Purpose: Although emerging therapies for multiple myeloma (MM) have improved treatment options, long-term disease control in relapsed/refractory (r/r) MM remains a challenge. While the effect of natural killer cell alloreactivity in haploidentical allogeneic hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GvHD) prophylaxis is considered a standard treatment option for several hematologic neoplasms, its use in MM is controversial. In this retrospective analysis, we evaluated a small cohort of consecutive patients with MM who underwent haploidentical allogeneic HCT with PTCy. Patients and Methods: With a median follow-up of 68 months (range, 2-109 months), seven consecutive patients with r/r MM underwent haploidentical HCT. All were heavily pre-treated, having received proteasome inhibitors, anti-CD38 antibody, immunomodulatory drugs, and at least one autologous HCT. Three patients received a chemotherapy-based reduced-intensity conditioning regimen combined with radioimmunotherapy. GvHD prophylaxis in all patients consisted of PTCy in combination with tacrolimus and mycophenolate mofetil. Results: All patients showed stable engraftment with complete donor chimerism. Haploidentical HCT resulted in initial response in all patients, with four patients achieving a complete remission (CR) and three a very good remission (VGPR) at first disease assessment post-HCT. All individuals surviving beyond day +100 experienced disease relapse or progression. Among the six surviving patients median time to relapse was 26.5 months (range, 5-81 months). At last follow-up, four of five surviving patients maintained a CR, while one patient remained in a very good partial remission, all following subsequent individualized therapies. Acute GvHD grades III-IV were observed in two patients, while four developed mild-to-moderate chronic GvHD, with no GvHD-related deaths at the last follow-up. Conclusion: In this small, selected cohort, haploidentical allogeneic HCT with individualized pre-treatment and conditioning regimens was associated with disease control in heavily pretreated patients with r/r MM.

For patients (pts) with relapsed or refractory multiple myeloma (RRMM) after previous autologous hematopoietic cell transplantation (AHCT), novel agents, cellular and immunotherapies are increasingly available. Options for second-line treatment mostly include triplet regimens based on proteasome inhibitors, immunomodulatory drugs and anti-CD38 monoclonal antibodies and since recently also CAR T cells. The importance of autologous salvage transplantation (retransplantation, Re-AHCT) has significantly decreased in recent years due to the availability of many new treatment options. Therefore, we performed a retrospective analysis of 171 pts cases with RRMM who received Re-AHCT between 2002 and 2021. With a median follow-up of 74.7 months, the 5-year rates of progression-free survival (PFS) and overall survival (OS) were 18

In 2022, the European LeukemiaNet (ELN) risk stratification for patients with AML has been updated. We aimed to validate the prognostic value of the 2022 ELN classification (ELN22) evaluating 1,570 newly diagnosed AML patients (median age, 56 years) treated with cytarabine-based intensive chemotherapy regimens. As compared to the 2017 ELN classification (ELN17), allocating 595 (38%), 413 (26%) and 562 (36%) patients to the favorable, intermediate and adverse risk category, ELN22 risk was favorable, intermediate, and adverse in 575 (37%), 410 (26%), and 585 (37%) patients, respectively. Risk group allocation was revised in 340 patients (22%). Most patients were re-classified into ELN22 intermediate or ELN22 adverse risk group. The allocation of patients according to the ELN22 risk categories resulted in a significantly distinct event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS). As compared to ELN17, reallocation according to the ELN22 recommendations resulted in a significantly improved prognostic discrimination for OS (3-year area under the curve (AUC) 0.71 vs. 0.67). In patients with ELN22 favorable risk AML, co-occurring MR gene mutations did not significantly impact outcome. Within the ELN22 adverse risk group, we observed marked survival differences across mutational groups (5-year OS rate of 21% and 3% in patients with myelodysplasia-related (MR) gene mutations and TP53-mutated patients, respectively). In patients harboring MR gene mutations, EZH2-, STAG2- and ZRSR2-mutated patients showed an intermediate-like OS. In patients with secondary AML and those who underwent allogeneic HCT, EFS and OS significantly differed between ELN22 risk groups, while prognostic abilities of ELN17 and ELN22 classifications were similar. In conclusion, the ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML patients. Given the heterogeneous outcome in patients with MR gene alterations, ranging between those of intermediate and adverse risk patients, we suggest reevaluation of risk allocation in these patients.

