Poor Cytogenetics Research Articles

Comparison of survival in elderly patients with acute myeloid leukemia treated with oral arsenic-containing Qinghuang Powder and low intensive chemotherapy

Objective To investigate the survival of oral arsenic-containing Qinghuang Powder (QHP) and low intensive chemotherapy (LIC) in the treatment of elderly patients with acute myeloid leukemia (AML). Methods Forty-two AML patients older than 60 years in Xiyuan Hospital from January 2015 to December 2017 were retrospectively analyzed. Of them, 20 cases were treated with QHP (QHP group), 22 cases were treated with LIC (LIC group). The survivals of the two groups were compared. Results There was no significant difference of median survival time (13 months vs. 13.5 months, χ2= 0.096, P= 0.757), 1-year survival rates (59.1% vs. 70.0%, χ2= 0.543, P= 0.461), 2-year survival rates (13.6% vs. 15.0%, χ2= 0.016, P > 0.05), and 3-year survival rates (4.6% vs. 5.0%, χ2= 0.005, P > 0.05) between LIC and QHP groups. There was no significant difference of median survival time in age ≥75 year (12 months vs. 12.5 months, χ2= 1.317, P= 0.251), performance status scores > 2 (12 months vs. 12 months, χ2= 0.834, P= 0.361), hematopoietic stem cell transplantation with combined disease index > 2 (12 months vs. 13 months, χ2= 1.726, P= 0.189), secondary AML (10 months vs. 14 months, χ2= 1.552, P= 0.213), and poor cytogenetics (12 months vs. 8 months, χ2=0.479, P= 0.489) between LIC and QHP group. Conclusion The survival of elderly AML patients is considerable in patients treated with oral QHP and LIC, which suggests that oral QHP may be an equivalent alternative treatment since elderly AML (especially more than 75 years) patients refused to LIC therapy. Key words: Leukemia, myeloid, acute; Low intensive chemotherapy; Qinghuang Powder; Elderly

Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT.

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Multiple Myeloma: Front Line Therapy and Autologous Stem Cell Transplantation

Prognosis of multiple myeloma (MM) has improved during the past two decades. This has been attributed to the better understanding of the biology of disease leading to introduction of two new classes of molecules, namely immune-modulators (e.g. thalidomide, lenalidomide), and proteasome inhibitors (e.g. bortezomib), use of high dose chemotherapy and autologous stem cell transplantation (ASCT) and better supportive care. Current management of myeloma for young patients (≤65 years) includes initial induction therapy followed by consolidation with ASCT followed by maintenance therapy with low dose thalidomide or lenalidomide or bortezomib for 1-2 years. The choice of initial therapy for patients of MM is based upon their eligibility for ASCT which in turn is based on their age and major co-morbid conditions pertaining to cardiac and renal systems. Patients who are ≤65 years of age (or 65 to 70 years) with no major co-morbid conditions are considered potential candidates for ASCT. Four cycles of induction therapy are administered; a combination of 3 drugs (bortezomib, thalidomide, and dexamethasone (BTD) or bortezomib, lenalidomide, and dexamethasone (BLD) or bortezomib, cyclophosphamide and dexamethasone (BCD) is associated with higher complete response (CR) (approx. 30-40%) and very good partial response (VGPR) and better progression free survival (PFS). Further consolidation with ASCT results in CR rates of 50%–70%; patients who achieve CR, have improved event-free and overall survival. Our initial experience with 225 ASCT supports these observations. It is now possible to individualize therapy in a given patient. For example, for patients with renal failure (present in 20-30% of patients at diagnosis) —bortezomib, dexamethasone and/or doxorubicin combination could be an option; for patients with pre-existing peripheral neuropathy—lenalidomide and dexamethasone is preferred; for patients at high risk of venous thrombo-embolism bortezomib- based regimens can be used safely. Treatment with bortezomib or bortezomib + lenalidomide for patients with poor cytogenetics (chromosome deletion t(4;14), t(14;16), 17p–) appears to result in an outcome similar to that in patients without these abnormalities. In conclusion, from being incurable, myeloma is now a chronic illness. Along with earlier diagnosis, improved treatment and better management of complications have resulted in longer disease control and survival with a better quality of life. Novel agents have provided an opportunity to tailor therapy in an individual patient. Further research is needed to improve outcome for patients who fail to achieve complete response, those with ISS stage III, and extra-medullary disease. Availability of oral proteasome inhibitors and monoclonal antibodies (e.g. IL-6 receptor) are likely to expand choice of agents for maintenance therapy in future.

Haploidentical T-Repleted Stem Cell Transplantation (SCT) Has Comparable Survival to 10/10 and 9/10 Unrelated SCT in Poor-Cytogenetics Risk Acute Myeloid Leukemia in First Complete Remission: A Study on Behalf of the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Background: Allogeneic stem cell transplantation (SCT) is the most powerful therapy to prevent relapse in poor-cytogenetics risk acute myeloid leukemia (poorAML) patients (pts) in first complete remission (CR1). For pts who lack a matched related donor (MRD), SCT from an unrelated (UD) or alternative donor is indicated. Pts with poorAML and thus at high risk of relapse can theoretically benefit the most from SCT from haploidentical donors (HaploSCT), which is an attractive option as the time required to find a well-matched UD could be inacceptable. Several recent reports show comparable outcomes between HaploSCT and transplants from UD (Piemontese S, JHO 2017; Versluis J, Blood Advances 2017). Comparative studies able to include sufficient numbers of pts with poorAML in CR1 are limited; this prompted us to compare the outcomes of HaploSCT to those of 10/10 and 9/10 HLA-matched UD in this disease category.Methods: We retrospectively selected denovo poorAML pts in CR1 receiving T-repleted haplo (n=74), 10/10 UD (n=433) and 9/10 UD SCT (n=123) from 2007 to 2015 who were reported to the ALWP of EBMT Registry. PoorAML was defined as the presence of: complex karyotype (at least 3 structural abnormalities per clone); monosomal karyotype (1 autosomal monosomy plus 1 monosomy or structural abnormality); inv(3)/t(3;3); -5 or del(5q); -7 or abn(7q); t(v;11)(v;q23); abn(17p); t(6;9); t(9;22). Primary endpoints were leukemia-free survival (LFS) and overall survival (OS). Secondary endpoints were acute and chronic GVHD (aGVHD and cGVHD), relapse and nonrelapse mortality (NRM).Results: Main population characteristics are depicted in Table 1. Recipients of haplo-, 10/10 UD- and 9/10 UD-SCT were comparable concerning time from diagnosis to SCT and time from CR1 to SCT. HaploSCT more likely received bone marrow as stem cell source. In-vivo T cell depletion (TCD) with ATG was most likely adopted in UD-SCT, with a conversely increased use of high-dose post-transplant Cyclophosphamide as GvHD prophylaxis backbone in HaploSCT (65% Vs 3% for 10/10 UD and 2% for 9/10 UD, p<10¯³).LFS and OS at 2 years were not significantly different between haploSCT, 10/10 UD SCT and 9/10 UD SCT (53±12% and 59±12%, 43±5% and 50±6%, 44±9% and 50±9%, respectively, p=0.5 and p=0.5, respectively).In Haplo-SCT, the 100-day cumulative incidence (CI) of grade≥2 aGvHD was in line with the one reported for 10/10 and 9/10 UD (33±11% for haplo, 30±4% for 10/10 UD and 34±9% for 9/10 UD, p=0.6). Likewise, the 2-y CI of cGvHD (35±12%) of HaploSCT was similar to those of 10/10 UD (36±4%) and 9/10 UD (36±9%), p=0.8. The 2-y CI of NRM was 19±8% after haploSCT, 18±4% after 10/10 UD SCT and 18±6% after 9/10 UD SCT (p=0.9). Relapse incidence was not significantly affected by donor source, with a 2-y CI of 27±9% for haploSCT, 39±5% for 10/10 UD SCT and 37±9% for 9/10 UD SCT (p=0.3).After adjustment for centre effect, pts age, time from diagnosis to SCT, conditioning intensity, in-vivo TCD, donor/pts gender and CMV serostatus, the multivariable model showed that haploSCT recipients didn't experience worse outcomes compared to 10/10 and 9/10 UD. Indeed, compared to haploSCT (reference) the hazard ratio (HR) for LFS was 1.2 for 10/10 UD (p=0.3) and 1.2 for 9/10 UD (p=0.4). The hazards for OS in 10/10 and 9/10 UD did not differ from haplo-SCT (1.3, p 0.3 and 1.2, p 0.4, respectively). Moreover, compared to haplo, SCT from 10/10 and 9/10 UD was not associated with lower hazards for relapse (HR: 1.4, p=0.2 and 1.4, p=0.3, respectively), NRM (HR: 1, p=0.9 and 1, p=0.9, respectively), grade≥2 aGvHD (HR: 1.2, p=0.6 and 1.4, p=0.3, respectively) and cGvHD (HR: 1.2, p=0.5 and 1.3, p=0.4, respectively). The only factor associated with worse LFS and OS was pts age (for each 10-year interval: HR 1.1, p=0.02 and 1.2, p=0.001, respectively).Conclusions: In the present series of poorAML pts transplanted in CR1, haploSCT recipients experienced comparable outcomes with respect to 10/10 and 9/10 HLA-matched UDs. This suggests that the immunotherapeutic effect of allogeneic SCT is exerted similarly across these different donor sources in this peculiar population. Therefore, in the absence of a MRD, pts with poor risk cytogenetics who have a very high risk of relapse could be allocated to haploSCT in their first remission, especially in the context of the recent improvements, which fostered an abatement of GvHD and NRM rates, historically the main detrimental factors for Haploidentical transplants. [Display omitted] DisclosuresCiceri:GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty:Sanofi: Honoraria, Speakers Bureau.

