CR Patients Research Articles

Leukemia relapse following unmanipulated haploidentical transplantation: a risk factor analysis on behalf of the ALWP of the EBMT

BackgroundAs information on incidence, risk factors, and outcome of acute leukemia (AL) relapse after unmanipulated haploidentical stem cell transplantation (haplo-SCT) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.MethodsAmong 1652 transplants performed for lymphoblastic and myeloid AL between 2007 and 2014, 587 patients (acute lymphoblastic leukemia (ALL) 131, acute myeloid leukemia (AML) 456) with detailed information were analyzed aiming to identify risk factors for post-transplant relapse and for overall survival (OS) after relapse.ResultsThe cumulative incidence of relapse at 3 years was 44% (35–53%) for ALL and 32% (27–36%) for AML (p = 0.023). In ALL, risk factors for relapse were disease status different from the first complete remission (CR1) at haplo-SCT (CR2 vs CR1: HR 2.85, p = 0.011; advanced vs CR1: HR 14.28, p < 0.0001) and male donor gender (HR 3.64, p = 0.0002), while in AML, risk factors were advanced disease at haplo-SCT (advanced vs CR1: HR 3.95, p < 0.0001) and comorbidities (HCT-CI) ≥ 3 (HR 1.75, p = 0.014). Transplants performed in more recent years were associated with lower relapse incidence (RI) in AML, but not in ALL (HR 0.91, p = 0.042). After relapse, median follow-up was 13 months (mos). OS at 1-year post relapse was 18%. Prognostic factors for superior OS after relapse were remission at time of haplo-SCT (CR vs advanced: HR 0.71, p = 0.028), time from transplant to relapse (≥ 5 mos vs < 5 mos: HR 0.530, p < 0.0001), and bone marrow as a stem cell source (peripheral blood (PB) vs bone marrow (BM): HR 1.473, p = 0.016).ConclusionsRisk factors for relapse after haploidentical transplantation were disease specific. Longer OS after relapse was achieved in particular by patients both in CR at haplo-SCT and relapsing more than 5 months after transplant (1-year OS 33%).

Haploidentical, Unmanipulated Granulocyte Colony-Stimulating Factor (G-CSF)-Primed Peripheral Blood Stem Cell Transplants for Acute Myeloid Leukemia (AML) in Remission: A Single Center Experience.

BackgroundData about application of related haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) on patients with high-risk or intermediate-risk acute myeloid leukemia (AML) in the first complete remission (CR1) are lacking. In this study, we report the outcomes of using unmanipulated haploidentical allogeneic peripheral blood stem cell transplantation (haplo-PBSCT) as post-remission therapy for patients with high-risk or intermediate-risk AML in CR1.Material/MethodsFrom January 2008 to July 2016, 33 patients diagnosed as high-risk or intermediate-risk AML in CR1 undergoing haplo-PBSCT in our institution were enrolled for analysis. The cumulative incidence of platelet and neutrophil recovery, the occurrence of acute graft-versus-host-disease (GVHD) and chronic GVHD, relapse and non-relapse mortality were assessed. Patients’ survival rates were estimated using the Kaplan-Meier method.ResultsThe cumulative incidence of grade 2–4 acute GVHD, overall and extensive chronic GVHD was 18.2%, 9.1%, and 6.1%, respectively. 2-year probability of relapse was 9.1%. Disease-free survival and overall survival at 2 years were 72.7% and 75.8%, respectively.ConclusionsOur results showed that unmanipulated haploidentical transplantation with G-CSF primed PBSC alone as a graft source could be an acceptable alternative post-remission treatment for high-risk or intermediate-risk AML patients in CR1 lacking a matched donor.

PB2345 A SUBSET OF DIFFUSE LARGE B CELL LYMPHOMA PATIENTS MAY NOT BENEFIT FROM AUTOLOGOUS HEMATOPOIETIC CELL TRANSPLANTATION

Background:Diffuse Large B Cell Lymphoma (DLBCL) is the most common type of non‐Hodgkin lymphoma and, despite its aggressive course, it is potentially curable, particularly with R‐CHOP chemotherapy. However, for patients unresponsive or relapsing after such therapy the prognosis is worse, and salvage treatment with intensive chemotherapy followed by consolidation with Autologous Hematopoietic Cell Transplantation (AHCT) is the standard of care, based on the pivotal PARMA trial. However, this trial was developed in the pre‐Rituximab (R) era and the more recent CORAL trial shed new light on this issue and identified patients with early relapse following R‐based chemotherapy as having much worse outcomes, which was confirmed by subsequent trials.The Center for International Blood and Marrow Transplant Research evaluated the role of AHCT relative to the timing of treatment failure and noted that early rituximab failure had a higher risk of disease relapse in the 1st year after transplantation but beyond that timepoint no survival difference was observed.Aims:Our aim was to analyze the results of patients transplanted for relapsed or refractory DLBCL at our transplant center, when achieving first chemo‐sensitive remission (CR1p) following progressive disease after fist line chemotherapy or when achieving a second chemo‐sensitive remission because of relapse (CR2).Methods:We retrospectively collected data from patients submitted to AHCT at a single institution between 2007 and 2018, with a diagnosis of relapsed or refractory DLBCL and analyzed the outcomes in terms of time to relapse (TTR), progression‐free survival (PFS) and overall survival (OS).Results:We identified a total of 52 patients, with a median age of 43 years at diagnosis, and a median of two prior lines (1‐4) with R‐based chemotherapy. Before AHCT 32 patients were in CR1p and 20 were in CR2 and disease status was classified as complete remission (CR) in 38 patients, partial remission (PR) in 13 and 1 patient had stable.Following consolidation treatment with AHCT, 45 patients achieved CR, 5 patients were in PR and 2 presented progressive disease.With a median follow‐up time of 84 months, median OS was not reached for both patients in CR1p and CR2, however we can observe a trend towards better survival for patients in CR2. Time to relapse was significantly different between these groups, with patients transplanted in CR2 having higher median time to next relapse (91 vs 36 months, p = 0.01), however this difference was not transposed in terms of survival.Eleven patients died, seven of which because of progressive disease and the remaining four due to unrelated causes and in remission.Summary/Conclusion:Our results are in accordance with those from previous studies on this theme and, similarly, we cannot prove clear benefit of AHCT for primary refractory patients with DLBCL, despite the longer time to relapse observed in patients in CR2. It appears that lack of optimal response to first line chemotherapy has a negative impact on the duration of disease control post‐AHCT (despite the lack of influence in OS). Perhaps molecular and cytogenetic alterations may define subgroups of patients who may benefit the most from AHCT, which we did not evaluate because only the more recent diagnosis had such information available.It is evident, however, that new approaches for primary refractory patients with DLBCL are clearly needed.

