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Purpose of review The treatment of patients with relapsed or refractory (R/R) acute myeloid leukaemia (AML) has been an unequal challenge for many decades. Although significant progress has been made in the discovery of the mechanisms underlying the molecular pathogenesis of the disease, more than 50% of AML patients still die, mostly from relapsed disease. Currently, the only potential curative option for patients with R/R AML remains allogeneic bone marrow transplantation in second complete remission, which is far being easy to achieve, mainly for patients with primary induction failure or older than 65 years. The purpose of this review is to discuss recent advances in the management of patients with R/R AML, with particular emphasis to new therapeutic options that are replacing conventional salvage chemotherapy. Recent findings The development of new agents selectively targeting molecular abnormalities offer more effective and less toxic alternative to chemotherapy, potentially useful as a bridge to allogeneic stem cell transplantation in second complete remission. Summary The recent approval of new drugs for R/R is transforming the paradigm of care we have relied on for the past 50 years. Ongoing clinical trials will tell us how bright is the future for R/R AML patients.

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) is one of the curative treatment options for acute lymphoblastic leukaemia (ALL). However, the outcomes in patients transplanted without complete remission (non-CR) have not yet been fully reported, and detailed analyses are required to identify subgroups in which optimal prognosis is expected and to optimize pre-transplant therapeutic strategies. Hence, we performed a multicentred retrospective cohort study including a total of 663 adult ALL patients transplanted at non-CR status; the median bone marrow (BM) blast counts at HSCT was 13·2%, and 203 patients (30·6%) were treated at primary induction failure status. The overall survival (OS) was 31·1% at two years, and the multivariate analyses identified five prognostic risk factors, including older age (≥50 years), increased BM blasts (≥10%), poor performance status, high haematopoietic cell transplantation (HCT)-comorbidity index, and relapsed disease status, among which BM blast was the most significantly related. A predictive scoring system composed of these risk factors clearly stratified OS (15·6-59·5% at two years). In conclusion, this is the first large-scale study to analyze the correlation of patient characteristics with post-transplant prognosis in ALL transplanted at non-CR status. The importance of blast control before HSCT should be focused on for better patient prognosis.

This study aimed to analyze the factors associated with outcomes of bone marrow transplantation (UR-BMT) or cord blood stem cell transplantation from unrelated donors (UR-CBT). We assessed the time from diagnosis to transplantation among acute myeloid leukemia (AML) patients with intermediate- or poor-risk cytogenetics to identify the potential clinical efficacy of transplantation. We retrospectively analyzed 5331 patients who received UR-BMT or UR-CBT between 2008 and 2017. Patients were divided into four groups according to time from diagnosis to transplantation: (1) UR-BMT and 5 months (n = 2353), (2) UR-BMT and ≤ 5 months (n = 379), (3) UR-CBT and 5 months (n = 1494), and (4) UR-CBT and ≤ 5 months (n = 1106). There was no difference in overall survival (OS) for transplantation at ≤5 months and 5 months in patients with first complete remission for both UR-BMT and UR-CBT, but OS in patients with primary induction failure (PIF) and transplantation at ≤ 5 months was significantly higher in the UR-CBT group compared with that at5 months (P 0.001). Multivariate Cox regression analysis also showed that transplantation at5 months in patients with PIF was an independent predictor of poorer OS. Therefore, UR-CBT at ≤ 5 months after diagnosis is an alternative option for AML patients with PIF.

Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts. Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 < 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death. Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956] 1 Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020. Disclosures Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy:Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano:Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt:Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Takeda: Research Funding; OBI: Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (&lt, 5%). The majority of cases are classified as Primary Induction Response (PIR), unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

With the increasing efficacy of induction therapy in multiple myeloma (MM), primary induction failure (i.e. less than a partial response) is an extremely rare phenomenon. Alexanian et al. was one o...

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen, none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations &lt, 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.

The phase 3 ALFA-0701 trial demonstrated improved outcomes with fractionated-dose gemtuzumab ozogamicin (GO) combined with standard chemotherapy vs. standard chemotherapy alone in adults with de novo acute myeloid leukemia (AML). We examined post-transplant outcomes and occurrence of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients who received hematopoietic stem cell transplantation (HSCT) as follow-up therapy in ALFA-0701. Patients aged 50–70 years were randomized to standard chemotherapy with or without GO (3 mg/m2 on days 1, 4, and 7 of induction and day 1 on each of two consolidation courses). Allogeneic HSCT was recommended for patients in first complete remission with matched (related or unrelated) donor, except those with core-binding factor AML or normal karyotype and either NPM1+/FLT3-ITDwt or CEBPA+ AML. Eighty-five patients (GO: n = 32; control: n = 53) received HSCT in first complete remission or after relapse/primary induction failure. Three patients (GO: n = 2; control: n = 1 [received GO as follow-up therapy]) developed VOD/SOS after HSCT or conditioning. Post-transplant survival, non-relapse mortality, and relapse were not different between arms. Results indicate fractionated-dose GO as part of induction and consolidation chemotherapy for AML does not induce excess post-transplant VOD/SOS or mortality and thus does not preclude the use of HSCT as consolidation treatment.