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning.

Reduced-toxicity conditioning with fludarabine and treosulfan is a dose-intensive regimen with enhanced anti-leukemia effect and acceptable toxicity in AML/MDS. HLA-C regulates natural-killer (NK) cell function by inhibiting Killer immunoglobulin-like receptors (KIR) and is divided into C1 and C2 epitopes. The missing-ligand theory suggests that missing recipient KIR ligands drives NK-alloreactivity after SCT, in the absence of HLA-mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched-siblings (n = 97) or matched-unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m2 ). 34% expressed one HLA-C group 1 allele (C1C1), 19% one HLA-C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow-up was 48 months. 5-year relapse, nonrelapse mortality (NRM) and leukemia-free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate-analysis identified chemo-refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA-C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA-C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA-matched SCT with treosulfan conditioning in AML/MDS.

Isolated Extramedullary Relapse of Acute Leukemia after Allogeneic Stem Cell Transplantation: Different Kinetics and Better Prognosis than Systemic Relapse

Allogeneic stem cell transplantation (SCT) is curative treatment in patients with acute leukemia and myelodysplastic syndrome. However, recurrent disease is the major cause of treatment failure. Isolated extramedullary relapse (iEMR) after SCT is relatively rare and not well characterized. We performed a retrospective analysis of 566 consecutive patients with acute myeloid leukemia (n = 446) and acute lymphoblastic leukemia (ALL; n = 120) after SCT to study the incidence, risk factors, treatment options, and outcome of iEMR. The 5-year cumulative incidence of bone marrow relapse (BMR) and iEMR was 41.0% and 5.8%, respectively. iEMR occurred significantly later than BMR at 10 and 4 months, respectively (P < .001). Diagnosis of ALL (HR, 2.6; P = .05), poor cytogenetics (HR, 2.1; P = .06), and prior extramedullary disease (HR, 3.8; P = .002) were independent factors predicting iEMR. Acute and chronic graft-versus-host disease (GVHD) reduced the risk of BMR but did not protect against iEMR. Most patients with iEMR received systemic treatment combined with local radiation and donor lymphocyte infusions when feasible. The 3-year survival after relapse was 8.5% and 30.1% after BMR and iEMR, respectively (P = .002). Patients with a first iEMR continued to have recurrent EMRs, and only a minority progressed to BMR. Second iEMR was also common after first BMR and associated with longer survival than second BMR. iEMR is more frequent in patients with ALL and prior extramedullary disease. It occurs later than BMR and more commonly in patients with chronic GVHD, suggesting less effective graft-versus-leukemia effect in extramedullary sites. Second iEMR is common after a first iEMR but also after a first BMR. Long-term survival is feasible with aggressive treatment.

Efficacy, safety, and pharmacokinetics of subcutaneous azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes.

Clinical and pharmacokinetic effects of azacitidine in higher-risk myelodysplastic syndromes were established in mainly Caucasian populations. Because of inter-ethnic genotype variability of drug-metabolizing enzymes, it is important to evaluate azacitidine in populations expected to use the drug. In this single-arm study, Taiwanese patients with higher-risk myelodysplastic syndromes received azacitidine 75 mg/m2 /day for 7 days/28-day cycle for up to six cycles. Response-evaluable patients had baseline and cycle 6 marrow assessments. Clinical outcomes are compared descriptively with those from a phase 3 study comprising mainly Caucasian patients (N = 179). Pharmacokinetics in a subgroup of Taiwanese patients are descriptively compared with a historical control of North American patients (N = 45). Median age of Taiwanese patients (N = 44) was 64 years (range 36-90), and 46% had poor cytogenetics. Median number of azacitidine cycles was six (1-6). No response-evaluable patient (n = 33) achieved complete or partial remission; however, 22 patients (50%) achieved hematologic improvement, 12 of 32 patients attained RBC transfusion independence and 7 of 18 attained platelet transfusion independence. Most common grade 3-4 treatment-emergent adverse events were neutropenia (52%) and leukopenia (39%). Pharmacokinetic profiles were similar for Taiwanese (N = 12) and North American (N = 45) patients. Maximum plasma concentration was higher in Taiwanese patients; however, mean azacitidine exposure was within the range for North American patients. These data confirm the safety and efficacy of azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Clinical outcomes were generally comparable with those for Caucasian patients. No meaningful differences in azacitidine pharmacokinetics were observed for Taiwanese patients, and no initial dose adjustment is necessary.

Lenalidomide combined with intensive chemotherapy in acute myeloid leukemia and higher-risk myelodysplastic syndrome with 5q deletion. Results of a phase II study by the Groupe Francophone Des Myélodysplasies.