PURPOSE:Despite the development of novel drugs and the widespread use of hematopoietic cell transplantation, the prognosis of patients (pts) with multiple myeloma and extramedullary involvement (soft-tissue plasmacytoma, STP) is rather unfavorable. METHODS:A retrospective analysis of 120 pts with STP treated between 2007 and 2022 was performed. The effects of demographic and clinical characteristics on treatment response, progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS:The rate of serological response to first-line STP treatment (at least partial remission) was 67%, and the rate of imaging response was 59%. With a median follow-up of 84.2 months, the median PFS was 10.5 months (primary STP: 20.2 months; secondary STP: 5.8 months), and the median OS was 24.5 months (primary STP: 34.5 months; secondary STP: 12.4 months). Based on the multivariate regression analysis, secondary STP (HRPFS 2.75; HROS 2.63) and organ involvement (HRPFS 1.45; HROS 1.68) were found to be negative prognostic factors of both PFS and OS. In a prognostic model, pts with at least one of these factors had a significantly worse PFS (HRPFS 3.31) and OS (HROS 3.45) than those with none risk factor. CONCLUSION:In pts with STP, risk-adapted treatment strategies including immunotherapies and cell therapies are urgently required.

CONCLUSION Despite the development of new agents and the widespread use of hematopoietic cell transplantation (HCT), the prognosis of patients (pts) with multiple myeloma and extramedullary involvement (EMM) is rather unfavorable. Until now, there are no generally accepted standards for diagnosis and treatment of EMM. We performed a retrospective analysis of 130 pts with EMM treated at Klinikum Chemnitz between 2007 and 2022. Various demographic and clinical factors were recorded in a database and evaluated for their impact on response and survival. The data cut point was July 2022, and for follow-up a minimum of 3 months was required. One hundred and thirty pts (89 men, 41 women) with EMM at a median age of 68 years (range, 37-87 years) were included. In 78 pts extramedullary involvement was detected at the time of initial diagnosis (primary EMM), and in the remaining 52 pts a secondary EMM was diagnosed at the time of relapse (n=38) or refractory disease (n=14). In approximately two-thirds of pts EMM manifested exclusively in the paraskeleton (n=84), while roughly one-third of pts showed an extramedullary organ involvement (n=25), or both (n=21). Cytogenetic data were available in 125 pts, with 39 pts classified as high-risk EMM (including del17p in 11 pts). ISS could be evaluated in only 56 pts, of whom 22 pts had ISS III. Elevated serum LDH levels were observed in almost half of the pts (n=63) at the time of EMM diagnosis. Treatment regimens included mainly proteasome inhibitors (n=106), immunomodulatory drugs (n=74) and CD38 antibodies (n=42). Fifty-five pts (42.3%) received autologous (n=44), allogeneic (n=8) or autologous-allogeneic HCT (n=3). Serologic response to treatment (at least PR) according to IMWG criteria was 63.8% (83/130) and imaging response was 56.9% (74/130). With a median follow-up of 84.2 months, median progression-free survival was 10.3 months and median overall survival was 23.8 months. In univariate analysis for PFS and OS, we found significantly worse outcomes in patients with secondary EMM (vs. primary EMM), EMM with organ manifestation (vs. paraskeletal EMM only), ISS III (vs. ISS I +II), and elevated serum LDH (vs. not elevated). Furthermore, pts with del17p had significantly shorter PFS, while detection of ampl1q32 (n=14) was associated with significantly worse OS. For other tested factors [lambda light chain involvement, t(14;16), dupl1q21 or tripl1q21, EMM diagnosis 2007-2013 vs. 2014-2022] we found no negative effects on PFS or OS. Multivariate Cox regression analysis confirmed secondary EMM as an independent negative factor for PFS (HR 3.62, p<0.0001) and OS (HR 2.95, p<0.0001), whereas detection of del17p was only associated with unfavorable PFS (HR 2.02, p=0.03). Our data show that the prognosis of pts with EMM remains poor. Despite the introduction of many innovative agents, outcomes have not improved significantly since 2013. There is an urgent need for diagnostic/therapeutic guidelines of EMM as well as risk-adapted therapeutic strategies (using modern immunotherapies and cell therapies).