PF216 ROLE OF MEASURABLE RESIDUAL DISEASE (MRD) IN REDEFINING COMPLETE RESPONSE (CR) IN ELDERLY PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML): RESULTS FROM THE PETHEMA‐FLUGAZA PHASE III CLINICAL TRIAL

Background:The general outcome of elderly patients with AML is poor, even for those achieving morphological CR. However, the role of MRD in redefining CR remains poorly investigated in elderly AML due to the reluctance of treating with intensive chemotherapy and the renewed interest in low‐intensity therapy such as hypomethylating agents (HMA).Aims:To help defining the role of MRD assessment by multidimensional flow cytometry (MFC) and therapeutic decision making in older AML patients treated with semi‐intensive chemotherapy vs HMA.Methods:285 AML patients (median age, 75) were included in the phase 3 PETHEMA‐FLUGAZA trial and were randomized to receive 3 induction cycles with fludarabine and cytarabine (FLUGA) followed by 6 consolidation cycles with reduced intensity FLUGA, vs 3 induction cycles with 5‐azacitidine (AZA) followed by 6 consolidation cycles with AZA. After consolidation, patients continued with the same treatment if MRD ≥0.01% or stopped if MRD &lt;0.01%. MRD was prospectively assessed after induction and consolidation among patients in CR with or without incomplete blood count recovery. At diagnosis, the EuroFlow AML panel was used to identify leukemia‐associated immunophenotypes (LAIP). At CR, bone marrow samples were stained with 8‐color combinations based on previously identified maturation arrest, lineage commitment and LAIPs. MRD was assessed with an estimated sensitivity of 0.01%.Results:On intention‐to‐treat, 38/141 (27%) patients achieved CR after 3 cycles of FLUGA and 31/144 (21.5%) after 3 cycles of AZA (p = .33). Among patients in CR with previously identified LAIP, 14/69 (20%) achieved a negative MRD status whereas the remaining 55 (80%) had persisting MRD: 56% with ≥0.1% MRD and 24% with &lt;0.1% MRD. Regarding the effect of semi‐intensive chemotherapy vs HMA on depth of response, we observed a non‐significant trend toward higher MRD‐negative rates among patients in CR after FLUGA vs AZA (25% vs 15%, respectively; p = .38).The 2‐year rates of cumulative incidence of relapse (CIR) for MRD‐positive ≥0.1%, &lt;0.1% and MRD‐negative patients were 95%, 74% and 45%, respectively (HR, 0.45; p &lt; .001). Of note, the CIR of patients in CR but persistent MRD were similarly poor as compared to those in partial remission (HR, 1.2; p = .54). Furthermore, MRD‐positive patients with adverse cytogenetics displayed the poorest outcome with significantly higher 2‐year CIR rates than MRD‐positive cases with intermediate/favorable cytogenetics (HR, 2.0; p = .01). Among patients in CR and persistent MRD, 2‐year CIR rates showed a non‐significant trend towards slightly more frequent relapses in those treated with FLUGA vs AZA (91% vs 77%, respectively; HR, 1.6; p = .12). On multivariable analysis for CIR including MFC‐MRD and cytogenetics, both retained significant prognostic value. The median overall survival (OS) for MRD‐positive ≥0.1%, &lt;0.1% and MRD‐negative patients was 13, 12 and 21 months, respectively. On multivariable analyses for OS including age, WBC count, cytogenetic grouping and secondary disease, persistent MRD showed a trend for independent prognostic value (HR, 2.4; p = .08).Summary/Conclusion:This study reveals that sensitive MFC‐MRD assessment supersedes CR and is an independent prognostic factor in older patients with AML, treated with semi‐intensive chemotherapy or HMA. Nevertheless, the risk of relapse among the few patients with no MRD (5%) remains high after stopping treatment, and warrants innovative approaches aimed at maintaining an MRD‐negative CR status. Updated follow‐up and molecular data will be presented at the meeting.

PS1352 DISSECTING THE BONE MARROW IMMUNE MICROENVIRONMENT IN THE COMPLETE SPECTRUM OF MONOCLONAL GAMMOPATHIES: POTENTIAL IMPLICATIONS IN DISEASE PATHOGENESIS

Background: To discriminate different outcomes among patients in CR the IMWG introduced a more stringent CR (sCR) criteria by adding to the pre-existing CR criteria the requirement of a normal free-light chain ratio (sFLCr) plus the absence of clonal plasma cells (PCs) in bone marrow (BM) by immunohistochemistry (IHC). In 2011, the low-sensitivity cytometry was included as alternative methodology to IHC to define sCR. However, the prognostic significance of the kappa/lambda ratio values is not clear. Aims: To verify the conclusion of our previous study (Blood 2015. 126:858–62) regarding the lack of influence in the prognosis of abnormal serum free light chain ratios (sFLCr) in a more extensive series of newly diagnosed multiple myeloma (NDMM) patients in CR or sCR Methods: NDMM patients aged ≤65 years enrolled in GEM2012MENOS65 (NCT01916252). Of 458 patients, 8 discontinued early and were not evaluable. The definition of CR and sCR was made according to the IMWG criteria. SFLCr (FREELITE assay) was classified as normal (0.26–1.65) or abnormal (<0.26 if the patient was λ; >1.65 if the patient was κ). MRD was assessed using next-generation flow cytometry. The median limit of detection was of 3x10–6. All the CR with normal sFLCr and absence of clonal PCs by MFC with a sensitivity of 10–2 were considered sCR. Median follow-up was 47.5 months. Results: After induction, 425 patients were evaluable for response; 201 (47%) reached ≥CR. Data from sFLCr and MRD was available in 192 and 193 patients, respectively. In the CR evaluable patients for sCR assessment (n = 184), the rate of sCR was 64% (n = 117). In a landmark from the end of induction (median follow-up 39 months), sCR didn’t show significantly differences in PFS (2 years-PFS 89% vs 87%; P = .7) (fig 1a) neither in OS (2 years-OS 94% vs 94%; P = .9). Interestingly, patients with abnormal (n = 67) vs normal (n = 125) sFLCr showed superimposable PFS (2 years-PFS 88% vs 87%; P = .9) (fig 1b) and OS (2 years-OS 96% vs 94%; P = .8).By contrast, the few patients (n = 3) in whom BM clonality was detected by the low-sensitivity IHC-adapted MFC method had significantly worse PFS (2 years-PFS 89% vs 67%; P = .03) (fig 1c) and OS (2 years-OS 95% vs 67%; P = .8) than patients in whom BM clonality was undetectable or detected at levels below the threshold proposed for IHC assessment. On using our traditional MRD method, persistent MRD (>10–4) was detectable among 39 of the 193 (20%) patients who, compared with MRD-negative cases, had significantly inferior PFS (2-years PFS 91% vs 80%; P = .01) (fig 1b) and OS (2 years-OS 96% vs 87%; P = .01).As validation, we reproduced the analysis in the ASCT end-point. Of the 395 evaluable patients; 238 (60%) reached ≥CR. Once again, in the landmark analysis, sCR didn’t show significantly differences in PFS in respect to CR (P = .3) neither in OS (P = .6). Patients with abnormal (n = 51) vs normal (n = 173) sFLCr showed superimposable PFS (P = .9) and OS (P = .6). Patients with persistent MRD (>10–4), had significantly inferior PFS (P = .003) but similar OS (P = .2).Summary/Conclusion: These results confirm our previous analysis based on GEM05menos65/ GEM10mas65 clinical trials. For MM patients in CR, the stringent CR criteria does not predict a different outcome. If this essential criterion in the definition of sCR lacks for the prognosis connotations, it is not justified to maintain a response category whose real significance depends on the combination of the traditional CR criteria with a negative MRD status based on very low (IHC) or low resolution (<104) levels, today outdated.

