5.3%), colitis 6 (10.5%), port/line infection 1 (1.8%), hemorrhage/thrombus/DIC 5 (8.8%), and renal injury 3 (5.3%). Eight died within 30 days (14%) and 5 additional died within 60 days (8.8%) of treatment. Three died within 1 day of treatment, respectively from intracranial hemorrhage, blast crisis, and DIC. One died of STEMI on day 26. The remaining 9 early deaths were attributed to febrile neutropenia with septic shock. The most common primary cause of death over the course of treatment was refractory leukemia, 30 (52.6%).ConclusionOutcomes of FLAG +/- Ida in patients with R/R-AML and R/R-ALL at UCDCCC are similar to historical controls, confirming its role as a salvage regimen in these poor risk patients. As expected, adverse events were common in this population, and comparable to historical controls. Although supportive care advances, such as improved treatments for infection, have been developed since earlier publications of the FLAG regimen, our study suggests treatment outcomes remain similar. This further encourages the investigation of novel regimens for relapsed and refractory AML and ALL. [Display omitted] DisclosuresRosenberg:Amgen: Speakers Bureau. Jonas:Rigel: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding.

A Phase (ph) 1b/2 Study of TAK-659, an Investigational Dual FLT-3 and SYK Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)

A Phase (ph) 1b/2 Study of TAK-659, an Investigational Dual FLT-3 and SYK Inhibitor, in Patients (Pts) with Relapsed or Refractory Acute Myelogenous Leukemia (R/R AML)

Allogeneic Hematopoietic Stem-Cell Transplantation for GATA2 Deficiency Using a Busulfan-Based Regimen

Background: GATA2 deficiency is an increasingly recognized bone marrow failure syndrome responsible for: MonoMAC, monocytopenia with atypical mycobacterial infection (MAC); DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). GATA2 deficiency can be reversed by hematopoietic stem cell transplantation (HSCT). However, the intensity of conditioning required to ensure engraftment and reverse the myelodysplastic syndrome (MDS) characteristic of the disease remains controversial.Methods: We carried out a prospective study of allogeneic HSCT in 22 patients (mean age 26 years; range 17 to 45 years) with GATA2 deficiency, or the MonoMac syndrome, using a myeloablative, busulfan-based conditioning regimen. All 22 patients had MDS and two had AML. Eleven patients had clonal cytogenetic changes in the bone marrow. There were two matched related donor (MRD) recipients, 13 matched unrelated donor (URD) recipients, and 7 haploidentical related donor recipients. MRD and URD recipients received conditioning with 4 days of busulfan (days -6 to -3) to target an AUC between 3600 and 4800 min*microm/L and 4 days of fludarabine 40 mg/m2/day (days -6 to -3). Haploidentical related donor recipients received low-dose cyclophosphamide for two days (days -6 and -5), fludarabine 30 mg/m2/day for 5 days (days -6 to -2), 2-3 days of busulfan depending upon cytogenetics, along with 200 cGY total body irradiation (TBI) on day -1. MRD and URD recipients received tacrolimus and short course methotrexate for post-transplant graft-versus-host disease (GVHD) prophylaxis, whereas haploidentical recipients received high-dose post-transplant cyclophosphamide (PT/CY) followed by tacrolimus and mycophenolate mofetil for GVHD prophylaxis.Results: Nineteen of the 22 patients are alive with resolution of the clinical phenotype and correction of the bone marrow MDS with eradication of the cytogenetic changes at a median follow-up of 23 months (range, 6 to 48 months) giving an overall disease-free survival of 86 percent. The three deaths all occurred in the URD group. Of the three deaths, one resulted from refractory acute myelogenous leukemia (AML), and two from complications related to treatment for GVHD. There was a 26 percent incidence of grade III-IV acute GVHD (aGVHD) in the MRD and URD groups, and no grade III-IV aGVHD in the haploidentical related donor cohort. Similarly, there was a 46 percent incidence of chronic GVHD (cGVHD) in the MRD and URD cohort, whereas two of the 7 (28 percent) of the haploidentical related donor recipients had cGVHD.Conclusions: Despite overall disease-free survival of 86 percent with eradication of the clonal cytogenetic abnormalities in the bone marrow, GVHD remains a limitation in the MRD and URD cohorts treated with standard post-transplant tacrolimus/methotrexate prophylaxis for GVHD. We are currently de-escalating the busulfan dosing based on the AUC in all cohorts and incorporating PT/CY in the MRD and URD cohorts to decrease toxicity and reduce the incidence of aGVHD and cGVHD. Together with our previous studies using a nonmyeloablative regimen, it appears that when GATA2 deficiency patients are transplanted when they have a hypocellular bone marrow with MDS and without cytogenetic changes, a nonmyeloablative regimen results in reliable engraftment in GATA2 deficiency since the GATA2 deficient marrow has a proliferative disadvantage. However, with clonal progression and unfavorable cytogenetic changes and/or a hypercellular marrow, where the malignant clone has a proliferative advantage, a higher dose regimen results in more reliable engraftment and eradication of the clone. Studies to identify the precise level of conditioning for the stages of the disease are ongoing. DisclosuresNo relevant conflicts of interest to declare.