Background: In 2022, the ELN risk stratification for patients (pts) with acute myeloid leukemia (AML) has been updated. The key changes of the revised ELN recommendations are as follows: i) bZIP in-frame CEBPA mutations are now considered favorable-risk (ELN22fav), irrespective of monoallelic/biallelic mutation status; ii) pts with FLT3-ITD are now considered intermediate-risk (ELN22int), irrespective of allelic ratio or NPM1 status; and iii) pts with alterations in myelodysplasia-related (MR) genes (BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1 and ZRSR2) are categorized as adverse-risk (ELN22adv) AML. Aims: We aimed to validate the prognostic value of the ELN22 recommendations in a large, intensively treated patient cohort. Methods: We evaluated 1,570 pts aged ≥ 18 years with newly diagnosed AML intensively treated on Study Alliance Leukemia (SAL) protocols (AML96, AML60+, AML2003 or SORAML trial, respectively). Pretreatment genetic alterations were assessed using G banding, FISH, PCR, fragment length analysis and targeted next generation sequencing. Results: Pts’ median age was 55.5 years (range, 18−89 years), 47.3% were female. Most pts (84.1%) were diagnosed with de-novo AML. ELN22 risk was favorable-, intermediate-, and adverse-risk in 575 (36.6%), 410 (26.1%), and 585 (37.3 %) pts, respectively. As compared to the ELN17 classification, risk group allocation was revised in 340 pts (21.7%). Most pts were re-classified into ELN22int (45.6%, mainly due to FLT3-ITD) or ELN22adv risk group (32.9%, mostly because of evidence of MR gene alterations), respectively. However, there were only slight net effects on the percentage of pts classified as favorable-, intermediate- and adverse-risk (-0.7%, -3.4%, and +4.1%, respectively) (Fig. 1A). The CR rates in pts assigned to the ELN22fav, ELN22int and ELN22adv-risk groups were 87.3%, 76.6% and 49.2%, as compared to 86.4%, 70.5% and 53.2% in pts stratified according ELN17, respectively. The allocation of pts according to the ELN22 risk categories resulted in a significantly distinct EFS, RFS and OS. The 5-y OS for pts in the ELN22fav, ELN22int and ELN22adv-risk category was 53%, 32%, and 13%, while the corresponding 5-y OS in pts classified according ELN17 was 49%, 30% and 16%, respectively; indicating a more accurate discrimination of favorable- and adverse-risk pts in ELN22 (Fig. 1B). Within the ELN22fav-risk group, pts with CBF-AML or CEBPA bZIP in-frame mutations showed superior OS as compared to patients with NPM1 mutations (5-y OS 59% and 58% vs. 41%). Within the ELN22adv-risk group, we observed marked survival differences across mutational groups with TP53-mutated pts having the worst prognosis (5-y OS 3.3%), followed by pts with ASXL1 and/or RUNX1 mutations (5-y OS 14%), and pts with MR gene mutations (5-y OS 22%) (Fig 1C). In pts harboring MR gene mutations, EHZ2, STAG2 and ZRSR2 mutated pts showed an intermediate-like OS (5-y OS ~30%), while patients with U2AF1 mutations had significantly worse OS (5-y OS 4.6%). As compared to ELN17, reclassification according to the ELN22 recommendations resulted in an improved prognostic discrimination for OS (2-y AUC 0.67 vs. 0.70, p=.003), as evaluated by inverse-probability-of-censoring weighting area under time-dependent receiver-operating-characteristic curves. Summary/Conclusion: In conclusion, the novel ELN22 risk stratification improves prognostic discrimination in a large cohort of intensively treated AML pts. Given the heterogeneous outcome in pts with MR gene mutations, ranging between those of intermediate- and adverse-risk pts, we suggest reevaluation of risk allocation in these patients.Keywords: AML

Background Bispecific antibodies and CAR-T cells are currently changing the treatment landscape of relapsed and refractory multiple myeloma (RRMM), having shown high response rates and durable remissions of more than a year in clinical trials. However, some discrepancies to these results have been observed lately, with lower median progression free survival (PFS) and overall survival (OS) in the real-world setting for idecabtagene vicleucel (ide-cel), possibly related to strict entry criteria of the study and known general benefits for patients participating in clinical trials regardless of study arm allocation. Whether this also holds true for Teclistamab, a B-cell maturation antigen (BCMA) x CD3 bispecific antibody approved for treatment of RRMM in 2022 in several countries, has yet to be determined. Therefore, we thought to assess Teclistamab efficacy and tolerability in the real-world setting. Methods Data of 115 patients with RRMM treated with Teclistamab at 18 different German centers from July 2022 to July 2023 were retrospectively collected and analyzed. The patients had received at least one full