PS945 KTE-X19, AN ANTI-CD19 CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY, IN ADULT PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA: END OF PHASE 1 RESULTS OF ZUMA-3

Background: Standard therapy for adult patients with high-risk acute lymphoblastic leukemia (ALL) is allogeneic-hematopoietic cell transplantation (HCT) from a matched-sibling (MSD) or matched unrelated donor (MUD). When the conventional donor is not available, HCT from a partially-mismatched unrelated donor (MMUD), cord blood transplantation (CBT), or familial haploidentical mismatched transplantation (FMMT) are considered Aims: We analyzed long-term HCT outcomes according to the donor types including MMUD-HCT and double-CBT (DCBT) as an alternative choice compared to the conventional donor transplantation. Methods: We initially enrolled 440 adult ALL patients who underwent transplantation from 2005 to 2015 in their first remission (CR1). Before 2010, our post-remission strategy for high-risk ALL was to offer allogeneic-HCT according to the donor availability (MSD or MUD) and sometimes used MMUD for next step. After 2010, DCBT was mainly used as an alternative choice. Conditioning regimen for DCBT was TBI, ARA-C and fludarabine. Graft-versus-host disease (GVHD) prophylaxis was attempted by administering calcineurin inhibitors (cyclosporine for MSD, tacrolimus for others) plus methotrexate. Antithymocyte globulin (ATG) was administered to the patients who received grafts from MMUD. Results: Engraftment was successful in all donor types, but neutrophil and platelet recovery was significantly delayed only after DCBT (median recovery for neutrophil and platelet was 25 and 33.5 days respectively). After median follow-up of 58.1 months (range, 6.5–145.7), 5-year OS for the entire 440 patients was 58.3%. In detail, 5-year OS for MSD, MUD, MMUD, and DCBT was 60.1%, 57.2%, 62.9%, and 65.1% (p = 0.918). DCBT showed significantly higher NRM rate (29.6%) and lower relapse rate (7.2%). Interestingly, calculated GVHD and relapse-free survival (GRFS) for MSD, MUD, MMUD, and DCBT was 33.1%, 14.5%, 42.1%, and 50.3% (p = 0.001), respectively, which was related with higher incidence of severe chronic GVHD in MUD (30.1%) and MSD (14.8%) compared to DCBT (4.2%, p < 0.001). In high-risk subgroup (n = 379) including 200 Philadelphia chromosome (Ph)-positive ALL, 5-year OS for MSD, MUD, MMUD, and DCBT was 57.9%, 58.5%, 59.2%, and 60.7%, but the 5-year GRFS was 29.7%, 14.0%, 36.5%, and 47.7%, respectively, which was related with lower relapse rate (8.7%) and low severe chronic GVHD (2.6%) of DCBT subgroup. Multivariate analysis showed that younger age <40 yrs and mild to moderate chronic GVHD was related with favorable OS and GRFS, while MUD-HCT and severe chronic GVHD were related with poor GRFS. Summary/Conclusion: Our data showed similar transplant outcomes of alternative donors such as DCBT and ATG-applied MMUD compared to conventional donor transplants in ALL patients in CR1. In addition, GRFS was rather superior in patients treated with DCBT. Our long-term outcome results revealed that DCBT might be a good alternative choice for patients who are not available with conventional allogeneic donors.

FRONTLINE THERAPY RESULTS IN UNSELECTED PRIMARY CNS LYMPHOMA PATIENTS WITHOUT CONSOLIDATION HD CHEMOTHERAPY FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION

Introduction: Therapy results from large prospective clinical trials in primary CNS lymphoma (PCNSL) are influenced by restrictive inclusion and exclusion criteria. Herein we present frontline therapy results in unselected patients with PCNSL based on retrospective analysis from single center database over the past 17 years, when consolidation high-dose chemotherapy with autologous stem cell transplantation (ASCT) was not a standard therapeutic approach. Methods: Between 2000 and 2017 we register 79 patients with newly diagnosed PCNSL, median age 64 years (31 – 84). Frontline regimen for patients ≤ 70 years was 5-7x MPV +/- rituximab. Consolidation therapy conceded 2 cycles of cytarabine for selected patients in complete remission instead whole brain radiation therapy (WB RT) up to 45 Gy. None of the patients had consolidation HD chemotherapy with ASCT. Results: Chemotherapy was administered to 72 patients (91 %), in 71 % (51 pts.) MPV regimen +/- rituximab. The rest of the patients had single agent methotrexate or cytarabine or WB RT. Only 35 patients completed at least 5 cycles of MPV-based chemotherapy, the others failed to complete because of unacceptable toxicity or progressive disease. Median OS in the whole unselected cohort was 38 months, 2-year PFS was 40 % and median PFS 14 months. Response rates were evaluated only in the subgroup of 35 patients who completed at least 5 MPV-based chemotherapy. Median age was 57 years (31 - 70), ORR was 80 %, progression was seen in 5 patients (14%), 2 were unable to assess. In this subgroup of relatively fit patients 2-year PFS was 45 % and 2-year OS was 55 %. 10 patients in CR after frontline therapy did not undergo WB RT consolidation, but received 2 courses of single agent cytarabine instead. 5 of them reached durable remission and in the other 5 late relapses occured with median PFS 31 months (12-72). Keywords: autologous stem cell transplantation (ASCT); primary CNS lymphoma (PCNSL).

PF470 FIVE‐YEAR SURVIVAL AND DURABILITY RESULTS OF THE BEGEV REGIMEN FOLLOWED BY AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) FOR RELAPSED/REFRACTORY CLASSICAL HODGKIN LYMPHOMA

Background:There is a consensus that classical Hodgkin lymphoma (cHL) patients who are refractory to or relapse (R/R) after first‐line therapy may benefit of second‐line salvage treatment followed by autologous stem cell transplantation (ASCT) provided they are chemosensitive. As previously reported, the BEGEV (BEndamustine, GEmcitabine, Vinorelbine) regimen used as second‐line salvage therapy induces an objective response rate (ORR) &gt;80% in R/R cHL, thereby resulting in a highly effective induction treatment before ASCT (Santoro et al., J Clin Oncol, 2016).Aims:Here, we assess safety, efficacy and durability results of the BEGEV regimen followed by ASCT after extended follow‐up (registered at www.clinicaltrials.gov as #NCT01884441).Methods:R/R cHL patients after first‐line chemotherapy were eligible. The primary endpoint was CR after four cycles of BEGEV. Secondary endpoints were: ORR, stem cell mobilization, toxicity, progression‐free survival (PFS) and overall survival (OS). The BEGEV regimen consisted of Bendamustine (90 mg/sqm, days 2–3), Gemcitabine (800 mg/sqm, day 1 and 4) and Vinorelbine (25 mg/sqm, day 1) every three weeks for a total of 4 courses. Patients achieving CR or partial remission (PR) after completion of BEGEV were autografted.Results:Fifty‐nine consecutive patients with relapsed (46%) or primary refractory (54%) cHL were enrolled. After BEGEV completion, 44 (75%) patients achieved CR and 5 (8%) PR for an ORR of 83%. In univariate analysis, the only factor which resulted associated with a different probability to reach CR before ASCT was disease status at study entry, with CR being achieved by 84% of relapsed patients and 59% of refractory patients (P = 0.031). With a median follow‐up of 5 years (range, 3.4–79), the overall patient population (n = 59) has an OS of 78% and a PFS of 61%, respectively, without significant difference between relapsed and refractory patients. Of the 49 BEGEV responders, 43 (73% by intention‐to‐treat) proceeded to ASCT and among them, 33 are in continuous CR, 7 relapsed and 3 died [pneumonia (n = 1), infection (n = 1) and multi‐organ failure (n = 1)]. The remaining six patients did not proceed to ASCT due to mobilization failure (n = 2), physician decision (n = 2), early relapse (n = 1), patient refusal (n = 1). Of the 33 patients in CR after ASCT, 15 had primary chemorefractory disease and received ASCT while in PR (n = 3) or CR (n = 12). Relapse occurred after a median of 6.2 months (range 4.8–28) from ASCT with only two patients relapsing beyond 12 months. Patients who relapsed after transplant could be rescued by Brentuximab Vedotin and subsequent allogeneic SCT. For autografted patients, the 5‐yr OS and PFS are 91% and 77%, respectively, without significant difference between patients with relapsed or primary refractory disease (Figure 1). With extended follow‐up, no patient experienced secondary leukemia or myelodysplasia.Summary/Conclusion:With extended follow‐up, the BEGEV regimen is a highly effective and safe salvage regimen allowing a high percentage of patients (73% by ITT) to proceed to ASCT. The salvage program, i.e., BEGEV followed by ASCT, represents a chemotherapy‐based curative strategy for nearly 60% of R/R cHL. However, about 30% of R/R cHL patients progress before BEGEV completion or after ASCT and represent an unmet medical need requiring further development of the BEGEV/ASCT program in combination with anti‐PD‐1 inhibitors used either during the induction phase with BEGEV or as consolidation in the post‐ASCT setting.image