Patients with acute myeloblastic leukemia or higher risk myelodysplastic syndromes with 5q deletion (generally within a complex karyotype) respond poorly to intensive chemotherapy and have very poor survival. In this population, we evaluated escalating doses of lenalidomide combined with intensive chemotherapy in a phase II study. Treatment consisted of daunorubicin (45 mg/m2/day, days 1–3 in cohort 1, escalated to 60 mg/m2/day, days 1–3 in cohorts 2 and 3) combined with cytosine arabinoside (200 mg/m2/day, days 1–7) and lenalidomide (10 mg/day, days 1–21 in cohorts 1 and 2, escalated to 25 mg/day, days 1–21 in cohort 3). Eighty-two patients with 5q deletion were enrolled, including 62 with acute myeloblastic leukemia, 62/79 (78%) of whom had a complex karyotype (median 7 cytogenetic abnormalities, all but 2 of them monosomal) and three had unknown karyotypes. Thirty-eight patients (46%) achieved complete remission and the overall response rate was 58.5%. Among the 62 patients with a complex karyotype, 27 achieved complete remission (44%) and 21 had cytogenetic responses. A lower response rate was observed in patients with acute myeloblastic leukemia but other pretreatment factors, including cytogenetic complexity and treatment cohort, did not significantly influence response. Fifteen patients underwent allogeneic stem cell transplantation, including 11 patients in first remission. The 1-year cumulative incidence of relapse was 64.6% and the median overall survival was 8.2 months. By comparison with conventional intensive chemotherapy, the treatment protocol we used appeared to produce higher hematologic and cytogenetic complete remission rates in patients with very poor cytogenetics, but response duration was short in this very poor risk population, highlighting the need for better post-induction strategies. Clinical trial registry number: NCT00885508

Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or Relapsing after Azacitidine (AZA) Treatment

Background: Hypomethylating agents (HMAs) have become the reference treatment of higher risk MDS, but the median survival of about 2 years obtained with AZA remains modest, and median survival after HMA failure is only about 6 months (Prebet et al, JCO 2011). Guadecitabine (GDAC, SGI-110) is a novel HMA dinucleotide of Decitabine and deoxyguanosine, administered SC, which results in extended DAC exposure. In a phase I-II study in AML (Issa, Lancet Oncol, 2015) a dose of 60mg/m2/day for 5 consecutive days was recommended. We designed a national multicenter phase II study evaluating the efficacy of GDAC in higher-risk MDS patients, refractory or relapsing after AZA (NCT02197676). Methods: Main inclusion criteria were (1) IPSS int-2 or high MDS, or CMML with WBC 10%, or AML with 20-30% marrow blasts (2) Refractory to 6 cycles of AZA or relapsing after response, but without overt progression (i.e., greater than doubling of marrow blasts compared to pre AZA values) (3) Age ≥ 18 years (4) Normal liver and renal functions. Patients received GDAC 60mg/m2/d x5 d every 28 d until progression, death or no response after 6 cycles (extended to 9 cycles after the 20 first pts). Global DNA methylation was assessed at baseline and on d 8, 15, 22 and 28 of cycle 1 in blood, and on d 28 of cycles 1 , 3 and 6 in BM and blood ,using bisulfite-converted DNA followed by pyrosequencing technology measuring 3 representative CpG sites of the LINE-1 promoter region. An intent-to-treat analysis was performed on June 2016, with a median FU of 9.6 months Results: Between Aug 2014 and Jan 2016, 56 pts from 13 centers were enrolled, M/F: 37/19, median age 75 years [IQR, 69-76]. 15 patients had primary resistance after 6 cycles of AZA, and 41 patients had relapsed after a response and a median of 13 AZA cycles [IQR 9.75-23]). 15 pts had IWG 2006 progression between onset of AZA and inclusion. At inclusion, WHO classification was RCMD in 2 pts, CMML in 1 pt, RAEB-1 in 11 pts, RAEB-2 in 31 pts and AML in 11 pts; . IPSS was int-1, int-2 and high in 4 (6%), 27 (50%) and 23 (42%) pts, resp. (2NA), and R-IPSS was low, int., high and very high in 1 (2%), 3 (6%), 13 (26%), and 34 (60.7%) pts resp (5NA). 43 (77%) pts were RBC transfusion-dependent (TD) and ECOG was >1 in 5 (9%) pts. The average baseline LINE-1 methylation level in the 45 pts evaluated was 73% in blood and 72% in BM. One pt died before any treatment, and 55 patients received at least one cycle of GDAC, with a median of 3 cycles [IQR, 2-5.5]. 9 pts responded (8 after 3 cycles) with 1 (3%) CR, 2 (5%) CRp, 5 (14%) marrow CR and 1 HI; ie an ORR of 16% (95%CI, 8-28%). Responses were seen in 4/15 (26.6%) primary refractory, and in 5/41 (12.2%) relapsing patients (p=NS). On average, the maximum LINE-1 demethylation occurred during the first cycle on day 8 in blood (median -11.3%), and on day 28 in BM (median -3.1%). Median duration of response was 9 months including so far 2 responses ≥ 1 year (12 and 18 months). 49 SAE occurred in 44 pts, and were mostly hematological, with myelosupression in 35/56 (63%) of pts 49 patients ended the study, because of progression (n=20), death (n=14), investigator or patient decision (n= 8), toxicities (n= 6) and pt withdrawal (n=1). Median OS from inclusion was 6.7 months (IC95% [5.6-11.8]). 33 pts had died, because of MDS progression in 14 (42%), infection in 13 (39.3%), bleeding in 1 (3%), and other causes in 5 (15%) pts (2 UK, 2 general deterioration, 1 heart attack). No significant prognostic factor of response to GDAC, including age, sex, ECOG, TD, baseline Hb, platelet, ANC, marrow blast %, cytogenetics, IPSS, IPSS-R, type of AZA failure (primary or secondary), LINE1 baseline methylation or demethylation rate was found. OS was significantly shorter in pts with high IPSS (HR=2.1, 95%CI, 1.04-4.20, p=0.04), and with very poor IPSS-R cytogenetics (HR=4.3, 95%CI, 2.0-9.1, p=0.0015), the latter remaining prognostic in multivariate analysis. Using the recent prognostic model for MDS pts having failed HMA (Nazha et al, hematologica 2016), that includes ECOG>1, very poor cytogenetics, age, marrow blasts >20%, TD, platelets Conclusion: Response rates with GDAC, in this population of higher risk MDS, CMML or low blast count AML with failure to AZA (and often with IWG 2006 progression) were modest. Tolerance was similar to that of conventional HMA treatment. Disclosures Beyne-Rauzy:Celgene, Novartis: Honoraria. Park:Novartis: Research Funding. Jueliger:astex: Employment. Bevan:astex: Employment. Ades:Celgene, Takeda, Novartis, Astex: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding.

Results of the Randomized Phase II Study Decider (AMLSG 14-09) Comparing Decitabine (DAC) with or without Valproic Acid (VPA) and with or without All-Trans Retinoic Acid (ATRA) Add-on in Newly Diagnosed Elderly Non-Fit AML Patients