Graft-versus-Host Disease Prophylaxis with Post-Transplantation Bendamustine in Patients with Refractory Acute Leukemia: A Dose-Ranging Study

The prognosis of acute leukemia refractory to induction chemotherapy or immunotherapy is dismal. Salvage allogeneic hematopoietic stem cell transplantation (HSCT) is widely used option for these patients, but only 10% to 15% of patients are cured by the procedure. Preclinical studies indicate that substitution of post-transplantation cyclophosphamide with bendamustine (PTB) in a prophylaxis regimen may be associated with an augmented graft-versus-leukemia (GVL) reaction. The aim of this study was to establish the optimal dose of PTB and evaluate the antileukemic effect of HSCT with this type of graft-versus-host disease (GVHD) prophylaxis. In the prospective trial (NCT02799147), PTB was administered in doses of 140, 100, and 70 mg/m2 on days +3 and +4. Myeloablative conditioning with fludarabine and oral busulfan was provided to all patients. The first 12 patients received single-agent PTB, and subsequent patients received combination therapy with tacrolimus and mycophenolate mofetil (MMF). Inclusion criteria were acute myelogenous leukemia (AML) or acute lymphoblastic leukemia (ALL) refractory to at least one induction course of chemotherapy or target therapy and ≥5% clonal blasts in the bone marrow. The study cohort comprised 22 patients with AML and 5 with ALL. Seven patients were enrolled in the 140 mg/m2 group (due to a stopping rule), and 10 each were enrolled in the 100 mg/m2 and 70 mg/m2 groups. Primary refractory disease was documented in 41% of the patients, and secondary refractory was documented in 59%. The median blast count in the bone marrow at the start of the conditioning was 18% (range, 6% to 97%). Transplantation was performed with a matched sibling donor in 5 patients, a matched or mismatched unrelated donor in 15, and a haploidentical donor in 7. Engraftment was documented in 93% of the patients, including 89% with complete remission and 63% without measurable residual disease. After PTB prophylaxis, we observed an unusual complication, a cytokine release syndrome (CRS), in 70% of the patients, including grade 3 to 5 CRS in 44%. The most frequent clinical symptoms included high fever in 67% of patients, abnormal liver function tests in 67%, pancreatitis in 63%, skin vasculitis in 56%, enterocolitis in 48%, inflammation of oral mucosa in 37%, disseminated intravascular coagulation in 37%, and central nervous system toxicity in 26%. The development of CRS was associated with use of an HLA-mismatched donor (75% versus 20%; P=.0043). Classic acute GVHD was documented in 44% of the patients. Grade II-IV acute GVHD was associated with grade 3 to 5 CRS (67% versus 25%; P=.031). Moderate and severe chronic GVHD in the 100-day survivors were more often observed after single-agent PTB than after the combination immunosuppression (100% versus 18%; P=.002). A relatively low relapse rate was observed for this patient population. Three-year overall survival was 28% (95% confidence interval [CI], 13% to 46%), and event-free survival was 29% (95% CI, 13% to 46%). Nonrelapse mortality was 46% (95% CI, 25% to 64%), and the cumulative incidence of relapse was 26% (95% CI, 11% to 44%). No relapses were documented after day +100. There were no statistically significant differences among the dose groups (P=.3481); however, survival was higher in the 100 mg/kg group. Survival was higher in patients with AML compared with those with ALL (35% versus 0%; P=.0157). PTB represents a promising option to augment the GVL effect in refractory AML; however, the high CRS-associated mortality necessitates additional studies to reduce the risk of this complication. Thus, routine clinical application of PTB cannot be currently recommended. Combination immunosuppression with tacrolimus and MMF partially ameliorates these complications, at least in the setting of HLA-matched allografts. Biological mechanisms of CRS and GVL after PTB require further elucidation.