treatment dose of Teclistamab. Responses were evaluated in accordance with the IMWG response criteria; in addition, near complete response was defined as serological complete remission lacking bone marrow assessment, as this was not always part of clinical routine. In non-secretory disease, response evaluation was based on radiological criteria. Kaplan-Meier methods were applied for time-to-event-analyses. For comparison of survival among groups, the log-rank test and Cox regression analysis were used. For comparison of response rates among groups, the Chi square test was applied. Results The included 115 patients (49 female, 66 male with a median age of 66.0 years) had a median history of MM diagnosis of 6.5 years and were heavily pretreated with a median of 6 (range 3-14) prior lines of therapy. The majority of patients had triple-class (91.3%) or even penta-drug (58.3%) refractory disease. 35.6% (41/115) had received BCMA-directed pretreatment, among them 20 with ide-cel, 21 with belantamab mafodotin and single patients with both or a BCMA-directed study medication. Cytogenetic high-risk features defined as del(17p), t(4;14) and/or t(14;16) and extramedullary disease (EMD) were present in 38.0% and 37.2% of patients, respectively. Around one third of patients had high disease burden with bone marrow infiltration ≥60% (37.0%) or ISS 3 (35.2%) in the latest assessment before initiation of Teclistamab. Overall, a substantial proportion of 40.9% of the treated patients would not have met selected inclusion criteria of the MAJESTEC-1 trial like measurable disease, stable hematopoiesis and kidney function. With median times to response and best response of 4.3 weeks and 8.0 weeks, we observed an ORR, defined as partial remission or better, of 56.8%. 20.9% of all patients reached a near complete or complete response. With a median follow-up of 3.9 months, median PFS was 8.7 months. Median duration of response and median OS were not reached. In the group of patients with BCMA-directed pretreatment, the ORR of belantamab-pretreated patients (70%) was comparable to that in anti-BCMA naïve patients (60.0%), whereas ide-cel pretreated patients showed a significantly lower ORR of 27.8%. Interestingly, PFS did not differ significantly between ide-cel pretreated and ide-cel naïve patients. In further subgroup analyses, the presence of EMD and an ISS of 3 were associated with inferior ORR and PFS in univariable and multivariable analysis. Safety was similar to the experience in MAJESTEC-1. 60.0% of patients developed CRS and 6.9% neurotoxicity with grade 3 or 4 events in 1.7% and 0.9% of patients, respectively. Tocilizumab was administered in 25.2% and dexamethasone in 15.7% of patients. Infections occurred in 49.6% of patients, nearly half of them requiring hospitalization. 53.9% experienced grade 3 or 4 cytopenia according to CTCAE during treatment. Conclusions With an ORR of 56.8% in all patients and 60.0% in anti-BCMA naive patients, Teclistamab showed a similar ORR in the real-world setting to that observed in the MAJESTEC-1 trial. PFS was slightly lower, but our patient collective comprised higher proportions of patients with high risk disease, extramedullary disease, high disease burden, hematopoietic or renal impairment.

Outcome in younger patients (pts) with ALL has been improved considerably using intensive pediatric-based therapy, but limited data on this approach have been reported for older pts and even the age cut-off is heavily debated. The German Multicenter Center Study Group for Adult ALL (GMALL) has conducted a clinical trial (>55 years) (NCT00198978) which was followed by a registry trial based on standard management recommendations with prospective documentation in the GMALL registry (NCT02872987). Strategies were modified over the years (yrs). The backbone included: Pre-phase (Dexa, Cyclo), induction I (Dexa, VCR, Idarubicine), induction II (Cyclo, AraC), ±post-induction PEG-ASP, consolidation (C) cycles with IDMTX (± E.coli ASP), HDAraC (earlier: VM26), reinduction (VCR, Idarubicine, Cyclo, AraC), ± Rituximab in CD20+, i.th. prophylaxis and maintenance (6-MP/MTX) (group 1). The latest protocol (from 2017) additionally included IDMTX/PEG-ASP in consolidation and recommended MRD-based treatment modification (Blinatumomab in B-Lin and Nelarabin in T-Lin) in molecular failure (MolFail) after C2 (group 2). 882 patients (pts) from 142 sites were included 2003-2021 (table 1). 5% were withdrawn early and therefore not evaluable. The median age was 68 (56-86) yrs. 61% were older than 65 yrs. B-Lin-ALL was present in 68%; 7% of B-Lin-ALL (N=45) had a KMT2A-rearrangement. 