Background: Despite the recent approval of DNA-hypomethylating agents (HMAs) for treatment of elderly AML patients (pts) ineligible for induction, their prognosis is still poor, and rational, effective HMA-based combination treatments are under study. Histone deacetylase inhibitors (HDACi) show synergism with HMAs in vitro. ATRA - as single agent clinically ineffective in non-M3 AML - in combination with HMAs also shows in vitro synergistic antileukemic activity in non-M3 AML cells. We previously conducted a non-randomized phase II trial in elderly non-fit AML pts with DAC (3-dy schedule), given alone or combined with ATRA (45 mg/m2 dy 4-28, only during course 2), with encouraging results (Lübbert et al., Haematologica 2012). We now expanded this approach to a 4-arm randomized phase II study (2x2 factorial design) asking whether the addition of either VPA (HDACi activity) or ATRA or both to DAC as first-line treatment of elderly AML pts might improve the effect of DAC monotherapy (NCT00867672).Patients and Methods: Inclusion criteria: newly diagnosed pts >60 yr unfit for induction (reasons for treatment decision prospectively captured) with non-M3 AML (WHO, de novo or after antecedent hematologic disorder [AHD], therapy-associated [t]AML), ECOG performance status (PS) 0-2. Pts with >30,000 WBC/µl were to receive a short course of hydroxyurea. Treatment: DAC 20 mg/m2 dy 1-5 (treatment arms A/B/C/D), VPA p.o. continuously (target serum levels: 50-110 mg/l) from dy 6 (arms B/D), ATRA p.o. dy 6-28 (arms C/D) of each 28-dy course (repeated until relapse/progression, prohibitive toxicity, withdrawal or death). Key endpoints: objective response rate (ORR): CR/CRi/PR (ELN criteria), overall survival (OS). Sample size calculation was based on the primary endpoint ORR, assuming an ORR of 25% in arm A (Lübbert et al., Haematologica 2012). For a power of 80% (test in this phase II study at 1-sided alpha=0.1) for an increase of ORR to 40% with VPA or ATRA, 176 pts were necessary, planned sample size 200. Efficacy analyses were performed in the intention-to-treat (ITT) population including all randomized pts for whom treatment was started. VPA was investigated by comparing arms B+D vs arms A+C, ATRA by comparing arms C+D vs arms A+B. ORR was analyzed with logistic regression, OS with Cox regression, without adjustment for prognostic factors. Odds ratios (OR) for the effect on ORR and hazard ratios (HR) for the effect on death with 95% confidence intervals (CI), and two-sided p values of the tests of no treatment effect are presented. Central hematopathological review by an independent morphologist was conducted in a blinded fashion as to treatment arms.Results: Between 12/2011 and 2/2015, 204 pts were randomized (4 were excluded from the analysis because no treatment was administered). Median age: 76 yrs (interquartile range 72-79, range 61-92), ECOG PS 0/1/2-3: 19/61/20%: 52% had an HCT-CI >3, 16.5% WBC >30.000/µl, 31.5% poor cytogenetics (ELN), 51% had an AHD, 13.5% tAML (characteristics overall balanced across all 4 treatment arms). A median of 3 DAC courses were administered (per arm: 2/3/5.5/4), however 53 pts (26.5%), who were older, with reduced PS and a higher HCT-CI compared to the other 147 pts, received only a single course. The ORR (usually achieved only after >3 courses) was 17.5%, median OS 6.2 mths (arm A: 8.5% and 4.8 CI [2.8,7.6] mths, arm B: 17.5% and 6.1 CI [3.7,7.2] mths, arm C: 26.1% and 8.4 CI [4.0,14.0] mths, arm D: 18% and 7.7 CI [4.6,11.2] mths, respectively). Effect on ORR of VPA vs no VPA (17.8 vs 17.2%): OR 1.06, CI [0.51,2.21], p=0.88; of ATRA vs no ATRA (21.9 vs 13.5%): OR 1.80, CI [0.86,3.79], p=0.12. Effect on OS of VPA vs no VPA (6.2 vs 6.4 mths median OS): HR 0.94, CI [0.70,1.28], p=0.70; of ATRA vs no ATRA (8.2 vs 5.1 months median OS): HR 0.65, CI [0.48,0.88], p=0.006 (after adjustment for PS, HCT-CI, WBC, LDH: HR 0.59, CI [0.43,0.82], p=0.002). Improved survival with ATRA was also seen in pts with poor cytogenetics. Toxicities (predominantly hematologic) did not show relevant differences between the 4 treatment arms.Conclusions: Based on this ITT analysis of a randomized trial, the addition of ATRA to standard-dose DAC resulted in a higher ORR and in a clinically relevant extension of OS, without additional (hematologic and non-hematologic) toxicity. In contrast, the addition of VPA did not affect ORR or OS. DisclosuresLübbert:Celgene: Other: Travel Funding; Janssen-Cilag: Other: Travel Funding, Research Funding; Ratiopharm: Other: Study drug valproic acid. Schlenk:Pfizer: Honoraria, Research Funding; Amgen: Research Funding. Heuser:Pfizer: Research Funding; Tetralogic: Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Bayer Pharma AG: Research Funding; Celgene: Honoraria; Novartis: Consultancy, Research Funding. Bug:Janssen: Other: Travel Grant; Astellas: Other: Travel Grant; Teva Oncology: Other: Travel Grant; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Grant; Nord Medica: Consultancy. Giagounidis:Celgene Corporation: Consultancy. Brugger:Astrazeneca: Employment. Niederwieser:Amgen: Speakers Bureau; Novartis Oncology Europe: Research Funding, Speakers Bureau.

CLL: A Prognostic Model Comprising Only Two Biomarkers (IGHV Mutational Status and FISH-Cytogenetics) Separates Patients with Different Prognosis and Simplifies the CLL-IPI.

Background: Survival of pts with chronic lymphocytic leukemia (CLL) ranges from a few years to a normal lifespan. Clinical stages (i.e. Rai, Binet) are the basis for CLL prognostication but do not reflect the complex biology of CLL, which ultimately shapes the disease heterogeneity. Recently, a CLL-International Prognostic Index (CLL-IPI) which includes five clinical and biological variables (i.e. age, IGHV mutational status, del(17p), beta2-microglobulin [B2M] and Rai or Binet stages) and stratifies pts into four different categories has been proposed. This prognostic index is obtained by the sum of the score given to each parameter and includes dichotomized continuous variables. The aim of this study was to determine whether a prognostic model based only on biomarkers could separate CLL patients with different outcomes and simplify the CLL-IPI.Material and Methods: Five hundred twenty-four CLL pts from the Hospital Clínic, Barcelona, in whom information at diagnosis included age, clinical stage (Rai and Binet), IGHV mutational status, B2M, and FISH-cytogenetics were analyzed. For validation purposes a cohort of 417 pts from the Brno Hospital, Czech Republic was used. The two series included patients as seen in clinical practice. Primary endpoints were overall survival (OS) and time to first treatment (TTFT). The internal validity of the models was evaluated using bootstrapping, and the discriminatory value by c-statistics. Double sided P values < .05 were considered significant.Results: First, we confirmed that all five covariates included in the CLL-IPI were independently predictive of OS. Both sets of five covariates (age + B2M + IGHV + FISH + Rai or Binet) were incorporated into the regression models. All four patient subgroups had a significantly different survival (c-statistic: 0.72), although the high- and very-high risk groups overlapped and the number of patients in the very-high-risk group was small. We then evaluated all possible combinations of these five covariates to identify the simplest model with robust discriminatory value. A prognostic model based on IGHV mutational status + FISH [del(17p) and/or del(11q)] separated three subgroups of pts [i.e, good-biomarkers (mutated IGHV + no poor FISH cytogenetics), intermediate-biomarkers (either unmutated IGHV or poor FISH cytogenetics), and poor biomarkers (unmutated IGHV + poor FISH cytogenetics)] with different prognosis (c-statistic: 0.68). In the Barcelona series, the good-biomarkers category identified around 50% of pts from the whole series whose survival did not differ from the general population; patients with intermediate-biomarkers had a projected 10-year survival of 68%. Finally, the poor-biomarkers category captured pts with a projected 10-year survival of 17%. The corresponding TTFTs at 3 years from diagnosis were 16%, 50% and 63%, respectively (Figure). Furthermore, it separated patients with different outcome within clinical stages, notably Binet A or Rai 0, and across all age groups. This model was fully validated in the Brno series.Conclusions: The biomarkers-only CLL prognostic model presented here is based on the two most important CLL biomarkers (i.e. IGHV mutational status and FISH cytogenetics) which are included as a backbone in the CLL-IPI and other CLL prognostic systems. This model is simple, easy to apply and to remember; it separates three groups of pts rather than four; it does not contain continuous variables; it can be applied to younger and older pts, and has clinical implications. This prognostic model could be useful in CLL prognostication either alone or in combination with clinical stages and warrants prospective validation, including in patients receiving targeted therapies. [Display omitted] DisclosuresMontserrat:Pharmacyclics: Consultancy; Vivia Biotech: Equity Ownership; Janssen: Honoraria, Other: travel, accommodations, expenses; Gilead: Consultancy, Other: Expert Testimony; Morphosys: Other: Expert Testimony.