Clinical Benefits of Preconditioning Intervention in Patients with Relapsed or Refractory Acute Myelogenous Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation: A Kanto Study of Group for Cell Therapy Multicenter Analysis

A multicenter retrospective study was conducted to evaluate the clinical significance of preconditioning intervention (PCI) before allogeneic hematopoietic cell transplantation (HCT) in patients with acute myelogenous leukemia (AML) not in remission. The study cohort consisted of 519 patients classified according to the intensity (intensive/moderate) of PCI and their response to PCI. The group treated with PCI had higher blast counts in the peripheral blood (PB) and had a lower overall survival (OS) rate (P < .001) and higher nonrelapse mortality (NRM) rate (P=.035) compared with those without PCI (no PCI group). Approximately 40% of the patients (68 of 236) achieved a good response to PCI (good PCI group), and those patients had lower blast counts in the PB compared with the group with poor response to PCI (poor PCI group). OS in the good PCI group was comparable to that in the no PCI group and significantly better than that in the poor PCI group (hazard ratio, .54; 95% confidence interval, .39 to .77; P < .001). However, OS was significantly lower in patients with intensive/moderate PCI compared with the no PCI group. These results suggest that PCI increases NRM without decreasing the post-transplantation relapse rate, but may be beneficial for patients with lower blast counts in PB irrespective of its intensity.

Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial

Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P=.018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without allo-HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition, post-transplant quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML.

A Phase 1 Study of IRX195183, a RARα-Selective CYP26 Resistant Retinoid, in Patients With Relapsed or Refractory AML.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.

A Phase 1a/b Dose Escalation Study of Apto-253 in Patients with Relapsed or Refractory AML or High-Risk MDS

INTRODUCTION: APTO-253 has captured attention because of its distinguishing mechanism of action as the only known a small molecule in clinical development to target a conserved structure in the promoter of the MYC oncogene and interrupt MYC gene expression. In preclinical studies of acute myeloid leukemia (AML) cell lines, APTO-253 was discovered to potently down-regulate MYC gene expression, reduce MYC mRNA and protein level, induce apoptosis, and deplete cells of the MYC oncoprotein. APTO-253 demonstrated broad killing of primary mononuclear cells isolated from the bone marrow of patients with AML, MDS or MPN and enhanced AML cell killing when combined with BET bromodomain inhibitors or FLT3 inhibitors (Kurtz, Blood 2017 126:1358). Because dysregulated MYC is considered a major oncogenic operator in AML and myelodysplasias and because APTO-253 has such a distinct mechanism to kill such cells, APTO-253 has been granted orphan drug designation for the treatment of AML by the US FDA and is currently in a Phase 1a/b clinical trial in patients with relapsed or refractory AML (R/R AML) or high-risk myelodysplasias (high-risk MDS). METHODS: APTO-253 is being evaluate in an ongoing clinical trial, entitled "A Phase I a/b Dose Escalation and Expansion, Multicenter, Open-label, Safety, Pharmacokinetic and Pharmacodynamic Study of APTO-253 in Patients with Relapsed or Refractory Acute Myelogenous Leukemia or High-Risk Myelodysplasia (NCT02267863)". The protocol provides for patients to be dosed once weekly on days 1, 8, 15, and 22 of each 28-day cycle with the intended dose levels of 20, 40, 66, 100, 140, 180 or 220 mg/m2. Eligible patients must be ≥18 years old, have a life expectancy of at least 2 months, and have acceptable hematologic, renal and liver functions and coagulation status parameters. Primary objectives are to determine the safety and tolerability of APTO-253, to determine the maximum tolerated dose (MTD) and the dose limiting toxicities (DLT), and to establish the recommended Phase 2 dose for patients with specific types of hematologic malignancies. Key secondary objectives are to seek evidence of antitumor activity by hematologic and bone marrow evaluations and to assess the impact of APTO-253 on the expression of pharmacodynamic biomarkers (including MYC and p21 gene expression). RESULTS: To date, R/R AML and high-risk MDS patients have been enrolled and treated at dose levels of 20, 40 and 66 mg/m2 APTO-253. As specified by the protocol, only one patient was required at each of the 20 and 40 mg/m2 doses. The AML patient on the lowest dose level completed the 28-day cycle and demonstrated approximately a 72% reduction in MYC expression levels in peripheral white blood cells during the cycle. The high-risk MDS patient who received 40 mg/m2 demonstrated a 79% reduction in MYC expression during the first cycle. To date (as of July 2019), no drug related TEAEs, SAEs or dose limiting toxicities have been reported. Two patients are receiving treatment with 66 mg/m2, and samples are being analyzed for a series of pharmacodynamic markers. CONCLUSIONS: APTO-253 is a potent molecule with a particularly interesting and novel mechanism of action that results in robust suppression of MYC expression. The Phase 1 a/b trial has successfully enrolled R/R-AML and HR-MDS patients into the first three cohorts at 20, 40 and 66 mg/m2. Clinical data to date suggest APTO-253 is generally well tolerated at the doses tested, and target engagement has been evidenced by the reduction in cellular MYC gene expression in whole blood samples from R/R AML and high-risk MDS patients. Recruitment and enrollment are continuing, and updated safety, PK and biomarker data will be presented at the meeting. Disclosures Howell: Aptose Biosciences, Inc: Consultancy, Research Funding. Zhang:Aptose Biosciences, Inc: Employment. Rice:Aptose Biosciences, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