19% and 9% had immature subtypes, pro-B and early T-ALL resp.. 50% had at least one comorbidity according to the Charlson-Score (ChS); 11% had a score ≥3; 28% had an BMI≥30 mg/m2. Group 2 vs group 1 had a significantly lower median age (66 vs 68 yrs; p=.001) and a higher proportion of T-ALL (21% vs 14%; p=.0003). In 841 pts the CR rate after induction was 73% with 14% early death (ED) and 13% failure. The ED rate was lower in group 2 vs group 1 (9% vs 15%; p=.04). CR rates were 76%, 73% and 63% in three age groups (56-65, 66-75, ≥76 yrs) with ED rates of 9%, 14% and 26% resp. (p<.0001). CR rates were significantly lower in pts with WBC ≥30.000/µl (table 1). BMI (≥30 kg/m2) was not associated to CR/ED but ED rates were correlated to ChS with a high ED rate (26%) in those with ChS ≥3 (table 1). MRD response data were available in 163, 239 and 173 pts after induction II, C1 and C2 resp. The molecular CR (MolCR)/ MolFail rates were 41%/52%, 57%/38% and 64%/30% resp. The remaining pts had intermediate MRD (MolIMR). MolCR rates were similar in B-Lin only (43%/58%/64%). With a median follow up of 2.7 yrs overall survival (OS) in 841 pts at 3, 5 and 10 yrs was 36%, 28% and 22% resp. The 3y remission probability was 37%. Mortality in CR was 5% (3%, 6% and 7% by age) and 12% of the pts were withdrawn from protocol. OS strongly correlated to age and was very poor in pts older than 75 yrs (7% at 3 yrs; table 1). Only 8% (N=51) of all CR pts received an allogeneic stem cell transplantation (SCT) in CR1 (N=20 ≥65 yrs) but the SCT-rate increased in group 2 vs group 1 (9% vs 5%). 3y-OS after SCT in this selected group (N=51) was 56%. OS was significantly superior in group 2 vs group 1 (50% vs 32%; p<0.001) (figure 1). This improvement occurred mainly in the younger age group (56-65 yrs): 62% vs 38% 3y OS in group 2 vs group 1 resp. (p<0.0001) with no significant improvement in pts older than 65 yrs. WBC and ChS≥3 were associated with poorer OS (table 1). MRD response had a significant impact on OS at all timepoints. Pts with MolCR after C1 had a 3 yr OS of 80% vs 52% for MolFail and 62% for MolIMR (p=.0004). Interestingly the 3y-OS of 52 MolFail pts tended to be superior in group 2 (74% vs 46%;p>.05). The CR rate and OS of MLL-rearranged cases was 62% and 19% resp. With this age-adapted, pediatric-based regimen a reasonable CR rate was achieved up to 75 yrs. Pt numbers were small and OS very poor in pts >75 yrs. MolCR rates were overall lower compared to more intensive protocols in younger pts. Thus, treatment modification based on MolFail is a promising approach and might produce benefits in many older pts. The optimal time-point for treatment change remains to be defined. Together with more intensive consolidation including PEG-ASP this modification likely contributed to the improved outcome with 62% OS in the youngest cohort (56-65 yrs) in group 2. In all older pts, but specifically in those >65-75 yrs or with multiple comorbidities, alternative protocols with targeted therapies and further step-wise reduction of chemotherapy require prospective exploration in clinical trials with the major goal to reduce ED rate and to improve MRD response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patients with cancer are at high risk of severe coronavirus disease 2019 (COVID-19), with high morbidity and mortality. Furthermore, impaired humoral response renders severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines less effective and treatment options are scarce. Randomized trials using convalescent plasma are missing for high-risk patients. Here, we performed a randomized, open-label, multicenter trial ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001632-10/DE ) in hospitalized patients with severe COVID-19 ( n = 134) within four risk groups ((1) cancer ( n = 56); (2) immunosuppression ( n = 16); (3) laboratory-based risk factors ( n = 36); and (4) advanced age ( n = 26)) randomized to standard of care (control arm) or standard of care plus convalescent/vaccinated anti-SARS-CoV-2 plasma (plasma arm). No serious adverse events were observed related to the plasma treatment. Clinical improvement as the primary outcome was assessed using a seven-point ordinal scale. Secondary outcomes were time to discharge and overall survival. For the four groups combined, those receiving plasma did not improve clinically compared with those in the control arm (hazard ratio (HR) = 1.29; P = 0.205). However, patients with cancer experienced a shortened median time to improvement (HR = 2.50; P = 0.003) and superior survival with plasma treatment versus the control arm (HR = 0.28; P = 0.042). Neutralizing antibody activity increased in the plasma cohort but not in the control cohort of patients with cancer ( P = 0.001). Taken together, convalescent/vaccinated plasma may improve COVID-19 outcomes in patients with cancer who are unable to intrinsically generate an adequate immune response.