Safety and Eficacy of Low Dose- Bortezomib Plus Melphalan/Prednisone (velcadito protocol) in Elderly Patintes Not Eligible to Transplant in Newly Dignosed Multiple Myeloma. Restrospective Study of 26 Patients

Introduction: Protocols based on bortezomib have become the standard therapy in the elderly and not eligible for transplantation. The VISTA study showed OR 71%, CR 30%, regardless of adverse factors such as age, renal failure or cytogenetic changes, but the patient had a high rate neuropathy (44%). The Spanish group and the Italian group modified the dose of bortezomib achieving rates of CR 22% and 20%, reducing neurotoxicity 8% and 5% respectively.We present the experience of 26 newly diagnosed patients treated with low-dose bortezomib associdados the melphalan / prednisone (Velcadito protocol).Objective: The aim of this study is to assess the effectiveness and safety of low-dose bortezomib in elderly patients not eligible to transplant. We evaluated according to the criteria IMWG.Results: We evaluated 26 patients treated at the Hospital Universitario de Alava (Spain) and Hospital Israelita Albert Einstein (Brazil) among 2004 to 2016. The patients received 1 cycle with bortezomib 1.3mg/m2 (days 1,4,8,11) associated with melphalan 9 mg/m2 (1- 4 days) and prednisone 60mg/m2 (1- 4 days) 28 days cycle. From the 2nd cycle the patient received low doses of bortezomib (1 mg / m2, days 1 and 4) no change in other drugs and treatment regimen.The mean age was 78 years. 50% men/ 50% women. 2 patients had poor cytogenetics Pronóstico, 1 intermediate and 23 standard. According to the IMWG: ISS1 = 7 (26%) ISS 2 = 10 (38.5%), ISS3 = 6 (23%). 38,4% (n=10) of patientes had neuropathy but only 11,5%(n=3) grade 3-4. 61,5% (n=16) presented as neutropenia toxicity, 19,2% (n=5) with grade 3 (neutrophils <1000). 15,3% (n=4) had thrombocytopenia with grade greater than 3. Response rate was 100%, and if we consider at least PR was 92% (CR 38.5% VGPR 31%). The global survival had median of 80 months (95% confidence interval 57,8 - 102,1%) and the survival free of progression had median of 37 months (95% confidence interval 15 - 58,9%) with follow-up of 91 months.Conclusion: The use of velcadito protocol is safe, very effective and seems to be a good option for elderly patients with newly diagnose MM. A pharmacoeconomic analysis is recommended to assess the impact of the cost of treatment. Being a prospective clinical trial where an analysis of this impact of all patients treated with subcutaneous bortezomib beyond the characteristics of this study. DisclosuresNo relevant conflicts of interest to declare.

Clonal Architecture of MDS Somatic Mutations Dynamically Changes during Azacitidine Therapy and Has Very Limited Potential to Predict Patient Outcome

Introduction: Myelodysplastic syndromes (MDS) are clonal disorders of myeloid hematopoietic stem cells. Recent studies has shown that nearly 90% of patients with MDS carry somatic mutations in bone marrow (BM). These findings triggered a number of studies to identify potential uses of these mutations for diagnostics and prognostics purposes. We focused on a group of 38 patients with advanced stages of the disease that were selected for Azacitidine (AZA) therapy. We then utilized a set of 98 BM samples from the patient cohort that were collected in different stages before, during, and after the period of 4-12 cycles of the therapy. Each patient provided 3 samples on average. This study excludes patients that died early on AZA. Median OS on AZA therapy was 31 Mo. Most prevalent MDS subtypes were RAEB-2 (55%), RAEB-1 (24%), and MDS/AML (13%). 20% of patients had complex karyotype or poor cytogenetics (MedOS=22Mo) and the rest had mostly normal karyotype or intermediate cytogenetics (MedOS=40Mo) prior to AZA. Progression to AML was observed in 55% of patients (PFS= 16 Mo). After 4 cycles, PR was achieved in 59% of patients, CR in 12%, while SD was maintained in 21%, and 9% of patients progressed (PD) to AML.Methods: We detected relevant mutations in MDS samples using the following approach. We collected genomic DNA from separated BM samples: either a CD3-negative population containing the myeloid compartment, or CD3-positive T cells representing an internal control. We prepared amplicon libraries from these samples using the Illumina TruSight Myeloid Panel that covers 54 key genes involved in myeloid malignancies (notably MDS and AML). We sequenced these libraries using the Illumina NGS platform. To achieve greater sensitivity in detecting SNVs and InDels we utilized two different variant calling pipelines (using samtools mpileup or FreeBayes). Since the (PCR) validation efficacy of each mutation from the single NGS run was below 60%, we improved specificity by using two independently prepared sequencing libraries. The intersection of the variant detections from both libraries was considered accurate and only these data were reported as variants.Results: When we excluded all germinal variants, 43 somatic variants in ~18 genes were identified per patient on average. The majority (31/43) of these variants had an intermediate impact (on amino acid sequence), while 12/43 had high impact on the protein structure. Importantly, the majority of them had ~1% VAF (variant allele frequency) representing putative clones with low proliferative potential. In contrast, only 8 genes (~14 variants) were mutated with VAF>2%. The following genes were mutated most frequently: TET2, STAG2, ASXL1 in approximately 60-80% of patients. Data from repeatedly analyzed patient samples on AZA therapy led to an unexpected observation that the variants with WAF>2% often exhibit dynamically changing mutation pattern while the variants of non-proliferating clones (with VAF ~1%) remain very stable. We observed prominent development of some variants (ASXL1, STAG2, CUX1, BCOR) as well as an increase in VAF of others (TP53, RUNX1, CUX1) on AZA therapy. Most of these genes when mutated were reported previously as altering prognosis of MDS (Bejar R et al, 2014). Surprisingly, in some samples we found a mutation in the RUNX1 gene before AZA therapy that was not present after the treatment however, after the treatment another not previously observed mutation of RUNX1 emerged. Furthermore, the presence of any of the mutations before AZA including SF3B1 or TP53 did not have any prognostically significant association with OS or PFS. This contention is supported by the fact that many mutations actually disappeared on AZA.Conclusions: Using an internal sample control combined with a duplicate NGS library preparation we achieved a very high accuracy of detecting somatic variants in MDS-BM sub-separated samples. We observed that variants above 2% VAF change dynamically over the course of AZA therapy while the variants with ~1% VAF remain stable. Our data suggest that development of somatic mutations in AZA-treated MDS patients is a dynamic process, which involves previously identified high risk genes including TP53, RUNX1, CUX1, ASXL1 and BCOR.Grant support: GAČR 16-05649S & P305/12/1033, AZV: 16-27790A, CZ.1.05/1.1.00/02.0109, UNCE 204021, LH15170, PRVOUK P24, LQ1604 and RVO-VFN64165. DisclosuresNo relevant conflicts of interest to declare.