PB2322 SPLEEN SIZE AS CLINICAL RISK FACTOR FOR GRAFT FAILURE FOLLOWING ALLOGENEIC STEM CELL TRANSPLANTATION IN ACUTE LEUKEMIA PATIENTS

Background:Primary and secondary graft failure (GF) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) leads to prolonged neutropenia, infection complications and as a consequence lowered overall survival. Bone marrow as a graft source, HLA‐mismatched donor is a main factors which can influence GF in acute leukemia patients (pts) during first six months after allo‐HSCT. Nevertheless not all GF episodes can be explained by this factors. Here we report data about influence of spleen size (length width) assessed by transabdominal ultrasound on graft failure in first 6 months in acute leukemia patients in CR who underwent allo‐HSCT.Aims:Identify risk factors for GF in patients with acute leukemia remission.Methods:We analyzed medical records of 143 pts with acute leukemia (AML n = 100 (69.9%), ALL n = 43 (30.1%)) who underwent allo‐HSCT between 2013 and 2018 at National Research Center for Hematology and was alive for more than 28 days after allo‐HSCT. A median age of patients was 34 (19‐66) years, 66 (46.2%) males and 77 (53.8%) females. At the time of transplantation 124 (86.7%) pts were in complete remission and 19 (13.3%) pts had advanced disease. Most pts (n = 112; 78.3%) received reduced intensity conditioning regimen (RIC) and 31pts (21.7%) underwent myeloablative conditioning (MAC). Donors were: HLA‐matched unrelated (MRD) – 43.4% (n = 62); mismatched unrelated donor (MMUD) 27.3% (n = 39); matched related donor (MRD) ‐25.9% (n = 37); haploidentical (excluding TCR ab‐depletion) – 3.4% (n = 5), Bone marrow (BM) was used as a graft source in 60.1% (86 pts) and peripheral blood stem cell (PBSC) ‐ in 39.9% (57 pts). Spleen size was routinely evaluated before allo‐HSCT using transabdominal sonography. Cox Proportional‐Hazards model was used to identify influence of spleen size (≥3600 mm2 vs &lt;3600 mm2) as independent prognostic factor (conditioning regimen, donor type, graft source, HLA‐disparity were also entered as covariates as well known risk factors for GF).Results:Results of Cox Proportional‐Hazards model are shown on Figure 1. According to our data spleen size (length width) ≥3600 mm2 assessed by transabdominal sonography before allo‐HSCT was associated with high risk of GF within six months of follow up period after allo‐HSCT.HR‐3.67 (95% Cl, 1.05‐12.74, p = 0.04).Figure 1. Results of Cox Proportional‐Hazards modelSummary/Conclusion:HLA‐disparity, BM as a graft source is characterized by increased probability of GF. In addition we identify that spleen size ≥3600 mm2 assessed by transabdominal sonography before allo‐HSCT also increased GF (up to 3.67 times). Due to that fact it's not recommended to use BM as a graft source for acute leukemia patients who underwent allo‐HSCT especially from MMUD.image

PS1392 CONSOLIDATION WITH A SHORT COURSE OF DARATUMUMAB CAN SIGNIFICANTLY IMPROVE COMPLETE RESPONSE RATES IN PATIENTS WITH AL AMYLOIDOSIS OR LCDD

Background:A deep hematologic response is associated with the highest probability of organ function and survival improvement in patients with AL amyloidosis. Bortezomib‐based therapy is the primary therapy for patients with AL amyloidosis but less than 40% achieves a CR. Further improvement of hematologic response may be achieved by consolidation strategies but HDM‐ASCT is associated with significant toxicity, and only a minority of AL patients is eligible for this treatment. Recent data indicate that even a short course of daratumumab (DARA) was able to induce hematologic responses in patients with relapsed or refractory AL. Thus, DARA may be a unique treatment to improve the outcomes of patients with AL amyloidosis.Aims:To evaluate the feasibility and activity of a short course of daratumumab as a consolidation strategy, in patients with AL or LCDD which had achieved either PR or VGPR after completing their primary therapy, with bortezomib‐based therapy.Methods:The endpoint of this exploratory approach was improvement of response post completion of DARA consolidation. All patients received 4 weekly infusions of daratumumab 16 mg/kg with dexamethasone 20 mg. Pre‐emptive therapy for IRR was given starting two days before the first infusion of DARA. In all patients next generation flow (NGF) according to Euroflow protocol was performed before and after consolidationResults:26 patients (23 AL and 3 with LCDD) received DARA consolidation. Median age is 67 and 73% were males. Kidneys and heart were involved in 80% and 73% respectively, baseline Mayo stage was 20%, 67% and 13% for stage 1,2 &amp; 3 respectively. Baseline immunofixation in serum or urine was positive in all patients (19/23 of AL patients were lambda). Median time from start of first line therapy to DARA consolidation was 8 months and all patients had completed the planned bortezomib‐based treatment. Before consolidation all patients were in either VGPR (23/23 AL patients and 2/3 LCDD patients) or in PR (1/3 LCDD patients); all patients had positive serum and/or urine immunofixation with or without abnormal FLC ratio. All but one patient received the planned 4 infusion of DARA. Mild IRR (Gr1) were observed in 3 patients. After consolidation with DARA, 42% of the patients (10/23 with AL and 1/3 with LCDD) achieved a CR. In 9/26 patients small monoclonal IgGk was observed 1 month post DARA and in all but one patient IgGk resolved at 2–3 months post DARA. The patient that received only one dose of daratumumab also achieved a CR. In all patients MRD by NGF was positive before DARA consolidation while DARA 6/11 patients in CR became MRDnegative. All patients that did not achieve a VGPR remained MRD positive. One patient with IgGk AL that remained with positive immunofixation after DARA was MRD(neg). Because of interference with daratumumab we repeated immunofixation, which 2 months after daratumumab became negative.Summary/Conclusion:Consolidation with a short course of DARA can improve the depth of response in patients with AL or LCDD that have not achieved a CR after primary therapy, including MRD negative disease in some.We will further explore this strategy in a formal clinical trial with a longer duration of daratumumab therapy so that CR and MRD negative rates may improve further.

PS1241 CHECKPOINT INHIBITOR TREATMENT BEFORE HAPLOIDENTICAL TRANSPLATATION IN RELAPSED OR REFRACTORY HODGKIN LYMPHOMA (HL) PATIENTS IS ASSOCIATED WITH HIGHER PFS WITHOUT INCREASED TOXICITIES