Patients with hematological malignancy or other cancers as well as immunosuppression bear a high risk for severe COVID-19. Monoclonal antibodies (mAb) are efficient at early stages of the disease but may lose potency with new variants. Trials on plasma from convalescent donors in unselected patients have not shown clinical benefit. No randomized trials focussing on patients with underlying disease have been published. We conducted an open-label, multicenter, randomized controlled trial to evaluate efficacy of plasma (CVP - convalescent or after vaccination) in patients with COVID-19 at high risk for adverse outcome in Germany. We assessed the effect of high-titer CVP (2 units from different donors, 238-337 ml each, on subsequent days). Patients with hematological or other malignancy (group 1), immunosuppression (group 2), age >50 and ≤75 years and lymphopenia and/or high D-dimers (group 3) or age >75 years (group 4) who were hospitalized with confirmed SARS-CoV-2 infection and with an oxygen saturation ≤94% were included. Primary outcome measure was time to clinical improvement on a seven-point ordinal scale, secondary outcome was mortality (Janssen et al. Trials 2020 Oct 6;21(1):828). Overall, 133 patients were randomized, 68 received CVP with an additional 10 patients as a crossover on day 10. Median age (range) was 68 years (39-95) in the CVP group and 70 (38-90) in controls. For the entire cohort, no significant difference was seen in time to improvement (median days: CVP 12.5 vs. control 18; HR 1.24 (95% confidence interval (CI) 0.83-1.85), p=0.29). Subgroup analysis (group 1+2) revealed shortened time to improvement (median days CVP 13 vs. control 32; HR 2.03 (95%CI 1.17-3.6), p=0.01) and mortality was reduced (mortality CVP n=6 (18%) vs. control n=10 (29%). No significant differences in time to improvement were observed in group 3 or 4 (HR 0.72 (95%CI 0.41-1.28), p=0.26). No relevant adverse events were observed. CVP improves time to clinical improvement and mortality for COVID-19 patients with underlying hematological disease/cancer or other reasons of impaired immune response. Even with new variants, high-titer CVP may offer a widely available and inexpensive therapy option in high-risk groups. BMBF FKZ 01KI20152; EudraCT 2020-001632-10. Uta Merle, MD, Gilead: Sponsored congress travel and accommodation Markus Weigand, MD, Bbraun: Speakers fee/ad boards fee|Biotest: Speakers fee/ad boards fee|Eumedica: Speakers fee/ad boards fee|Gilead: Speakers fee/ad boards fee|MSD: Speakers fee/ad boards fee|Pfizer: Speakers fee/ad boards fee|Shionogi: Speakers fee/ad boards fee|SOBI: Speakers fee/ad boards fee Martin Bornhäuser, MD, Alexion: Honoraria|Jazz Pharmaceuticals: Honoraria|MSD: Honoraria|Novartis: Honoraria Nael Alakel, MD, Amgen: personal fee, travel grant|Gilead: personal fee, travel grant|MSD Sharp and Dohme GmbH: personal fee, travel grant|Pfizer: personal fee, travel grant Timo Wolf, MD, Gilead Sciences: Lecture fee, travel grant|Janssen Pharmaceuticals: Lecture fee, travel grant|Merck Sharp Dome: Lecture fee, travel grant Maria Vehreschild, Prof. Dr., 3M: speaker fee|Astellas: Advisor/Consultant|Astellas: speaker fee|biologische heilmittel heel gmbh: Grant/Research Support|BioNtech: Grant/Research Support|EUMEDICA: Advisor/Consultant|Farmak International Holding: Advisor/Consultant|Ferring: Advisor/Consultant|Ferring: Speaker fee|Gilead Sciences: Advisor/Consultant|Immunic AG: Advisor/Consultant|MaaT: Advisor/Consultant|Merck: Advisor/Consultant|Merck: speaker fee|MSD: Advisor/Consultant|MSD: Grant/Research Support|MSD: speaker fees|Pfizer: speaker fee|Roche Molecular Systems: Grant/Research Support|Roche Molecular Systems: speaker fees|SocraRTec R&D GmbH: Advisor/Consultant|Takeda California: Grant/Research Support Hanns-Martin Lorenz, MD, Abbvie: Advisor/Consultant|Abbvie: Honoraria|Actelion: Advisor/Consultant|Actelion: Honoraria|Alexion: Advisor/Consultant|Alexion: Honoraria|Amgen: Advisor/Consultant|Amgen: Grant/Research Support|Astra Zeneca: Advisor/Consultant|Astra Zeneca: Honoraria|Baxter: Advisor/Consultant|Baxter: Advisor/Consultant|Baxter: Honoraria|Baxter: Honoraria|Bayer Vital: Advisor/Consultant|Bayer Vital: Honoraria|Biogen: Advisor/Consultant|Biogen: Honoraria|BMS: Advisor/Consultant|BMS: Honoraria|Boehringer Ingelheim: Advisor/Consultant|Boehringer Ingelheim: Honoraria|Celgene: Advisor/Consultant|Celgene: Honoraria|Fresenius: Advisor/Consultant|Fresenius: Honoraria|Genzyme: Advisor/Consultant|Genzyme: Honoraria|Gilead/Galapagos: Advisor/Consultant|Gilead/Galapagos: Honoraria|GSK: Advisor/Consultant|GSK: Honoraria|Hexal: Advisor/Consultant|Hexal: Honoraria|Janssen-Cilag: Advisor/Consultant|Janssen-Cilag: Honoraria|Lilly: Advisor/Consultant|Lilly: Honoraria|Medac: Advisor/Consultant|Medac: Honoraria|MSD: Advisor/Consultant|MSD: Honoraria|Mundipharm: Advisor/Consultant|Mundipharm: Honoraria|Mylan: Advisor/Consultant|Mylan: Honoraria|Novartis: Advisor/Consultant|Novartis: Honoraria|octapharm: Advisor/Consultant|octapharm: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Roche/Chugai: Advisor/Consultant|Roche/Chugai: Honoraria|Sandoz: Advisor/Consultant|Sandoz: Honoraria|Sanofi: Advisor/Consultant|Sanofi: Honoraria|Shire: Advisor/Consultant|Shire: Honoraria|SOBI: Advisor/Consultant|SOBI: Honoraria|Thermo Fisher: Advisor/Consultant|Thermo Fisher: Honoraria|UCB: Advisor/Consultant|UCB: Honoraria.