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse&ndash, Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%, relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0&ndash, 32), 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27&ndash, 45), 24.7% (95%CI: 1&ndash, 33) and 19.7% (95%CI: 1&ndash, 28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

A recent phase 3 trial showed that the outcome of patients with relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) improved with gilteritinib, a single-agent second-generation FLT3 tyrosine kinase inhibitor (TKI), compared with standard of care. In this trial, the response rate with standard therapy was particularly low. We retrospectively assessed the characteristics and outcome of patients with R/R FLT3-mutated AML included in the Toulouse–Bordeaux DATAML registry. Among 347 patients who received FLT3 TKI-free intensive chemotherapy as first-line treatment, 174 patients were refractory (n = 48, 27.6%) or relapsed (n = 126, 72.4%). Salvage treatments consisted of intensive chemotherapy (n = 99, 56.9%), azacitidine or low-dose cytarabine (n = 9, 5.1%), other low-intensity treatments (n = 17, 9.8%), immediate allogeneic stem cell transplantation (n = 4, 2.3%) or best supportive care only (n = 45, 25.9%). Among the 114 patients who previously received FLT3 TKI-free intensive chemotherapy as first-line treatment (refractory, n = 32, 28.1%; relapsed, n = 82, 71.9%), the rate of CR (complete remission) or CRi (complete remission with incomplete hematologic recovery) after high- or low-intensity salvage treatment was 50.0%, with a bridge to transplant in 34.2% (n = 39) of cases. The median overall survival (OS) was 8.2 months (interquartile range, 3.0–32); 1-, 3- and 5-year OS rates were 36.0% (95%CI: 27–45), 24.7% (95%CI: 1–33) and 19.7% (95%CI: 1–28), respectively. In this real-word study, although response rate appeared higher than the controlled arm of the ADMIRAL trial, the outcome of patients with R/R FLT3-mutated AML remains very poor with standard salvage therapy.

Context: Ponatinib (PON) is active against native BCR-ABL1 and all identified single-resistance mutations, including T315I. In the PACE study, heavily pretreated patients with Ph+ ALL treated with PON had nondurable responses because of new compound mutations (Cortes 2013, 2018). Sequential use of tyrosine kinase inhibitors (TKIs) can select for T315I and compound BCR-ABL1 mutants. Use of first-line PON in Ph+ ALL may decrease likelihood of these mutations. A Phase 2 study of PON with chemotherapy in newly diagnosed Ph+ ALL reported improved long-term outcomes (5-year event-free survival, 67%; overall survival, 71%) versus a second-generation TKI (Sasaki 2016). Objective: Compare efficacy and safety of first-line PON versus imatinib with reduced-intensity chemotherapy in patients with newly diagnosed Ph+ or BCR-ABL1–positive ALL (p190/p210 transcript type). Methods: PhALLCON (NCT03589326) is a Phase 3, open-label, parallel-assignment, randomized study. Patients remain on treatment until they complete study, relapse from complete remission (CR), have progressive disease, have unacceptable toxicity, withdraw consent, proceed to hematopoietic stem cell transplant (HSCT), or sponsor terminates study. The study started August 2018 and will be conducted in up to 35 countries. Currently, 115 sites are active globally. Accrual is ongoing, with 134 patients enrolled. The trial will enroll ≈230–320 patients (≥18 years) with ECOG performance status ≤2. Patients will be randomized 2:1 to PON 30 mg/d or imatinib 600 mg/d orally, with reduced-intensity chemotherapy in induction (Cycles 1–3), consolidation (Cycles 4–9), and maintenance (Cycles 10–20). Primary endpoint is measurable residual disease (MRD)-negative (BCR-ABL1/ABL1 ≤0.01%) CR at end of induction (≈3 months). The key secondary endpoint is event-free survival, defined as dates of randomization until death (any cause), failure to achieve MRD-negative CR by end of induction, or relapse from CR. Other secondary endpoints include CR/incomplete blood count recovery rates, molecular response rates, MRD-negative CR duration, primary induction failure, overall response rate, CR duration, time to treatment failure, MR4.5 duration after induction, overall survival, and safety, including arterial occlusive/venous thromboembolic events. Other analyses include a subgroup analysis of patients with/without HSCT and an exploratory analysis by mutation status. PhALLCON is sponsored by Takeda Development Center Americas, Inc.