Background:Immune checkpoint inhibitors (CPI) before allogeneic stem cell transplantation (SCT) could enhance allogeneic T‐cell responses, increasing both the graft‐versus‐tumor effect and the incidence of immune complications.Aims:The aim of this study was to compare the outcomes of patients who received CPI before haploidentical (haplo)‐SCT to patients who underwent haplo‐SCT without prior CPI.Methods:We retrospectively analyzed the outcome of 52 consecutive HL patients undergoing haplo‐SCT with post‐transplant cyclophosphamide as Graft Versus Host Disease (GVHD) prophylaxis at 3 centers between 2014 and 2018. Patients’ characteristics are listed in Table 1. The two cohorts (CPI treatment before SCT = 28 patients and no CPI treatment before SCT = 24 patients) were similar in their main pre‐transplant characteristics, except for the CPI group who received more lines of therapy before SCT (4 vs 6, p = 0.0006).Results:After a median follow‐up of 26 months (range 7.5–55), taking into account all the patients, the 6‐months cumulative incidence (CI) of acute GVHD grade 2–4 was 33% (95% CI, 20–45), whereas the 2‐year CI of moderate to severe chronic GVHD was 11.5% (95% CI, 4–24). The 1‐year CI of NRM was 15% (95% CI, 8–31) and the 2‐year CI of relapse was 13% (95% CI, 5–25). The 2‐year OS and PFS were 78% (95% CI, 62–88) and 69.5% (95% CI, 52–82), respectively. In univariate analysis, prior use of CPI had no effect on either acute or chronic GVHD. The 6‐ months CI of grade 2–4 aGVHD was 39% (95% CI, 21–57) in the CPI group and 25% (95% CI, 10–44) in the non‐CPI group (p = 0.23), while the 2‐year CI of moderate to severe cGVHD was 16% (95% CI, 3–39) and 9% (95% CI, 1–26), respectively (p = 0.67). The 2‐year CI of relapse in the CPI group was only 4% (95% CI, 0–16) versus 22% (95% CI, 8–41) (p = 0.08) in the non‐CPI group. A significantly higher 2‐year PFS was observed in the CPI group (89% (95% CI, 70–96) vs 54% (95% CI, 31–72), p = 0.029)). No differences were observed in OS and NRM between the two cohorts: the 2‐year OS was 88% (95% CI, 66–96) in the CPI group vs 71% in the non‐CPI group (95% CI, 47–86) (p = 0.30) and the 2‐year CI of NRM was 11% (95% CI, 4–27) vs 24% (95% CI, 8–44) (p = 0.26), respectively. Based on the other pre‐transplant characteristics, only a correlation between disease status at SCT and OS was found: the 2‐year OS was 84% (95% CI, 61–94) in CR patients, 73% (95% CI, 35–91) in PR patients and 50% (95% CI, 6–85) in PD/SD patients (p = 0.04). In multivariate analysis, disease status other than CR had a negative impact on OS (hazard ratio (HR) 6.18 (95% Cl, 1.13–33, 72) for PR and HR 14 (95% CI, 199–98.29) for PD/SD). Treatment with checkpoint inhibitors before SCT was an independent protective factor for PFS (HR 0. 23 (95% CI, 0.05–0.92)).Summary/Conclusion:Treatment with CPI as a bridge to haplo‐SCT significantly improves the PFS in relapse/refractory HL, lowering the relapse rate, and does not enhance the toxicity. However, the main limitation of our study lies in the small number of patients; further studies are warranted to extend our findings.image

PS1394 FLOW-MEDIATED DILATATION AND AORTIC BLOOD PRESSURE PREDICT CARDIOVASCULAR ADVERSE EVENTS DURING CARFILZOMIB TREATMENT: A PROSPECTIVE STUDY IN PATIENTS WITH RELAPSED/ REFRACTORY MULTIPLE MYELOMA

Background: Bortezomib/dexamethasone with cyclophosphamide or melphalan are commonly used as primary treatment for AL amyloidosis, but limited data exist on the safety and activity of bortezomib with IMiDs combinations. Aims: To evaluate the safety and activity of VRD combination in newly diagnosed, previously untreated patients with AL amyloidosis. Methods: Between March 2017 and March 2018, 34 consecutive newly diagnosed patients with AL amyloidosis were treated with VRD; standard organ involvement and updated organ and hematologic response criteria were used. Results: The median age of all patients was 66.5 years (range 46–84); 71% were males, 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81- >30000), per Mayo stage 14%, 54%, 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement, median eGFR was 59 ml/min/1.73 m2 (range 10–133) and renal stage distribution was 13%, 53% and 33% for stages 1, 2 & 3. Measurable FLCs (i.e. a dFLC≥40 mg/L) were present in 29 (85%) patients; in 4 patients baseline dFLC was >20 mg/dl and were also evaluable for response. Twenty-two patients completed the planned 8 cycles, 9 died prior to completion of planned therapy, 1 patient discontinued therapy for personal reasons (while in VGPR), 1 discontinued therapy after physician's decision (while in VGPR) and one discontinued due to bortezomib-related toxicity (while in CR). After the first cycle of VRD, 24/34 (70.5%) patients had achieved a hematologic response (42% a VGPR or CR and 27% a PR). After 3 months of VRD, 82% of the evaluable patients (N = 27) had achieved at least VGPR, including CR in 6 (22%), and PR in 5 (18%). After 6 VRD cycles, CR, VGPR and PR rates among evaluable (N = 24) patients were 9 (37.5%), 13 (54%), and 2 (8%) respectively. On intent to treat, best hematologic response was CR in 11/34 (32%) and among CR patients 5/11 were MRD negative by NGF; 17/34 (50%) achieved VGPR and in 9 of them dFLC was <10 mg/dl; 2/34 (7%) achieved a PR. Median time to first response (at least a PR) was 28 days (1 treatment cycle), median time to at least VGPR was 84 days (3 cycles of therapy). Cytogenetics were available in 28 patients; among patients with t(11;14) (N = 7), all achieved at least a VGPR (3 a CR and 4 a VGPR). Organ responses were documented in 12 (35%) patients. Median follow up for all patients is 12.5 months and 6 and 12 month survival is 73.5% (100%, 85% and 71% for stage 1, 2 & 3A patients respectively, but only 20% for stage 3B). Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; common non-hematologic toxicities included rash (Gr3/4:16%), infections (≥Gr3:12%), constipation (≥Gr3:9%), peripheral neuropathy (Gr2:20%), while, 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide before planned therapy completion, 38% required bortezomib dose reduction and 12% discontinued bortezomib. We then compared the efficacy of VRD to that of CyBorD given in 68 patients matched for Mayo stage and baseline dFLC and found a trend for deeper responses at 3 months in patients treated with VRD (≥VGPR in 82% vs 45%) and at 6 months (≥VGPR in 92% vs 61%, p = 0.049). Summary/Conclusion: VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy. However, toxicity of VRD in patients with AL amyloidosis is significant, despite the use of low doses of lenalidomide.

PS1393 PRIMARY TREATMENT OF LIGHT CHAIN (AL) AMYLOIDOSIS WITH BORTEZOMIB, LENALIDOMIDE AND DEXAMETHASONE (VRD)