Introduction: Allogeneic hematopoietic cell transplantation (HCT) during chemotherapy-induced aplasia may offer long-term survival in acute myeloid leukemia (AML) with otherwise poor prognosis including ELN adverse risk, relapsed or refractory disease. However, the value of residual morphologic disease prior HCT in this context has not been conclusively settled until yet. Therefore, we aimed to investigate variables predicting outcome in this unique setting of sequential conditioning therapy, with a focus on pretreatment morphologic blast count. In contrast to the most popular FLAMSA-RIC protocol, we used a melphalan-based conditioning regimen during aplasia. Methods: We retrospectively analyzed data from 173 AML patients who underwent a sequential melphalan-based conditioning therapy between 2003 and 2015 at our centre. All patients participated either in the prospective Phase 2 BRIDGE trial (NCT01295307), the Phase 3 AML2003 study (NCT00180102) or were treated according to this protocol and underwent allogeneic HCT after melphalan-based conditioning in treatment-induced aplasia. Results: Median bone marrow blast count prior to conditioning was 10% (range, 0-96%). Four year probabilities of EFS and OS were 34% (95% CI, 28-43%) and 43% (95% CI, 36-52%), respectively. In multivariate analysis, blast count >20% was associated with worse EFS (HR = 1.93; p = 0.009) and OS (HR = 1.80; p = 0.026). This effect was not significant anymore for HCT during 1st line therapy. Conclusion: Allogeneic HCT in aplasia with a melphalan-based conditioning regimen has the potential to cure a subset of adverse risk AML patients, even with persistent morphological disease prior HCT. However, a high pre-transplant blast count still indicates patients with a dismal prognosis, especially in the relapsed patient group, for whom post-transplant strategies should be considered to further optimize post HCT outcome.

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26–80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10 −3 ) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response ( p = 0.0001), while pretreatment with hypomethylating agents ( p = 0.02) and adverse European LeukemiaNet 2017 genetic risk ( p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients ( p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.

Abstract Background In a recent phase-III trial CPX-351 (Jazz Pharmaceuticals, Palo Alto, CA), a liposomal encapsulation of cytarabine and daunorubicin, has shown higher remission rates and longer overall survival (OS) in patients aged 60 to 75 years with AML with myelodysplasia-related changes (AML-MRC) or therapy-related AML (t-AML) in comparison to conventional 7+3 regimen. Based on this CPX-351 has been approved in the USA 2017 and in Europe 2018 for adult patients with newly-diagnosed AML-MRC or t-AML. Still, several issues such as age (<60 years), measurable residual disease (MRD), molecular subgroups and outcome after allo-HCT were not addressed in the phase-III trial. Aiming to investigate these open aspects and to provide more clinical experience with CPX-351, we performed a real-world analysis of patients with AML treated with CPX-351 as first-line therapy. Design/Methods: For this retrospective analysis, we collected data on baseline characteristics, treatment details including allo-HCT and outcome from patients with newly-diagnosed AML-MRC or t-AML, who were treated with CPX-351 according to the EMA label between 2018 and 2020 in 25 German centers participating in the Study Alliance Leukemia (SAL), German Cooperative Transplant Study Group and the AML Study Group (AMLSG). Results: A total of 188 patients (median age 65 years, range 26 to 80) with t-AML (29%) or AML-MRC (70%) including 46 patients (24%) <60 years could be analyzed. Eigthy-six percent received one, 14% two induction cycles and 10% received consolidation with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10-3) as measured by flow cytometry at local laboratories. Additionally, 35 patients were categorized as MLFS at first remission control, which achieved CRi (n=16) or CR (n=10) in the further course without additional therapy. After median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate was 64%. In multivariate analysis, complex karyotype predicted lower response (p=.0001), and pretreatment with hypomethylating agents (p=.02) and adverse European LeukemiaNet 2017 genetic risk (p<.0001) were associated with lower OS. Allo-HCT was performed in 116 patients (62%) including 101 of these patients with CR prior transplant and resulted in 1-year OS of 73% (median survival not reached), especially in MRD negative patients (p=.