Background: There is no standard of care treatment for Acute Myeloid Leukemia (AML) in relapse post-allogeneic hematopoietic stem cell transplant (post-HSCT), with overall 5-year survival about 5-10%. Venetoclax (Ven) is a novel BCL2 inhibitor approved by the FDA for treatment of newly diagnosed AML in combination with hypomethylating agents (HMA) or low dose cytarabine for patients unfit for intensive induction. However, data in relapsed/refractory AML are limited, especially in the post-HSCT setting. In this retrospective study, we reviewed outcomes of patients with AML relapse post-HSCT who received Ven in combination with HMA in a single center. Methods: Charts of 17 patients who had AML relapse post-HSCT treated with combination of Ven and HMA between November 2018 - March 2020 at the University of Kansas Medical Center were reviewed. We utilized descriptive statistics for baseline characteristics and outcomes, and Kaplan-Meier log-rank test for calculating overall survival. Results Seventeen patients received Ven+HMA for AML relapse post-HSCT in our center. At the time of SCT, patients were in first complete remission (CR) (n=15); second CR (n=1) and primary failure induction (1). Median age was 62 at time of relapse (31-71) years, and 8 patients were female (47%). 9 patients (53%) had adverse risk AML (ELN 2017) 8 of them were in CR1 and 1 with primary induction failure. Common mutations included DNMT3a, ASLX-1, TET2 (3); TP53 (2); IDH1/2 (2); NPM1/FLT3 (1); NPM1/IDH2 (1); NPM1 (1 transplanted in CR2); FLT3 (1). 2/17 had received Ven+HMA prior to SCT; 4 patients received HMA alone prior to SCT. 11 patients (65%) were naïve to either Ven or HMA prior to relapse. Median time to relapse was 181 (44-851) days post-HSCT. 9 (53%) patients received Azacitidine+Ven and 8 (47%) received Decitabine+Ven. HMA+Ven was the first line of therapy post-HSCT relapse in 14 patients. 2 had donor lymphocyte infusion (DLI) after either MEC or dacogen but relapsed prior to Ven+HMA. 1 had IDH (2) inhibitor. Patients received median of 2 (1-10) cycles of HMA+Ven. Six (35%) patients achieved complete remission/complete remission with incomplete hematologic recovery (CR/CRi), and 2/6 patients had negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 361 days from relapse (Figure 1). 3/14 patients received subsequent DLI with Ven+HMA. Disease progression was the most common cause of death in 8/9 of patients who died during the follow up period. Most common side effects included neutropenic fever (n=8, 47%) and acute graft versus host disease (aGVHD) (n=5, 30%). 2/5 developed new aGVHD on HMA+Ven with no prior history of aGVHD. However, aGVHD was mainly grade I-II and responsive to therapy. Discussion HMA+Venetoclax demonstrates potential activity in patients with AML relapse post-HSCT with a CR/CRi rate of 35%, comparable to other salvage therapies. There were no unexpected side effect in this high-risk population. Larger studies are needed to confirm efficacy and toxicity in this setting. Disclosures McGuirk: Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gamida Cell: Research Funding; Bellicum Pharmaceutical: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Celgene: Research Funding; Gilead Sciences: Research Funding; Incyte: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Trovagene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Astellas Pharma: Research Funding.

Autologous hematopoietic stem cell transplant (auto-HSCT) remains the cornerstone for relapsed and refractory Hodgkin lymphoma (HL) as well as patients with primary induction failure HL. Chemosensitive disease has better outcomes, and attaining a positron emission tomography (PET)–negative response before autologous transplant portends better overall survival (OS) and progression-free survival (PFS). The goal of salvage chemotherapy is to perform optimal cytoreduction before auto-HSCT with the least amount of toxicity. More intensive conditioning regimens have shown improved PFS and OS in phase II trials; however, randomized trials need to be explored in larger setting. Radiation therapy can improve disease control in the peri-auto-HSCT period for bulky disease and residual PET-positive disease. Maintenance therapy should be studied in clinical trials; however, for high-risk patients, brentuximab maintenance is now the standard. Allogeneic HSCT can provide a durable remission for patients who relapse after autologous HSCT and however can have significant complications associated with graft-versus-host disease and infection associated with immune suppression. Long-term side effects secondary to transplant remain an important issue that require careful follow-up and monitoring.

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P

The presence of >5% blasts at "day 14" (D14), in patients undergoing induction chemotherapy for acute myeloid leukemia (AML) is problematic. It is unclear if a second course of chemotherapy for early persistent disease will alter outcome in these patients. We conducted a retrospective study of AML patients undergoing induction chemotherapy where diagnostic, interim (around day 14), and recovery (days 21-42) bone marrow (BM) evaluations were available for review. Of the 113 patients included in the final analysis, 99 (87.6%) achieved CR at hematologic recovery. At D14, 90 patients (79.6%) had 5% blasts). Of these, 11 (47.8%) received a second course of chemotherapy (double induction [DI]) and 12 (52.2%) were observed until count recovery (single induction [SI]). No significant difference in CR rates was observed between these two groups (58.3% DI group vs. 45.5% SI group, P value = 0.684). In our analysis, D14 BM evaluation did not uniformly identify patients with primary induction failure. To unequivocally determine the value of a D14 marrow assessment in AML, prospective studies in the context of large cooperative group trials are required. Considering our findings and similar reports from others, we propose that D14 marrow assessment should be individualized, and that other factors, such as cytogenetics and early peripheral blood blast clearance should be considered, to identify patients most likely to benefit from interim disease assessment during AML induction therapy.