Background:Bortezomib/dexamethasone with cyclophosphamide or melphalan are commonly used as primary treatment for AL amyloidosis, but limited data exist on the safety and activity of bortezomib with IMiDs combinations.Aims:To evaluate the safety and activity of VRD combination in newly diagnosed, previously untreated patients with AL amyloidosis.Methods:Between March 2017 and March 2018, 34 consecutive newly diagnosed patients with AL amyloidosis were treated with VRD; standard organ involvement and updated organ and hematologic response criteria were used.Results:The median age of all patients was 66.5 years (range 46–84); 71% were males, 75% had cardiac involvement, median NTproBNP was 3649 pg/ml (81‐ &gt;30000), per Mayo stage 14%, 54%, 14% and 18% were stage 1, 2, 3A and 3B respectively; 54% had renal involvement, median eGFR was 59 ml/min/1.73 m2 (range 10–133) and renal stage distribution was 13%, 53% and 33% for stages 1, 2 &amp; 3. Measurable FLCs (i.e. a dFLC≥40 mg/L) were present in 29 (85%) patients; in 4 patients baseline dFLC was &gt;20 mg/dl and were also evaluable for response. Twenty‐two patients completed the planned 8 cycles, 9 died prior to completion of planned therapy, 1 patient discontinued therapy for personal reasons (while in VGPR), 1 discontinued therapy after physician's decision (while in VGPR) and one discontinued due to bortezomib‐related toxicity (while in CR). After the first cycle of VRD, 24/34 (70.5%) patients had achieved a hematologic response (42% a VGPR or CR and 27% a PR). After 3 months of VRD, 82% of the evaluable patients (N = 27) had achieved at least VGPR, including CR in 6 (22%), and PR in 5 (18%). After 6 VRD cycles, CR, VGPR and PR rates among evaluable (N = 24) patients were 9 (37.5%), 13 (54%), and 2 (8%) respectively. On intent to treat, best hematologic response was CR in 11/34 (32%) and among CR patients 5/11 were MRD negative by NGF; 17/34 (50%) achieved VGPR and in 9 of them dFLC was &lt;10 mg/dl; 2/34 (7%) achieved a PR. Median time to first response (at least a PR) was 28 days (1 treatment cycle), median time to at least VGPR was 84 days (3 cycles of therapy). Cytogenetics were available in 28 patients; among patients with t(11;14) (N = 7), all achieved at least a VGPR (3 a CR and 4 a VGPR). Organ responses were documented in 12 (35%) patients. Median follow up for all patients is 12.5 months and 6 and 12 month survival is 73.5% (100%, 85% and 71% for stage 1, 2 &amp; 3A patients respectively, but only 20% for stage 3B). Starting lenalidomide dose was 5 mg in 86% of patients. Hematologic toxicity was mild; common non‐hematologic toxicities included rash (Gr3/4:16%), infections (≥Gr3:12%), constipation (≥Gr3:9%), peripheral neuropathy (Gr2:20%), while, 37.5% of patients required lenalidomide dose reduction, 27% discontinued lenalidomide before planned therapy completion, 38% required bortezomib dose reduction and 12% discontinued bortezomib. We then compared the efficacy of VRD to that of CyBorD given in 68 patients matched for Mayo stage and baseline dFLC and found a trend for deeper responses at 3 months in patients treated with VRD (≥VGPR in 82% vs 45%) and at 6 months (≥VGPR in 92% vs 61%, p = 0.049).Summary/Conclusion:VRD with weekly bortezomib and low dose lenalidomide is a very effective and rapidly acting regimen that can induce deep hematologic responses within 3 months of therapy. However, toxicity of VRD in patients with AL amyloidosis is significant, despite the use of low doses of lenalidomide.

PS1168 CHROMATIN TOPOLOGY AND THREE‐DIMENSIONAL ORGANIZATION OF CHROMOSOME TERRITORIES 9 AND 22 IN CD34+ BONE MARROW CELLS FROM CHRONIC MYELOID LEUKEMIA PATIENTS

Background:During interphase, chromosomes occupy a limited space within the nucleus, referred to as chromosome territory (CT). The non‐random CT's spatial organization in the nucleus contributes to determining the outcome of chromosomal translocations (t). Comparative analysis of the spatial arrangement of t‐partners and their frequency suggest that this chromosome aberration occurs preferentially among proximally positioned genome regions. The consistence appearance of t(9;22) in hematopoietic stem cells, apart from being etiological factor for chronic myeloid leukemia (CML), is a clear example of what is considered a non‐random chromosome aberration. Besides, the CT's spatial distribution is regulated by epigenetic factors such as post‐translational histone modifications. These modifications are also directly related to the chromatin topology in these CTs, which is relevant since a chromatin misconfiguration has been related to the susceptibility to generate mutations and translocations.Aims:‐ Determine the 3D arrangement of interphase CTs 9 and 22 and BCR‐ABL genes in CD34+ bone marrow (BM) cells from CML patients at the time of diagnosis (CML RxDx) and patients with complete response (CML CR) compared to healthy donors’ CD34+ mobilized bone marrow cells (MBM) and peripheral blood mononuclear cells (PBMC).‐ Map and quantify the distribution of the histone modifications H3K27me3 and H3K9ac across CTs 9 and 22 in our study population.Methods:The study population consisted of 5 BM from CML RxDx and CML CR patients, 5 MBM and PBMC from healthy donors. CD34+ hematopoietic cells were isolated and subsequently processed for 3D‐FISH and 3D immuno‐FISH. Super‐resolution imaging was performed by 3D structured illumination microscopy (SIM) and images reconstructed and analysed using Imaris program (Bitplane).Results:We found that nuclear volumes were significantly larger in CD34 + cells from MBM and CML patients compared to PBMC controls. The absolute CTs volume analysis shows a major volume of CT9 compared to CT22. To determine the distance between BA genes and their CTs we calculated the nearest distance between the mass center of CT9 and CT22. The shorter distance was between de CML RxDx cells since the translocation presence. When we compare the samples without t(9;22), the shorter distances were observed between BA from MBM and CML CR cells compared to PBMC samples. After normalizing the distance between the CTs and BA genes against the radius of the nucleus. We observed that the location of CT22 tended towards the center, whereas that of CT9 towards the nuclear periphery. Meanwhile BA genes were located closer to the nuclear center than the respective CTs’ geometrical center. We have mapped relevant histone modifications like H3K9ac and H3K27me3 across CT9 and 22 using 3D immuno‐FISH. The enrichment of H3K27me3 seems to be significantly decreased in CT22 from samples of CML CR cells.Summary/Conclusion:The consistent appearance of specific chromosomal translocation in leukemias particularly t(9;22) in CML patients has suggested that the positioning and chromatin topology of CTs might play a role in the occurrence of particular chromosomal rearrangements associated with malignant transformation. Using 3D‐FISH and 3D‐SIM we have determined the positions, distances and volumes of CT9 and CT22 and in BCR‐ABL1 genes, in interphase nuclei of CD34+ bone marrow (BM) cells from CML RxDx and in CR patients compared to healthy donors’ CD34+ MBM and PBMC. Likewise, we mapped relevant histone modifications finding a particular difference in TC22 and H3K27me3 histone mark from CML CR CD34+ cells.image

S104 THE BRAF INHIBITOR VEMURAFENIB COMBINED WITH RITUXIMAB PRODUCES A HIGH RATE OF DEEP AND DURABLE REMISSIONS IN RELAPSED OR REFRACTORY HAIRY CELL LEUKEMIA: UPDATED RESULTS OF A PHASE‐2 TRIAL

Background:Up to 50% of hairy cell leukemia (HCL) patients relapse after purine analogs. We identified the BRAF‐V600E kinase mutation as the genetic cause of HCL (Tiacci et al., NEJM 2011). We then documented, in 26 relapsed/refractory patients treated with the oral BRAF inhibitor vemurafenib for a median of 16 weeks, 96% of overall responses (including 35% complete remissions ‐ CR), obtained after a median of 8 weeks (Tiacci et al., NEJM 2015). However, residual bone marrow (BM) HCL cells persisted even in CR patients (5–10% cells) and the median relapse‐free survival among all responding patients was 9 months.Aims:Since HCL strongly expresses CD20, rituximab could improve the efficacy of BRAF inhibition by targeting leukemic cells resistant to vemurafenib.Methods:In this academic, phase‐2, single‐arm, single‐center trial (EudraCT 2014‐003046‐27), relapsed/refractory HCL patients received vemurafenib (960 mg b.i.d.) for 8 weeks and concomitant rituximab (375 mg/m2 i.v.) every 2 weeks. Rituximab was then given as consolidation 4 times every 2 weeks after the end of vemurafenib. CR required normal blood counts, no palpable splenomegaly, and no leukemic cells at morphologic analysis of BM biopsies and blood smears.Results:We enrolled 31 patients (median age: 59 years) with a median of 3 previous therapies, including 8 primary refractory cases (26%). Toxicity was mostly of grade 1‐2, without myelosuppression, and overlapped that of either drug when used alone.Strikingly, a CR was achieved by 26/27 (96%) patients evaluable for efficacy, including 2 patients with incomplete platelet recovery at the end of treatment who however normalized the platelet count soon after; and 2 patients with incomplete resolution of splenomegaly who nonetheless remain in otherwise continuous CR at 22.5 and 25 months from the end of treatment. Among the 26 CR cases, all previously treated with purine analogs, there were also some patients previously refractory to rituximab (n = 5) and/or who had relapsed after a prior BRAF inhibitor (n = 7; 5 obtained a short‐lived PR and 2 a CR after treatment with the BRAF inhibitor). Notably, a CR was obtained after just 4 weeks of vemurafenib and two concomitant doses of rituximab in 15/24 evaluable patients (63%). Minimal residual disease (MRD) by allele‐specific PCR (sensitivity: 0.05% BRAF‐V600E alleles) was absent in the BM of 17/26 (65%) patients; in 8/17 patients (47%), MRD clearing was obtained before rituximab consolidation.Progression‐free survival (PFS) in the 29 evaluable patients was 83% at a median follow‐up of 29.5 months (range: 2–45) (Fig. 1A). Progressions (n = 5) always occurred in cases who were MRD‐positive, including 3/5 patients whose immediate prior treatment was a BRAF inhibitor (leading to PR in all 3 cases). Indeed, PFS was significantly longer in MRD‐negative CR cases (100% in 17 patients at 30.5 months of median follow‐up) than in MRD‐positive CR cases (44% in 9 patients at a median follow‐up of 24.5 months) (p = 0.001; Fig. 1B). In subsequent BM evaluations, 16/17 (94%) CR patients maintained a MRD‐negative status after a median of 22.5 months (range 12.5–36.5); in the remaining patient, MRD reappeared 12.5 months later but he remains in continuous CR at 38 months after the end of treatment.Summary/Conclusion:Vemurafenib plus rituximab is a brief, safe and non‐myelotoxic regimen that induces MRD‐negative durable responses in the majority of relapsed/refractory HCL patients. Randomized testing of this regimen against the chemotherapy‐based standard of care in the frontline setting is warranted.image