Impact of Bone Marrow Fibrosis and Early Response on Outcome after Azacitidine Therapy in 94 Patients with Myelodisplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myeloid Leukemia

▪Azacitidine (AZA) is effective in high risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia type 2 (CMML-2) and low blast count acute myeloid leukemia (AML) patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified.We evaluated clinical predictors of OS and overall response rate (ORR; complete/partial response CR/PR; stable/progressive disease SD/PD) to AZA in a real life cohort. We studied 94 consecutive patients, treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. OS was measured from the starting of AZA treatment. Table 1 shows the clinical characteristics pre- and post-AZA: most patients (68%) were AREB1 or AREB2, 13% RCUD/RCMD or MDS NOS according to WHO 2008 classification, 17% AML, 2% CMML. At the onset of AZA therapy the majority of MDS cases (68%) showed an intermediate-2 risk, according to the International Prognostic Scoring System (IPSS) and high/very high risk (78%) according to IPSS-revised. Secondary and de novo cases, as well as cytogenetics risk groups, were equally represented; 50% of patients were transfusion dependant and moderate to severe neutropenia or thrombocytopenia were present in roughly 50/70% of cases respectively. As expected, bone marrow biopsies pre-AZA showed hypercellularity in most patients (65%). Remarkably, 47,5% of cases showed bone marrow fibrosis of ≥1 grade before AZA initiation. These findings were mostly unchanged at post-AZA evaluation. On the whole, 93 patients receiving > 4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-44), ORR was 41.9% (CR 18.3%, PR 11.8%, SD with hematologic improvement HI 11.8%), SD was 21.5%, PD 10.7% and 25.8% failed to achieve a response. Thirteen percent of patients reached at least partial cytogenetic response and 50% a HI. ORR was not influenced by monocytosis, neutropenia or IPSS cytogenetic risk category. Interestingly, pre-AZA marrow blast percentage, cytogenetic risk, time from diagnosis to AZA and the interval from 1st to 6th cycle had no impact on response. As regards marrow characteristics, patients with MF-0 pre-AZA displayed significantly lower PD rate and higher ORR, SD and HI than those with any grade of fibrosis (21.4% vs 51.4% and 78.6% vs 48,6%, respectively p=0.006, Fig1). This observation was also confirmed at marrow evaluation after AZA (22% versus 48% for PD and 78% versus 52% for ORR/SD/HI, p=0.05, Fig1). Regarding cellularity pre- and post-AZA, higher ORR,SD and HI and lower PD were observed for patients with normo/hypo compared to those with hyper-cellularity (Fig1) although not significantly. Forty-one percent of cases presented a hematologic toxicity (33% neutropenia and 18% thrombocytopenia of any grade) occurring after a median of 2 (1-18) AZA cycles. Moreover 28.6% of patients had an infection during AZA treatment, not related to neutropenia degree. Of note, toxicities did not affect median time from the 1st to the 6th AZA cycle (170,115-240 days), nor ORR. Median OS from the beginning of therapy was 18.5 months (12.7-24.4, 95% CI). IPSS high category [HR 2.24 (1.19-4.20) p=0.01], poor cytogenetics [2.19 (1.27-3.78) p=0.005], and lower ORR [0.46 (0.26-0.80) p=0.006] significantly affected OS. Unexpectedly, a response obtained after less than 4 cycles negatively impact OS [HR 0.86 (0.80-0.92) p<0.0001]. Notably, cases with pre-AZA fibrosis ≥MF-1 showed lower OS [2.26 (1.28-3.99) p=0.005]. In conclusion we provide evidence of no relationship between neutropenia and infections and of no impact of toxicities on dose-density and ORR to AZA treatment. Moreover, high marrow fibrosis and hypercellularity may affect response to AZA therapy. Further studies are needed to disclose the clinical/biological significance of marrow fibrosis/cellularity in the era of hypomethylating agents. [Display omitted] [Display omitted] DisclosuresReda:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding.

Anti-Thymocyte Globulin for Graft-Versus-Host Disease Prophylaxis in Patients with Acute Myeloid Leukemia Undergoing Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation in First Complete Remission: A Survey on Behalf of the EBMT Acute Leukemia Working Party

Introduction: Anti-thymocyte globulin (ATG) prophylaxis was shown to be effective in reducing both acute and chronic graft-versus-host disease (GVHD) following allogeneic stem cell transplantation (allo-SCT). In previously published studies, the addition of ATG to the pre-allo-SCT conditioning regimen resulted in substantial reduction in GVHD incidence, but theoretically ATG could be associated with increased relapse rate, especially if administered at high doses (> 6 mg/kg of ATG Thymoglobulin or >15mg/kg of ATG Fresenius) to patients with high-risk acute myeloid leukemia (AML). To further address this question, we assessed transplantation outcome in adult AML patients who underwent reduced intensity conditioning (RIC) allo-SCT from a matched sibling donor (MSD) while in complete remission (CR1), with or without ATG. We used the registry data of the Acute Leukemia Working Party of the European Society forBlood and Marrow Transplantation (EBMT).Patients and Methods: Inclusion criteria were adult patients with AML (de novo or secondary) who underwent RIC allo-SCT from an MSD in CR1 between the years 2000 and 2014. RIC conditioning was defined as per the EBMT criteria. Only patients presenting with intermediate- or poor-risk cytogenetics or secondary AML were included in the analysis. Patients who received any kind of T cell depletion including Campath were excluded. Patients were considered to receive high-dose ATG if they received > 6mg/kg of ATG-Thymoglobulin or >15mg/kg of ATG-Fresenius. All other patients were considered as a control.Results: Two hundred and five of the 1750 patients, included in the analysis, received high-dose ATG. The median patient age at diagnosis was 56 years and the median donor age was 55 years for both groups. Fifty four percent of the patients were males. The graft properties were similar in the high-dose ATG and control groups, with female-to-male transplants in 48/205 (23.4%) and 378/1545 (24.6%) patients, respectively. Peripheral blood was the source of grafts in 193/205 (94.1%) and 1413/1545 (91.5%) patients, respectively (p=NS). Poor cytogenetics was reported in 28/205 (13.7%) patients who were given high-dose ATG and in 247/1545 (16%) patients from the control group. Secondary AML was more prevalent among patients from the high-dose ATG group compared to the control group [84/205 (41%) vs 425/1545 (27.5%; p=0.0003]. The median follow-up was 44.6 (0-177) months.The 3-year overall survival (OS) and leukemia-free survival (LFS) were almost identical in both groups, amounting to 54.9 and 46.3 months, respectively for patients who received high-dose ATG and to 54 and 49.5 months, respectively for patients in the control group (p=0.978 and 0.376 ). Differences in relapse incidence (RI) (40.9% vs 34.4%; p=0.1) and non-relapse mortality (NRM) (11.7% vs 16%; p=0.152) were insignificant. The composite endpoint of GVHD-free/relapse-free survival (GRFS) was similar in the groups after one and three years of follow-up (42.9 vs 49.7 and 31.1 vs 36 months, respectively; p=0.152 and p=0.124). In multivariate analysis, the use of ATG prophylaxis was not found to be associated with any of the evaluated parameters. In contrast, OS, LFS, RI, NRM and GRFS were all affected by patient age and presence of secondary AML. Poor cytogenetics correlated with inferior OS, LFS, RI and GRFS. Donor CMV positivity was associated with lower OS, LFS and GRFS and a higher rate of NRM.Conclusions: In AML patients presenting with intermediate- or poor-risk cytogenetics who are referred to RIC allo-SCT from an MSD in CR1, the addition of ATG to conditioning regimens does not influence the outcome. The composite GRFS endpoint is mainly affected by AML risk factors (hazard ratio of 1.43 for secondary AML and 1.37 for poor-risk cytogenetics; p=0.0001). The role of ATG prophylaxis in AML patients undergoing RIC allo-SCT should be prospectively evaluated. DisclosuresMaertens:Gilead: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy; Astellas: Consultancy, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau.