Background: MCL is an incurable, aggressive B-cell lymphoma. Allogeneic stem cell transplantation (allo-SCT) is often reserved for relapsed/refractory patients, but upfront allo-SCT transplant in younger patients is feasible and produces durable remissions in high-risk disease. Objective: To describe the SKCC experience with allo-SCT transplantation in MCL. Design: Retrospective data review of all consecutive MCL patients who underwent allo-SCT at SKCC between 1999 and 2019. Results: We identified 16 patients with MCL who underwent allo-SCT. Indications: blastoid variant (N=5), physician preference (n=5), relapse after auto-SCT (N=3), high-risk MIPI (N=2), inadequate autologous stem cell collection (N=1). The majority of patients were male (n=11, 69%) and Caucasian (n=14, 88%) with a median age at transplant of 50 years (range 40-69). Donor source was HLA haploidentical (n=8), matched-related (n=4), and matched-unrelated (n=4). The majority of haploidentical recipients were transplanted on our two-step T-cell tolerization approach. Conditioning was chemotherapy-based myeloablative (n=7) and reduced intensity (n=9); 69% were treated on clinical trial. Pretransplant induction regimens were heterogeneous over this span of time. Disease status at transplant: first complete remission (n=5), second complete remission (n=3), first relapse with chemosensitive disease (n=2), first relapse with chemoresistant disease (n=1), primary induction failure with chemosensitive disease (n=2), not evaluated (n=3). Median follow-up of surviving patients is 104 months (range 11-253). At 5 years, probability of overall survival is 52.5% and in haploidentical vs matched recipients is 73% vs 31%, respectively. Transplant-related mortality was 25% in the total cohort, all of which occurred in patients treated >15 years ago. Graft-vs-host disease (GVHD) occurred in 10/16 (63%) patients, with no GVHD-related death. Conclusions: For patients with aggressive MCL treated at SKCC on or off clinical trial, allo-SCT is feasible and effective, with evidence of a graft-vs-lymphoma effect. The increased tolerability of allo-SCT with recent approaches and the favorable outcomes with haploidentical donor source support the use of allo-SCT in high-risk MCL patients. TP53 gene status in this patient cohort is being evaluated to assess the effect of allo-SCT on outcomes and will be reported.

The prognosis of paediatric acute myeloid leukaemia (AML) with primary induction failure (PIF) is extremely poor, and effective treatment strategies have not been established. We investigated the clinical and biological features of paediatric AML patients with PIF registered to the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-05 study. The 3-year overall survival rate of the 41 PIF patients was 19.0%. High leucocyte count, M7 morphology, and unfavourable genetic aberrations, such as FLT3-internal tandem duplication, NUP98-NSD1 and high MECOM or PRDM16 expression, were risk factors for PIF. More effective treatment strategies based on leukaemia biology need to be urgently explored.

Primary refractory acute myeloid leukemia (AML), or primary induction failure, represents a continued challenge in clinical management. This review presents an overview of primary refractory disease and a discussion of risk factors for induction failure, including current evidence regarding the impact of karyotype and molecular mutation status on responsiveness to chemotherapy. We review the evidence for various treatment options for refractory AML including salvage chemotherapy regimens, allogeneic hematopoietic stem cell transplantation, targeted agents, and non-intensive therapies such as hypomethylating agents. A therapeutic approach to this patient population is presented, and several new and emerging therapies are reviewed.

Background Acute myeloid leukaemia not responsive to first induction chemotherapy (PIF-AML) still remains a challenge, and there are only few recent epidemiological data regarding the outcome of these patients. In this multicentre survey, we evaluate the prognosis and outcome of patients with PIF-AML, who were diagnosed and treated in the last 5 yrs in four Italian institutions. Results One hundred PIF-AML were recorded, 57 males and 43 females, with a median age of 63 yrs (19–79), 42% were younger than 60 yrs; 42% had a secondary AML and 40% had an adverse karyotype. According to cytogenetic/molecular risk stratification at diagnosis, 33% of patients were classified as favourable/intermediate-1 risk and 56% as intermediate-2/adverse risk. After a median follow-up of 11 months (1–49), 77% of patients died, while 23% were alive (with 12/23 in cCR). Thirty-six patients underwent allogeneic SCT, and of these, 11 of 36 (31%) were alive at last follow-up. The 12- and 24-month OS probability of the whole population was 45% and 21%, respectively. In multivariate analysis, the probability of OS of the whole population was significantly improved by Allo-SCT procedure (12-month OS probability 60% vs. 35%; P

BACKGROUND: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after 2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors’ knowledge, there currently are no data regarding factors influencing transplantation outcomes. METHODS: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after 2 courses of induction chemotherapy. RESULTS: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively. CONCLUSIONS: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL.