PF182 CLINICOBIOLOGIC CHARACTERISTICS AND OUTCOME OF ELDERLY FRAIL PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA INCLUDED IN A SPECIFIC PROTOCOL (ALL‐07FRAIL)

Background:Elderly patients with ALL are frequently excluded from clinical studies, especially if they have criteria of frailty. Treatment of these patients is considered palliative, but here are scarce studies analysing the tolerability and outcome of elderly frail patients included in specific trials.Aims:Here we present the clinicobiologic characteristics and outcome of elderly frail patients with Philadelphia chromosome‐negative (Ph‐neg) ALL included in the ALL‐07FRAIL (NCT01358201) study from the Spanish PETHEMA Group.Methods:Older (55–65 yrs.) and elderly (&gt;65 yrs.) patients with Ph‐neg ALL with Charlson comorbidity index &gt;3 were included in this study. Treatment schedule: pre‐phase (dexamethasone [DXM] for 1 week + triple intrathecal therapy [TIT]). Induction: vincristine (VCR) 1 mg/week x 4 wks and DXM (10 mg/m2/d x 28d) and TIT (d1 and d35). No consolidation. Maintenance: mercaptopurine (MP) (50 mg/m2/d) and methotrexate (MTX) (20 mg/m2/wk) for 2 years from CR, with monthly reinductions with VCR (1 mg), DXM (40 mg/m2, d1,2) and TIT during the 1st year.Results:From 2008 to 2018, 58 patients (pts) were included in the ALL FRAIL07 study. Mean (SD) age 73 (7) yrs., 42 pts (72%) over 70 yrs., 38 males (66%), median WBC count 8.2 x109/L (0.3–475), CNS involvement 5 pts (9%), B‐cell precursor ALL 48/56 (86%)(pro‐B [n = 12], common [n = 23], pre‐B [n = 12], non‐specified [n = 1]), T‐ALL 8/56 (14%)(pro‐T [n = 1], pre‐T [n = 4], mature T [n = 1], non‐specified [n = 2]). Results of induction treatment (n = 57, 1 on treatment): early death 9 (16%), failure 17 (30%), complete remission 31 (54%). The most frequent Grade 3–4 toxicities in induction were: neutropenia 39/51 pts (77%), thrombocytopenia 30/51 (59%), infection 11/51 (22%), neurologic 4/49 (8%) and gastrointestinal 2/49 (4%). Outcome of CR patients: treatment‐related mortality 6 (19%), withdrawn from study 2 (6%), relapse 20 (65%), persistent CR1 3 (10%). The cumulative incidence of relapse at 3‐yrs was 80% (median: 11.1 months [95%CI: 5.2–25.9]). With a median follow‐up of 23.7 months (0.1–53.7), 4 patients are alive, with a median OS of 7.7 months (95% CI, 5.6–9.9)(Figure 1).Summary/Conclusion:Older and elderly frail patients with Ph‐neg ALL can benefit from a structured study using non‐genotoxic drugs, with good tolerability and acceptable CR rate and survival. These results could serve as control for strategies including new drugs in this difficult‐to‐treat population.image

PF180 THE SIGNIFICANCE OF MONOSOMAL KARYOTYPE IN PHILADELPHIA CHROMOSOME NEGATIVE ACUTE LYMPHOBLASTIC LEUKEMIA

Background:Monosomal karyotype (MK) is a prognostic factor significantly associated with poor survival in acute myeloid leukemia and myelodysplastic syndrome. However, its significance in acute lymphoblastic leukemia (ALL) remains controversial.Aims:To explore the characteristics and outcomes of Philadelphia chromosome (Ph)‐negative ALL patients with MK.Methods:Data of consecutive patients with newly diagnosed Ph‐negative ALL were retrospectively analyzed. CODPL regimen and revised Hyper‐CVAD regimen were used as the induction and consolidation chemotherapy, respectively. Maintenance therapy consisted of monthly vindesine, prednisone, mercaptopurine and methotrexate for 2 years. Allogeneic hematopoietic stem‐cell transplantation (allo‐HSCT) was performed after at least 2 cycles of consolidation based on patients’ intention. Patients’ characteristics, treatment response and outcomes were compared between those with MK or not. COX regression model was used to identify factors associated with disease‐free survival (DFS) and overall survival (OS).Results:From January 1st 2008 to June 30th 2018, 313 patients with Ph‐negative ALL were included in this study. 184 (56%) were male. Median age was 30 years (range, 15–65 years). Compared with those without MK, patients with MK had lower platelet count (p = 0.021), higher blast percentage in peripheral blood (p = 0.010), and more complex karyotype (p &lt; 0.001) at diagnosis. There was no difference on the probabilities of complete remission (CR, 82% vs 87%, p = 0.356) and minimal residual disease (MRD) negativity after induction chemotherapy (51% vs 52%, p = 0.911) and the first cycle of consolidation (60% vs 70%, p = 0.253) between those with MK or not. In the 270 CR patients, 99 (37%) received continuous chemotherapy; 171 (63%), allo‐HSCT in CR1. With a median follow‐up of 33 months (range, 1.5–125.3 months) for living patients, probabilities of DFS and OS at 5 years were 54.6% (95%CI, 47.5%&gt;61.2%) and 57.8% (95%CI, 50.5%&gt;65.1%), respectively. Variables including patients’ characteristics at diagnosis and early responses associated with outcomes were assessed in univariate analysis. In multivariate analysis, MK was not a factor associated the outcomes, however, age &gt;45 year, plate count &lt; 88x109/L, not achieving CR within 4 weeks, and receiving chemotherapy rather than allo‐HSCT were adverse factors associated with DFS and/or OS. In further analyses by post‐remission therapy, MK was identified as an independent factor associated with lower probabilities of DFS (HR 2.1, 95%CI 1.0–4.4, p = 0.050) and OS (HR 5.3, 95%CI 2.5–11.2, p &lt; 0.001) in the chemotherapy group; in addition, age &gt;45 year and MRD positivity after cycle 1 of consolidation were associated with shorter DFS. However, no variable was found to affect the outcomes in the allo‐HSCT group.Summary/Conclusion:Ph‐negative ALL patients with MK had lower platelet count, higher blast percentage in peripheral blood, and more complex karyotype at diagnosis. MK was an independent poor predictor of outcome in the patients with Ph‐negative ALL receiving continuous chemotherapy, but it had no significance in those receiving allo‐HSCT. Our study suggested that Ph‐negative ALL patients with MK might benefit from allo‐HSCT.