TWO HITS FOR LACTIC ACIDOSIS: A STUDY IN DRUG-DRUG INTERACTION

SESSION TITLE: Wednesday Fellows Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Tumors with high mitotic activity undergo oxidative phosphorylation for ATP synthesis. In acute myelogenous leukemia (AML) new therapies that target energy metabolism and mitochondrial protein synthesis are being studied. When these new drugs are combined with medications that also effect mitochondrial activity serious complications may occur. Particularly when side-effects from new investigation therapies are not widely known, nor available to automated electronic medical record (EMR) drug interaction checks. We present a case of life-threatening lactic acidosis due to the use of a STAT3 (signal transduction activator of transcription) inhibitor - a drug currently in clinical trials -- in a patient also receiving linezolid, in whom the risk of a life-threatening drug interaction and toxicity was not fully appreciated. CASE PRESENTATION: A 61 year-old man with a history of refractory AML in a clinical trial with a STAT 3 inhibitor presented with sepsis, but despite appropriate antibiotics his clinical status declined requiring mechanical ventilation. Lab studies showed a rapidly worsening lactic acidosis (3.9 to 18 mmol/L) over a few hours. Later it was discovered that he had completed a prolonged course of linezolid for vancomycin-resistant enterococcus bacteremia the day prior to admission. Though inputted in the medical record as an investigation study drug, the drug-drug interaction with linezolid was not registered by the EMR. Plasmapheresis and dialysis were used to remove residual linezolid and the study drug. Subsequently his lactate decreased to 2.4 and he was extubated. However, given the lack of treatment options for refractory AML the family decided to pursue comfort measures. DISCUSSION: STAT3 is a member of the STAT family of proteins involved in intracellular and extracellular signals to the nucleus, controlling gene expression. STAT3 is involved in AML cells, antiapoptosis genes, cell cycle regulators and promotes OXPHOS (oxidative phosphorylation). A major concern for the use of OXPHOS inhibitors is lactic acidosis. Similarly, linezolid decreases mitochondrial respiratory chain enzyme activity, hence disrupting cellular energy production. In our patient, it is likely that the use of two OXPHOS inhibitors resulted in severe mitochondrial toxicity and lactic acidosis. With new medications being developed that inhibit mitochondrial oxidative phosphorylation, intensive care units may see patients who are suffering from their side effects. CONCLUSIONS: This case highlights the importance of reviewing mechanisms and adverse effects of study drugs. Our case also reminds us that study drugs may not be included in the EMR or not flagged by computerized drug interaction alerts. We believe the use of STAT3 inhibitor and other new OXPHOS inhibitors warrant careful monitoring, particularly when used simultaneously with other medications that increase the risk of mitochondrial toxicity. Reference #1: Redell MS, Ruiz MJ, Alonzo TA, Gerbing RB, Tweardy DJ. Stat3 signaling in acute myeloid leukemia: ligand-dependent and -independent activation and induction of apoptosis by a novel small-molecule Stat3 inhibitor. Blood. 2011;117(21):5701-9. DISCLOSURES: No relevant relationships by Alan Gandler, source=Web Response No relevant relationships by Alexys Monoson, source=Web Response No relevant relationships by David Oxman, source=Web Response No relevant relationships by MRINALINI VENKATA SUBRAMANI, source=Web Response