SUMMARY Background: Despite improvements in first-line therapies, the outcomes of relapsed or refractory childhood acute leukaemia that has not achieved complete remission after relapse, has relapsed after stem cell transplantation (SCT), has primary induction failure and has relapsed with a very unfavourable cytogenetic risk profile, are dismal. Objectives and Methods: We evaluated the feasibility and efficacy of T-cell-replete haploidentical peripheral blood stem cell transplantation (haplo-SCT) with low-dose anti-human thymocyte immunoglobulin (ATG), tacrolimus, methotrexate and prednisolone (PSL) in 14 paediatric patients with high-risk childhood acute leukaemia. Results: All patients achieved complete engraftment. The median time to reaching an absolute neutrophil count of more than 0.5 × 10 9 L −1 was 14 days. Acute graft-vs-host disease (aGVHD) of grades II–IV and III–IV developed in 10 (71%) and 2 (14%) patients, respectively. Treatment-related mortality and relapse occurred in one (7%) patient and six (43%) patients, respectively. Eleven patients were alive and seven of them were disease-free with a median follow-up of 36 months (range: 30–159 months). The probability of event-free survival after 2 years was 50%. Conclusion: These findings indicate that T-cell-replete haplo-SCT, with low-dose ATG and PSL, provides sustained remission with an acceptable risk of GVHD in paediatric patients with advanced haematologic malignancies.

Many patients with relapsed or refractory acute myeloid leukemia (AML) do not receive allogeneic hematopoietic cell transplant (alloHCT) because they are unable to achieve a complete remission (CR) after reinduction chemotherapy. Starting in January 2003, we prospectively assigned patients with AML with high risk clinical features to pre-emptive alloHCT (p-alloHCT) as soon as possible after reinduction chemotherapy. High risk clinical features were associated with poor response to chemotherapy: 1) primary induction failure (PIF), 2) second or greater relapse, and 3) first complete remission interval 0.1; PFS 18% versus 22%, p>0.1). Day 100 and one year transplant related mortality were similar (33.3% versus 22.2%, p>0.1 and 44.4% versus 42.9%, p>0.1, respectively). Pre-emptive alloHCT allowed 30 patients to be transplanted who would normally not receive alloHCT. Clinical outcomes for early p-alloHCT are similar to those for late p-alloHCT without excess toxicity. Early p-alloHCT is a feasible alternative to late p-alloHCT for maximizing therapy of AML that is poorly responsive to induction chemotherapy.

This study reviewed the clinical characteristics of 112 pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients with TCF3-PBX1 fusion treated according to the Japan Association of Childhood Leukemia Study (JACLS) ALL02 protocol (n = 82) and Children's Cancer and Leukemia Study Group (CCLSG) ALL 2004 protocol (n = 30). The 3-year event-free survival (EFS) and overall survival (OS) rates were 85.4 ± 3.9% and 89.0 ± 3.5% in JACLS cohort, and the 5-year EFS and OS were 82.8 ± 7.0% and 86.3 ± 6.4% in CCLSG cohort, respectively, which are comparable to those reported in western countries. Conventional prognostic factors such as age at onset, initial white blood cell count, and National Cancer Institute risk have also no impact on OS in both cohorts. Surprisingly, the pattern of relapse in JACLS cohort, 9 of 82 patients, was unique: eight of nine patients relapsed during the maintenance phase and one patient had primary induction failure. However, bone marrow status and assessment of minimal residual disease on days 15 and 33 did not identify those patients. Interestingly, the two patients with IKZF1 deletion eventually relapsed in JACLS cohort, as did one patient in CCLSG cohort. International collaborative study of larger cohort is warranted to clarify the impact of the IKZF1 deletion on the poor outcome of TCF3-PBX1 positive BCP-ALL.

Introduction Disease Status of AML patients at the time of HSCT is an important factor in predicting their survival. We hypothesize that MLFS (as per IWG criteria) identifies a group of patients that have better outcome than PIF (as per CIBMTR criteria). Objectives • To identify group of patients previously categorized as PIF by CIBMTR pretransplant that may have favorable outcome with HSCT. • To assess the outcome of patients with primary refractory disease by IWG criteria with HSCT. Methods We retrospectively analyzed 78 patients with AML who underwent allogeneic HSCT between June 2008 and December 2017 at our institution. We assessed the disease status at time of transplant as per CIBMTR criteria as complete remission (CR) defined as 1000, platelets >100,000 with transfusion independence, and primary induction failure (PIF) defined as not achieved CR or CRi. We also assessed the patients at time of transplant as per IWG criteria as CR (similar to CR as per CIBMTR but does not require normal maturation), morphologic leukemic-free state (MLFS) defined as 5%. We compared the OS at one year for the above groups. The patients received myeloablative conditioning with FBT or reduced intensity conditioning with FB2. Results Per IWG criteria, The OS at 1 year was 62 % in the CR group (n=29), 65% in the MLFS group (n=17) and 22% in the PRD group (n= 32). Our analysis revealed an overall statistically significant difference between CR v PRD, p=0.0009 and MLFS v PRD, p=0.0006. When we used the CIBMTR criteria, both MLFS and PRD were reclassified into the PIF group with OS of 34% (n=49). Conclusion Disease status prior to transplant is a predictor of outcome after allogeneic HSCT. Our analysis shows better survival for patients who achieved MLFS prior to transplant according to IWG criteria as compared to patients who were classified as primary induction failure by CIBMTR criteria. We intend to prospectively use the IWG criteria pre-transplant in our patients to help predict their survival at one year.