A Phase I/II Trial of Ixazomib (Ix), Pomalidomide (POM), and Dexamethasone (DEX), in Relapsed/Refractory (R/R) Multiple Myeloma (MM) Patients: Responses in Double/Triple Refractory Myeloma and Poor Risk Cytogenetics

Triplet regimens combining an immunomodulatory agent, a proteasome inhibitor (PI), and a steroid are used to treat newly diagnosed and relapsed multiple myeloma (MM). Although ixazomib (Ix), an oral PI with single agent activity, can be combined with lenalidomide (LEN), patients (pts) with relapsed/refractory (R/R) MM are often LEN-refractory. Pomalidomide (POM) has single agent activity in LEN-refractory disease, and both POM and Ix also show activity in poor cytogenetic risk pts.Methods: Primary objectives: 1) determine the maximum tolerated dose (MTD) of Ix in combination with standard dose POM and dexamethasone (DEX), and 2) evaluate the anti-tumor activity of the triplet. The treatment regimen included two dose levels (3 mg and 4 mg) of Ix on days 1, 8, 15; POM 4 mg days 1-21; and DEX 40 mg days 1, 8, 15, 22, of a 28 day cycle. Eligibility: R/R MM after >1 prior therapy, LEN-refractory, and ≤ grade(gr) 1 peripheral neuropathy (PN). Pts were treated until progression or unacceptable toxicity. Design: Phase I study utilizing a standard 3+3 design; dose limiting toxicities (DLTs) defined during cycle 1.Results: 32 pts treated, 31 evaluable for toxicity and response. Pts received a median 4 cycles (range 1-13); median follow-up is 5.5 months (range 1.8-21.1). Six pts treated on DL1, 25 treated on DL2, the MTD/Phase II dose (P2D). Median age: 62 years (range 38-84); median time from diagnosis: 3.7 years (range 1.0-8.9); median number prior therapies: 3 (range 1-5); prior transplant: n = 23 (74%); double (LEN/Bortezomib[BOR]) or triple (LEN/BOR/Carfilzomib[CFZ]) refractory: 19 (61%). Phase I: DL1 expanded to n=6 after 1/3 pts experienced DLT (gr3 lung infection); no further DLT seen on DL 1 or 2. Adverse events (AEs) related to POM and/or Ix: ANC decrease Gr1/2 n=11 (35%), Gr3/4 n=10 (32%), platelet decrease Gr1/2 n=9 (29%), lymphocyte decrease Gr1/2 n=8 (26%), Gr3/4 n=11 (35%), PN Gr1/2 n=9 (29%), no Gr3/4.Response: Phase I and II, n=31 pts treated. ORR: 45% (6 VGPR, 8 PR); Clinical Benefit Rate (CBR): 81% (6 VGPR, 8 PR, 3 MR, 8 SD). In the pts with high risk cytogenetics (7[23%] 1q, 3[10%] 17p, 2[6%] t(4;14)) an ORR of 58% (3 VGPR, 4 PR) was seen, and the CBR was 83%. In the double or triple refractory pts, an ORR of 26% and CBR of 79% (1 VGPR, 4 PR, 3 MR, 7 SD) were observed.Conclusions: Ix/POM/DEX is a well-tolerated oral combination therapy, and responses were seen even at DL1 and in high risk patients, including those with poor-risk cytogenetics or advanced refractory disease. DisclosuresKapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Kumar:Millennium: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy; Onyx: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding. Lonial:Novartis: Consultancy; BMS: Consultancy; Janssen: Consultancy; Merck: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Onyx: Consultancy. Nathwani:Carevive Systems, Inc.: Research Funding. Forman:Mustang Therpapeutics: Other: Construct licensed by City of Hope. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding.

Value of Different Comorbidity Indices for Predicting Outcome in Patients with Acute Myeloid Leukemia.

Age is a dominant predictor of outcome in acute myeloid leukemia (AML). However, it is not clear to which extent comorbidities contribute to this effect. The objective of this study was to determine the impact of pretreatment comorbidities on survival of AML patients. In a single-center retrospective study 194 adult AML patients were included. The Hematopoietic cell transplantation comorbidity index (HCT-CI), the Adult Comorbidity Evaluation-27 (ACE-27) score and the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) as well as data on demographics, cytogenetics, treatment and outcome were evaluated at the time of initial diagnosis by univariate and multivariate analysis. The study included 102 male and 92 female (median age 60.9 years) of which 173 (89.2%) received intensive chemotherapy. Median overall survival (OS) was 17 months. In univariate analysis, cardiovascular disease (26 vs 12 months, p = .005), severe hepatic disease (19 vs 4 months, p = .013) and renal impairment (17 vs 7 months, p = .016) was associated with inferior OS. For each index, the highest comorbidity burden was associated with reduced OS. However, in multivariate analysis only the ACE-27 score was associated with outcome. Besides ECOG ≥ 2 and poor cytogenetics only the ACE-27 score but not higher age was associated with OS in the group of patients receiving intensive therapy. Adjusted hazard ratios were 3.1, 3.5 and 4.0 for mild, moderate and severe ACE-27-assessed comorbidities, respectively (p = .012). Our study confirms that comorbidities significantly impact survival of AML patients and a pretreatment assessment of comorbidities may help to identify patients with poor outcome.

Monosomal karyotype of chromosome 5/7 was an independent poor prognostic factor for Chinese myelodysplastic syndrome patients

Monosomal karyotype (MK) was defined as the presence of at least 2 autosomal monosomies or of a single monosomy associated with at least one additional structural abnormality. 6.4-16.3% myelodysplastic syndrome (MDS) patients were reported to fulfill the criteria for MK and associated with poor prognosis in the majority of patients with MDS. In order to further clarify the prognostic significance of MK in Chinese MDS patients, 2080 primary patients were retrospectively analyzed in our center. MK was observed in 8.1% patients (168/2080), and monosomies of chromosome 5/7 were the most frequent types of MK. We further found that MK was significantly associated with elderly patients, higher bone marrow blasts and relatively poor cytogenetics. In addition, MDS patients with MK (n = 59) had poor survival than those without MK (n = 491) in total cohort (P < 0.001), and there was significant difference in the OS between the patients with MK (n = 56) and without MK (n = 53) in the relatively poor cytogenetics group (P = 0.0025). Incorporation of MK into IPSS-R could further stratify MDS patients into different prognostic groups (P < 0.001). Interestingly, monosomies of chromosome 5/7 rather than MK were significantly related to shorter OS (HR = 2.709, P < 0.001) by multivariate analysis. In conclusion, our results suggested that 8.1% MDS patients were presented with MK, and the incidence of MK increased with the number of cytogenetic abnormalities. Monosomies of chromosome 5/7 were the most frequent MK as well as an independent poor risk factor for OS in Chinese MDS patients.

Incidence, Risk Factors, Treatment and Outcome of Isolated Extramedullary Relapse after Allogeneic Stem Cell Transplantation for Acute Leukemia and Myelodysplastic Syndrome