Randomization of dose-reduced subcutaneous interleukin-2 (scIL2) in maintenance immunotherapy (IT) with anti-GD2 antibody dinutuximab beta (DB) long-term infusion (LTI) in front–line high-risk neuroblastoma patients: Early results from the HR-NBL1/SIOPEN trial.

10013 Background: We tested dose-reduced scIL2 in combination with DB-LTI and oral isotretinoin and evaluated toxicity and efficacy in high-risk neuroblastoma patients (EudraCT:2006-001489-17). Methods: High-risk patients (stage 4 ≥1y; stage 4 &lt; 1y with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received high intensity induction (rapid COJEC or N5-MSKC and TVD for insufficient response), surgery, high dose therapy with busulfan/melphalan and local radiotherapy. Patients ≤9 months between diagnosis and HDT/SCT who achieved at least a partial response prior to HDT/SCT and without progression thereafter were randomized to receive up to 5 cycles of 100mg/m2 DB-LTI (d8-17) ± 3x106 IU/m2 scIL2 (d1-5; d8, d10, d12, d14, d16) and 160mg/m2 oral isotretinoin (d19-32). Results: Between 04/2014 and 06/2018, 408 patients from 18 countries were randomized. Median follow-up is 1.8 years. Stage, age, MNA, induction treatments and remission status were well balanced between randomization arms. The 2yrs-EFS and -OS for DB-LTI (205 pts) vs. DB-LTI&amp;scIL2 (203 pts) was 64%±4%vs63%±5% (p = 0.844) and 83%±3%vs74%±4% (p = 0.337). For patients in CR the 2yrs-EFS was 69%±5% for DB and 66%±6% for DB&amp;scIL2. Patients with evaluable disease prior DB or DB&amp;scIL2, the end of treatment response rate was 57% (26% CR, 31% PR) vs 52% (27% CR, 25% PR) with 2yrs-EFS rates of 58%±7% and 64% ±8%, respectively. Grade 3&amp;4 toxicity was lower in the group with DB vs DB&amp;scIL2 for fever (14%vs31%, p &lt; 0.001) and pain (7%vs18%, p = 0.005), and no significant difference was seen for general condition (17%vs22%,ns), allergy (3%vs3%,ns), capillary leak (4%vs8%,ns), liver enzyme elevation (20%vs27%, ns) and neurological toxicities (2%vs2%,ns). Conclusions: We previously reported grade 3&amp;4 toxicity to DB short-term infusion (STI) ± 10x6x106IU/m2 scIL2 for general condition (16%vs41%, p = 0.000), fever (14%vs40%, p = 0.000), allergic reaction (10%vs20%, p = p = 0.006), capillary leak (4%vs15%, p = 0.004), liver enzyme elevation (17%vs23%, ns), central neurotoxicity (3%vs8%, p = 0.034) and pain (16%vs26%, p = 0.048). Our results indicate that DB-LTI and dose-reduced scIL2 clearly reduced the toxicity profile, but showed absence of benefits of scIL2. DB-LTI achieved 2yrs-EFS in line with DB-STI (Ladenstein, Lancet Oncology 2018; Yu, NEJM, 2010) and a response rate &gt; 50% supporting its use as standard of care IT. Clinical trial information: EudraCT:2006-001489-17.

PCN9 CLINICIAN PERSPECTIVES ON CURE IN ADULT ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) PATIENTS WITH MINIMAL RESIDUAL DISEASE (MRD) - FINDINGS FROM A GERMAN DELPHI PANEL

The presence of MRD in patients with Philadelphia chromosome-negative (Ph–) B-cell precursor (BCP) ALL in first complete remission (CR1) is an important negative prognostic factor. Evidence suggests that long-term survival can be achieved among patients with MRD+ by eradicating MRD. This study examined the concept of cure, the role of hematopoietic stem cell transplant (HSCT) in treatment, and long-term mortality risk in Ph– BCP ALL patients in CR1 in relation to MRD. A two-phase Delphi panel was conducted with four hematologists / hemato-oncologists from Germany with expertise in treating adults with ALL. Participants completed a questionnaire which gathered information about experience in treating ALL including treatments and outcomes using semi-structured and open-ended questions. Responses were discussed by all participants in a web-based meeting. Participant “poll” questions were used to establish if consensus (defined here as 75% agreement) was achieved on specific statements. Participants had a median of 20 years of experience treating adults with BCP-ALL and had treated a median of 10 Ph– BCP-ALL patients in the previous year (Range:8-20). Participants agreed that: cure is highly probable at 5 years of relapse-free survival (RFS) for patients who are MRD+ at CR1, and cure rates would be lower among patients’ ineligible for HSCT for patients in CR1 with MRD+ (participants provided their response within the current standard of care chemotherapy). Participants estimated that 50-60% of patients in CR1 with MRD+ who subsequently became MRD- after additional treatment can achieve cure. This study provides evidence via clinical consensus on the concept of cure in patients with BCP-ALL with MRD at CR1 in Germany, and that cure can be achieved in these patients by eradicating MRD. Implications of this research are that therapies that eradicate MRD and induce long-term RFS may increase the chance of cure.

Vaccination of cancer patients with dendritic cells electroporated with mRNA encoding the wilms' tumor 1 protein (WT1): correlation of clinical effect and overall survival with T-cell response

Background & Aim Dendritic cells (DC) have the capacity to induce potent tumor antigen-specific T-cell immunity. We have completed vaccination in the adjuvant setting in 77 cancer patients (acute myeloid leukemia (AML, n=30), metastatic breast cancer (MBC, n=12), glioblastoma multiforme (GBM, n=13), malignant pleural mesothelioma (MPM, n=10) and other solid tumors (n=12)) with autologous DC electroporated with mRNA encoding the nearly universal tumor-associated antigen Wilms’ tumor 1 protein (WT1). Methods, Results & Conclusion WT1-targeted DC vaccination was feasible and safe in all patients. The majority of the patients showed a positive delayed type hypersensitivity (DTH) response to the vaccine. Objective clinical responses were observed among all tumor types, including complete (CR) and/or molecular remissions or stable disease (SD) in the AML group, partial responses (PR) and SD in the GBM group and SD in the MBC and MPM groups. In AML patients in first CR, median overall survival (OS) calculated from time of diagnosis was 56.1 months (mo). Median OS from time of diagnosis of metastasis was 41.9 mo in MBC, 43.7 mo from diagnosis in GBM and 35.7 mo from start of therapy in MPM; this compares favorably to numbers reported in the literature, respectively 24.8 mo, 14.7 mo and 22 mo. In AML, long-term OS was correlated with WT1-specific polyfunctional CD8+ T-cells in the DTH reaction sites and long-term CR with polyepitope WT1-specific tetramer+ CD8+ T-lymphocytes. In solid tumors, PR or SD was correlated with interferon (IFN)-gamma+ and/or tumor necrosis factor (TNF)-alpha+ WT1-specific CD4+ and/or CD8+ T-cells; increased OS in the GBM+MPM cohorts was correlated with IFN-gamma+ WT1-specific CD4+ T-lymphocytes. In conclusion, WT1-targeted DC vaccination is feasible, safe and immunogenic, and displays relevant anti-tumor activity in patients with hematological and solid malignancies. Most importantly, this treatment modality can confer a significant survival benefit to the patients.