The optimal therapy for primary mediastinal B-cell lymphoma is a subject of ongoing debate, with no accepted standard of care. We performed a retrospective analysis of 63 patients in the modern era treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP), with or without radiation. Median age was 37 years (range 20-82). Eighty percent had limited stage disease and 71% were bulky. By age-adjusted International Prognostic Index (IPI), 15% were low-risk, 52% low-intermediate, 27% high-intermediate and 6% high-risk. Some 77% of responding patients received consolidative radiotherapy. Overall and complete response rates were 79% and 71%. Primary induction failure occurred in 13 (21%) patients. Five-year PFS and OS were 68% and 79%, respectively. Adverse prognostic features included increased IPI, advanced stage, advanced age and multiple extranodal sites. These data demonstrate an unacceptably high rate of primary refractory disease on R-CHOP, particularly among patients with high-risk features. Novel treatment approaches are needed that reduce primary refractory disease and reliance on mediastinal radiation in young people.

This report is a retrospective analysis of 65 patients with peripheral T cell lymphoma (PTCL), who underwent high-dose therapy and autologous hematopoietic stem cell transplantation (autoHCT) as a consolidation of first response achieved with either induction or salvage chemotherapy. We intended to determine the prognostic factors that influenced outcome after autoHCT and to define the predictive value of the scoring systems most often applied for transplant outcomes. Nineteen patients in either complete or partial remission underwent autoHCT after induction chemotherapy. Forty-six patients received second-line chemotherapy as a consolidation of partial response after induction chemotherapy (n = 34) or as a salvage therapy after primary induction failure (n = 12), and thereafter proceeded to autoHCT. Finally, the 36 patients were in complete remission, and 29 in partial remission at autoHCT. The median follow-up of survivors was 53 months (range 7–157 months). The 5-year overall survival and progression-free survival for all patients were 61.5 % (95 % CI 47.0–74.2 %) and 59.4 % (95 % CI 46.1–71.5 %), respectively. In multivariate analysis, bone marrow involvement at diagnosis and less than partial remission after induction chemotherapy were factors independently predictive for overall survival and progression-free survival. The prognostic index for PTCL could reliably stratify the prognosis of PTCL in this analysis.

Cure rates of children and adults with acute myeloid leukaemia (AML) remain unsatisfactory partly due to chemotherapy resistance. We investigated the genetic basis of AML in 107 primary cases by sequencing 670 genes mutated in haematological malignancies. SETBP1, ASXL1 and RELN mutations were significantly associated with primary chemoresistance. We identified genomic alterations not previously described in AML, together with distinct genes that were significantly overexpressed in therapy-resistant AML. Defined gene mutations were sufficient to explain primary induction failure in only a minority of cases. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in paediatric and adult AML.

Despite intense efforts, the cure rates of children and adults with AML remain unsatisfactory in large part due to resistance to chemotherapy. Whilst cytogenetic risk stratification proved valuable in identifying causes of therapy failure and disease relapse, cytogenetically normal AML remains the most prevalent disease type, with significant heterogeneity of clinical outcomes, including primary chemoresistance. Using targeted sequencing of 670 genes recurrently mutated in hematologic malignancies, we investigated the genetic basis of primary chemotherapy resistance and remission induction failure of 107 primary cases obtained at diagnosis from children and adults with cytogenetically normal AML. Comparative analysis revealed mutations ofSETBP1, ASXL1andRELNto be significantly enriched at diagnosis in primary induction failure as compared to remission cases. In addition, this analysis revealed novel genomic alterations not previously described in AML, as well as distinct genes that are significantly overexpressed in therapy resistant AML. However, identified gene mutations were sufficient to explain only a minority of cases of primary induction failure. Thus, additional genetic or molecular mechanisms must cause primary chemoresistance in pediatric and adult acute myeloid leukemias.Key PointsTargeted gene sequencing of 670 genes in adult and pediatric AMLProfiling of 107 primary AML samples identifies new genomic alterations for primary chemoresistance

Primary induction failure (PIF) in patients with acute myeloid leukemia (AML) is defined by the persistence of more than 5% of blasts [1] after 1–2 cycles of intensive chemotherapy (ICT) [1,2]. PIF...

Allogeneic stem cell transplantation (SCT) is the only curative therapy for patients with refractory or relapsed acute leukemia, although the prognosis remains poor. Few reports have described outcomes of SCT in pediatric patients with refractory acute leukemia. To identify prognostic factors for these patients, we retrospectively evaluated SCT outcomes for advanced acute leukemia in 82 pediatric patients from 3 transplant units in Nagoya City between 1990 and 2008. Median age at transplantation was 8 years (range, 0.5-17 years). Transplantation was performed in the first refractory relapse for 53 patients (64.6%), in the second or subsequent relapse for 16 patients (19.5%), and during primary induction failure for 13 patients (15.9%). Only 4 patients (4.9%) underwent transplantation in the untreated first relapse, and 39 patients (47.6%) received unrelated donor progenitor cells. Of the 82 patients, 61 died (77.9%), with a median survival of 7.1 months (95% confidence interval [CI], 4.2-10.0 months). Median disease-free survival (DFS) was 4.7 months (95% CI, 2.6-6.9 months). In multivariate analysis, peripheral blood blasts, cord blood transplantation, and more than 3 courses of previous salvage chemotherapy were predictive of DFS. These results support the notion that allogeneic SCT offers only a small chance of cure for most pediatric patients with refractory or relapsed acute leukemia, and suggest that reduction of the leukemia burden and earlier optimal timing of transplantation are essential for long-term survival even in patients with refractory acute leukemia.