Allogeneic stem cell transplantation (allo-SCT) is an effective treatment with a curative potential for acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL). The major cause of death after allo-SCT remains disease relapse, with relapse rate of 35-45%. Isolated extramedullary relapse (iEMR) after allo-SCT is considered relatively rare and there is limited data on this type of relapse. We performed a retrospective analysis in 685 consecutive patients with AML (n=446), MDS (n=119) and ALL (n=120) given allo-SCT from sibling or unrelated donor over a 13-year period in a single institution to study the incidence, risk factors, treatment options and outcome of patients with iEMR after allo-SCT. With a median follow-up of 57 months (range, 1-166), 271 patients are alive 158 died of treatment related causes and 292 patients relapsed. The 5-year overall and disease-free survival rates were 38.8% (95CI, 34.9-42.7) and 33.9% (95CI, 30.1-37.6) respectively. The cumulative incidence of relapse was 43.9% (95CI, 40.2-47.9). Among 292 patients who experienced relapse post-transplant, 260 had bone marrow relapse (BMR) (5 year cumulative incidence 39% (95CI, 35.4-42.9)) and 32 had iEMR (5 year cumulative incidence 4.9% (95CI, 3.5-7), 10.9% of all 1st relapses). Seventeen patients had combined BM and EMR and were included in the final analysis with the BM group since their disease course was similar to that of patients with BMR. Sixty four patients had EMR at some point of disease course thus the 5-year cumulative incidence for any EMR was 10.1% (95CI, 7.9-12.8). iEMR occurred significantly later than BMR, 11.1 (range, 0.9-67.2) vs 3.8 (range, 0.4-101.7) months post-transplant respectively (p Most of the patients with iEMR received systemic treatment combined with local radiation and DLI if feasible. With a median follow-up of 32.6 (1.6-140.4) months after 1st relapse, 37 patients are alive and 255 have died. The 1-year and 3-year OS were 21.8% (16.9-26.6) and 10.8% (6.9-14.7). The 3-year OS was 8.5% (4.8-12.2) and 29.1% (12.0-46.3) after BMR and iEMR, respectively (p=0.003). Female gender (HR=0.7, p=0.01), diagnosis of MDS vs AML or ALL (HR=0.57, p=0.01) and 1st iEMR (HR=0.56, p=0.02) were factors that independently predicted better 3-year survival after 1st relapse in multivariable analysis while advanced status at diagnosis (HR=1.45, p=0.01) and poor cytogenetics (HR=1.37, p=0.03) were independent predictors of inferior survival. One hundred and one patients achieved 2nd CR, 21 of them died of treatment related causes, 25 are alive and 56 had second relapse, 30 in the BM and 26 EM. The 3-year cumulative incidence of second iEMR was high and quite similar to BMR - 29.0 vs 32.3%. Among 32 patients who relapsed initially EM 13 relapsed again, the minority in BM (3 patients) while most EM (10 patients) (CI 16.7% (5.9-46.8) and 55.6% (36.8-84.0) respectively). The 3-year OS after 2nd relapse was 13.8% with significantly better survival after iEMR (23.8 vs 4.0% for BMR, p=0.03). In conclusion, the incidence of iEMR of acute leukemia and MDS after SCT is 4.9%, with higher incidence in patients with ALL or prior extra medullary disease. It occurs later than BMR and more commonly in patients with chronic GVHD, suggesting less effective protection of graft versus leukemia on extra medullary sites. When treated aggressively with a combination of chemotherapy, radiation and immunotherapy prognosis is better with iEMR than with BMR. Patients with iEMR tend to relapse again extra medullary, but long-term survival is feasible in these patients. *AN and AS equally contributed Disclosures Nagler:Novaratis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding.

Safety and Long-Term Efficacy of Maintenance Therapy with Alternating Azacytidine (AZA) and Lenalidomide (Len) Cycles in Elderly (≥ 60) Fit Patients (Pts) with Poor Prognosis AML in First Complete Remission (CR) After LIA Induction. A Phase II Multicentric GOELAMS Trial

In elderly pts, the prognosis of AML associated with poor risk cytogenetics or secondary to either MDS or previous cancer is so bad that only supportive care or investigational studies are usually recommended. Fit patients may achieve CR after conventional induction, but early relapse appears to be nearly inescapable whatever classical consolidation or maintenance therapy is used. Therefore, the GOELAMS investigated the impact of a maintenance using two agents mainly used in MDS, ie AZA and Len.Between March 2011 and February 2013, 117 pts from 27 centers (median age 69 yrs; 60-80) with previously untreated poor prognosis AML were included. Poor Risk factors were either preceding MDS (n=52), previous cancer (n=37) or centrally reviewed (IL) poor risk cytogenetics (n=83) defined as complex karyotype (≥3 abnormalities, n=65), monosomal karyotypes (n=54), del or - 5 (n=61) or 7 (n=44), 3q abnormality (n=9) or MLL rearrangement except for t(9;11) (n=5). Median WBC was 2.9 G/L (0.5-160), 7 pts had WBC ≥ 30 G/L. Induction chemotherapy included Lomustine 200 mg/m² po d1, Idarubicine 8 mg/m²/d (d1-5), Cytarabine 100mg/m²/d CI (d1-7). Patients in CR received 12 maintenance cycles alternating every 28 days AZA (sc 75 mg/m²/d1-7) and Len (10mg/d1-21), which started if PMN and platelets were >1 G/L and 100 G/L respectively. After d42, subsequent cycles were reduced to 50 mg/m²/d and 5 mg/d. GCSF was allowed in case of PMN < 0.5 G/L after 7 days or febrile neutropenia. At the end of induction, CR was achieved in 56% (65 pts) without any predictive factor, 9% died from infection (n=6), cerebral hemorrhage (n=1) or MOF (n=4) and 35% (41pts including 5 CRp) failed to achieve CR. The 12 planned maintenance courses could be given to 21 pts (32%) (median: 6). Few toxicities were observed. AZA courses were slightly more toxic than Len courses (table 1). Table 1AZA courses %Len courses %Gr 3/4 neutropenia46.8/ 27.339.7 /17.6Antibiotics for fever at home6.97Hospitalization for febrile neutropenia0.52.7RBC transfusions55.4Gr 3 Thrombopenia2016Platelets transfusion8.67.9Interval between courses > 35 days26.118.4Median time interval between courses31 d28 dCourses with doses reductions9.621.6Maintenance courses were interrupted because of relapse (n= 34, 77%), alloSCT (n=4 %), count error (n=1 %) or toxicities (n =5, 11%) occurring after Len (depression, vascular purpura and pseudomembranous diarrhea, sudden death, all during cycle 1) or after Aza (atrial fibrillation and cardiac dysfunction). Twenty Gr3/4 AE were reported among 441 cycles (0.56%/courses). Median follow-up for survivors was 38 mo (26-47). Median OS was 10 mo, with 21% 2y OS. Median CR duration was 7 mo (1-30). Impact of prognostic factors on DFS is shown table 2. Within poor risk factors, Cytogenetic abnormalities appeared as even poorer than previous MDS or cancer. Table 2CR %CR NDFS median moP VALUE1y DFS %2y DFS %All patients56657.941.512.3Age ≥ 7058.3288.6 vs 7.746.417.9WBC ≥ 3.3 G/L48.1267.0 vs12.423.111.5Previous MDS51.92713.8 vs 6.4.0551.922.2MDS only68.41316.8 vs 6.4.00869.230.8Previous cancer54207.5 vs 7.9355Cancer only80812.4 vs 7.755012.5Poor cytogenetic53445.1 vs 15.3.0429.56.8Complex caryotype49.2324.8 vs 12.9.012259.4Monosomal caryotype50274.6 vs 12.9.00218.57.4Chromosome 5 abnormality52.5325 vs 13.8.00218.86.3Chromosome 7 abnormality54.5243.6 vs 12.00120.84.23q55.6510.4 vs 7.740017p deletion48.5165.0 vs 10.52512.5MLL8043.4 vs 8.4250poor cytogenetic + MDS42.997.7 vs 7.944.422poor cytogenetic + cancer46.774.8 vs 7.928.90poor cytogenetic + cancer + MDS71.453.4 vs 8.4200cancer + MDS00---Poor cytogenetic only rev aza57.5236.3 vs 12.9.05521.74.3Poor cytogenetic only SA255436.430.220.9In the previous GOELAMS SA2 trial, 78 pts with poor risk cytogenetics without secondary leukemia received the same LIA induction followed in CR by maintenance therapy with 6 mini-reinductions (Ida 10mg/m² d1, cytarabine 50 mg/m²x2/d d1-5) and 6MP-MTX for 2years. In the present study, the DFS of the group of pts with poor risk cytogenetics without previous cancer or MDS is very similar.This alternating azacitidine/lenalidomide maintenance improved DFS and OS of pts without poor risk cytogenetics (median 15.7 and 24 mo). In this setting, it could be randomly compared to conventional chemotherapy maintenance. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.