Retrospective comparison of allogeneic vs autologous transplantation for diffuse large B-cell lymphoma with early relapse or primary induction failure

Many patients with Hodgkin lymphoma are cured with initial therapy, although a portion of patients will experience primary induction failure or disease relapse. Pathologic confirmation of refractory or relapsed Hodgkin lymphoma is important. Following two to four cycles of non-cross-resistant salvage chemotherapy, the standard of care is high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT), which is associated with long-term event-free survival rates of 45-68%. Of note, survival rates for studies integrating total lymphoid irradiation into the autologous HSCT-conditioning regimen are among the highest reported for relapsed/refractory Hodgkin lymphoma. Further treatment options are available for patients not fit to proceed to HSCT, for relapsed disease after autologous HSCT, and for 'high-risk' Hodgkin lymphoma including chemotherapy-resistant disease. Allogeneic HSCT is a valid treatment option, as a graft-vs.-Hodgkin-lymphoma effect has been demonstrated. In addition, novel targeted treatments are being investigated such as receptor-specific antibodies, radiolabeled antibodies, antiapoptotic agents including inhibitors of the nuclear factor-kappaB complex or X-linked inhibitor of apoptosis proteins, transcription pathway modulators such as histone deacetylase and mTOR inhibitors, and Epstein-Barr virus-directed therapy. Continued translational and collaborative prospective clinical research efforts are needed in order to continue to increase the survival rates for Hodgkin lymphoma and to lessen the toxicities associated with lymphoma-related therapy.

Salvage regimens containing mitoxantrone have been successfully used for the treatment of primary induction failure or relapsed acute myeloid leukemia. However, the combination of cyclophosphamide with mitoxantrone and cytarabine (MAC) has never been assessed in these patients. A total of 91 patients, including patients with primary induction failure (n=44) and relapsed (n=47), were treated with a salvage MAC regimen, which consisted of mitoxantrone, cytarabine and cyclophosphamide. The overall complete remission rate was 74.7 (68/91) and 72.7% (32/44) for primary induction failure, and 76.6% (36/47) for relapsed patients. The overall survival rate and disease-free survival rate were 72.1 and 59.7% at 1 year, 42.9 and 47.1% at 3 years, and 36.7 and 43.0% at 5 years, respectively. Only one patient succumbed to mortality during induction therapy. The toxicity level was acceptable. Therefore, the present study demonstrated that MAC is a highly effective and well-tolerated regimen for salvage in patients experiencing primary induction failure or relapse. This treatment significantly improved the prognosis.

Reduced-intensity conditioning regimens have demonstrated lower toxicity but increased relapse rates in the context of allogeneic hematopoietic stem cell transplantation (aSCT) for patients with acute myelogenous leukemia (AML). The FLAMSA- reduced-intensity conditioning (RIC) regimen, combining a cytoreductive and a transplant-conditioning part, has been described to be efficacious in patients with refractory disease. We retrospectively analyzed clinical data of 130 patients with AML after aSCT following FLAMSA RIC at our center. The median follow-up was 37 (10-125) months. The 4-yr overall and disease-free survival rates of the whole cohort were 45% and 40%. Cumulative incidence of relapse was 29%, 35%, and 40% at 1, 2, and 4 yr. There were no significant differences regarding overall and disease-free survival for patients transplanted in CR1, CR2, or primary induction failure (PIF). Patients with refractory disease after salvage therapy had significantly lower disease-free and overall survival (OS). Disease-free and OS rates were also significantly decreased in patients with 10% or more BLASTS at transplant. non-relapse mortality was 15%, 19%, and 20% at 1, 2, and 4 yr and similar in all cohorts. These data underscore the potency of the FLAMSA RIC regimen for patients with AML especially with PIF. The decision for re-induction therapy prior to aSCT in relapsed patients has to be weighed against the potential toxicity of this approach and might be influenced by the amount of leukemic BLASTS present. Only randomised trials will answer this important question.

Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary-resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high-risk group. For the whole patient population, the probability of overall survival, event-free survival (EFS) and disease-free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty-eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long-term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long-term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies. © 2015 John Wiley

Background AML is an aggressive disease. Current pediatric protocols ensure a 60% survival rate (Pession A et al, Blood 2013), reaching a plateau of intensiveness. Nevertheless, patients with primary induction failure (PIF) (10%) or relapse (30%) after stem cell transplantation (SCT) still have a very poor outcome. Novel therapeutic strategies are needed. Case 1. In January 2013, a 13 year-old female with FAB-M1-AML, presenting with chromosome 11 monosomy, was enrolled on AIEOP-AML-2002/01 protocol (Pession A et al, Blood 2013) and showed a PIF after two cycles of induction phase. Leukemic blasts arose in a low peripheral blood cell (PBC) count, even in response to second line treatment (I-BFM-AML-relapse2001 protocol). A third line experimental therapy, azacitidine (AZA) and rapamycin, failed to induce remission. Low PBC count with blasts still remained. Based on a bright expression of CD117/cKit, detected by flow cytometry, we designed a salvage therapy with AZA (75mg/mq/day for 7 days, every 21 days), in association with Imatinib Mesylate (375 mg/mq/day). We observed an increase of PBC count, with rapid disappearance of blasts. After two courses of AZA-Imatinib, the patient achieved complete remission. Subsequently she underwent SCT from an unrelated donor (UD) (Nov/2013). Nine months later, immune-suppressive therapy was withdrawn and we confirmed complete remission with a 100% donor engraftment. She is currently alive and in remission. Case 2. In October 2013, a 13 year-old male with FAB-M5-AML, presenting with a complex karyotype and specific molecular markers (FLT3-ITD and NSD1-NUP98), was enrolled on AIEOP-AML-2002/01 protocol. He achieved complete remission after induction phase. Nearby SCT-UD program, he presented colonization with two multi-resistant-gram-negative bacteria. For this reason, he was shifted to a haplo-identical SCT program. He received two haplo-SCT from his mother (April/2014) and his father (June/2014) respectively, after which he showed a bone marrow relapse (Sept/2014). Based on his low performance status, we designed a salvage therapy with cytosine arabinoside (100 mg/day i.v. in a total 8-days/cycle) Sorafenib (600 mg/day orally, already started before the first haplo-SCT), in association with PEG-Asparaginase (Oncaspar) at 3500 UI/i.v. weekly for 4 administrations. Surprisingly we observed an increasing signs of cutaneous grade II graft-versus-host-disease (GVHD), confirmed by flow cytometry analysis (high T-cell suppressors/NK cells), consistently with an increasing rate of donor's DNA (Dec/2014). Therefore, after a second cycle, the patient achieved the complete remission (Jan/2015) and a third haplo-SCT (Feb/2015) was given, using NK-alloreactive donor cells from his mother. Currently, the patient is alive and in complete remission with 100% donor. Conclusion. Our experience suggests that innovative combinational therapies are able to rescue patients with PIF or relapsed AML after SCT, the worst candidates. Association of a tyrosine kinase inhibitor with a demethylating agent showed a synergistic effect on leukemic blasts. More interestingly, PEG-LASP combined an anti-leukemic effect to an immune-modulation on donor's lymphocytes, as shown by immunophenotypic analyses. Disclosures Off Label Use: We used Imatinib Mesylate and PEG-L-Asparaginase in two children with AML: an off-label use for indication and age. .

To evaluate high-dose therapy and autologous or allogeneic blood or marrow transplantation (BMT) for mantle cell lymphoma, patients receiving BMT for newly diagnosed or relapsed mantle cell lymphoma were identified through the registry at Johns Hopkins. The pathologic diagnostic criteria were reviewed, and details of the presentation, transplant procedure, and survival outcomes were determined. Fifty-eight patients were identified, of whom 64% underwent transplantation in first remission and 12% had primary induction failure. Nineteen patients (one third) received an allograft. Preparative regimens consisted of cyclophosphamide in combination with either busulfan or total body irradiation. On multiple regression analysis, transplantation after 1 or more relapses (hazard ratio, 2.98; P = .02), primary induction failure (hazard ratio, 5.39; P = .002), and allogeneic transplantation (hazard ratio, 3.03; P = .007) were associated with an inferior event-free survival (EFS). However, EFS curves were not statistically different for autologous and allogeneic BMT performed in first remission, with an estimated 3-year EFS approaching or equaling 70%. Primary induction failure and residual bone marrow involvement were the only statistically significant predictors of relapse on multiple regression analysis. At 3 years, the estimated EFS for the entire cohort after BMT was 51%, the probability of relapse was 31%, and the overall survival was 59%. The benefit of autologous or allogeneic BMT for mantle cell lymphoma is thus most apparent when transplantation is performed in first remission. Whether allogeneic BMT ultimately confers an advantage because of a graft-versus-lymphoma effect remains to be determined.

Regardless of the salvage therapy used, primary induction failure in acute lymphoblastic leukemia (refractory ALL) and relapse after a complete remission (CR) are associated with dismal outcomes. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be the best treatment option for relapsed/refractory ALL. However, the outcome of allo-HSCT is very poor when a patient is not in CR. Quiescent leukemia cells protect them from the commonly used cell cycle-specific chemotherapeutic agents. Interleukin-2 (IL-2), a very well characterized T cell growth factor, is responsible for the progression of T lymphocytes from the G0 to the S phase of the cell cycle. IL-2 receptors are present on malignant T cells. Interaction of IL-2 with the IL-2 receptor triggers T cell proliferation, but T cells must change from a resting to an activated state, which leads to the de novo synthesis of IL-2 and expression of the IL-2 receptor. Thus, exogenous IL-2 administration is pivotal for the activation of T cells. Based on the findings above mentioned, we hypothesized that IL-2 priming chemotherapy improves the remission of refractory/relapsed T cell acute lymphoblastic leukemia.