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. Conclusion: The results from this real-world analysis confirm CPX-351 as an efficient treatment for these high-risk AML patients bridging to facilitating allo-HCT in many patients with encouraging outcome after transplantation. Disclosures Röllig: AbbVie: Honoraria, Research Funding; Amgen: Honoraria; Bristol-Meyer-Squibb: Honoraria, Research Funding; Janssen: Honoraria; Jazz: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Gaidzik: Janssen: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Unglaub: Novartis: Consultancy, Other: travel costs/ conference fee; JazzPharma: Consultancy, Other: travel costs/ conference fee. Thol: Abbvie: Honoraria; Astellas: Honoraria; BMS/Celgene: Honoraria, Research Funding; Jazz: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Krause: Siemens: Research Funding; Takeda: Honoraria; Pfizer: Honoraria; art-tempi: Honoraria; Kosmas: Honoraria; Gilead: Other: travel support; Abbvie: Other: travel support. Haenel: Celgene: Consultancy, Honoraria; Amgen: Consultancy; Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bayer Vital: Honoraria; Jazz: Consultancy, Honoraria; GSK: Consultancy. Vucinic: Novartis: Honoraria; Janssen: Honoraria, Other: Travel Sponsoring; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Fransecky: Novartis: Honoraria; Medac: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Kobbe: Celgene: Research Funding. Holderried: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Speakers Bureau; Daiichi Sankyo: Other: travel support; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Therakos: Other: Travel support; Janssen: Other: Travel support; Abbvie: Other: Travel support; Eurocept Pharmaceuticals: Other: Travel support; Medac: Other: Travel support. Heuser: Astellas: Research Funding; Bayer AG: Honoraria, Research Funding; BMS/Celgene: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BergenBio: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Tolremo: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Sauer: Pfizer: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Matterhorn Biosciences AG: Consultancy, Other: DSMB/SAB Member; Takeda: Consultancy, Other: DSMB/SAB Member. Goetze: Abbvie: Other: Advisory Board; BMS/Celgene: Other: Advisory Board, Research Funding. Döhner: Jazz Roche: Consultancy, Honoraria; Agios and Astex: Research Funding; Astellas: Research Funding; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Daiichi Sankyo: Honoraria, Other: Advisory Board; Novartis: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding. Döhner: Jazz Pharmaceuticals: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria; Helsinn: Honoraria; GEMoaB: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Oxford Biomedica: Honoraria; Roche: Honoraria. Schliemann: Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Other: travel grants; Astellas: Consultancy; AstraZeneca: Consultancy; Boehringer-Ingelheim: Research Funding; BMS: Consultancy, Other: travel grants; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Schetelig: Roche: Honoraria, Other: lecture fees; Novartis: Honoraria, Other: lecture fees; BMS: Honoraria, Other: lecture fees; Abbvie: Honoraria, Other: lecture fees; AstraZeneca: Honoraria, Other: lecture fees; Gilead: Honoraria, Other: lecture fees; Janssen: Honoraria, Other: lecture fees . Germing: Novartis: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Celgene: Honoraria; Jazz Pharmaceuticals: Honoraria. Schroeder: JAZZ: Honoraria, Research Funding.

Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare but life-threatening condition. In 2018, the nanobody caplacizumab was approved for the treatment of adults experiencing an acute episode of aTTP, in conjunction with plasma exchange (PEX) and immunosuppression for a minimum of 30 days after stopping daily PEX. We performed a retrospective, observational analysis on the use of caplacizumab in 60 patients from 29 medical centers in Germany during acute disease management. Caplacizumab led to a rapid normalization of the platelet count (median, 3 days; mean 3.78 days). One patient died after late treatment initiation due to aTTP-associated complications. In 2 patients with initial disease presentation and in 4 additional patients with laboratory signs of an exacerbation or relapse after the initial therapy, PEX-free treatment regimens could be established with overall favorable outcome. Caplacizumab is efficacious in the treatment of aTTP independent of timing and ancillary treatment modalities. Based on this real-world experience and published literature, we propose to administer caplacizumab immediately to all patients with an acute episode of aTTP. Treatment decisions regarding the use of PEX should be based on the severity of the clinical presentation and known risk factors. PEX might be dispensable in some patients.

Introduction of the nanobody caplacizumab was shown to be effective in the treatment of acquired thrombotic thrombocytopenic purpura (aTTP) in the acute setting. The official recommendations include plasma exchange (PEX), immunosuppression, and the use of caplacizumab for a minimum of 30 days after stopping daily PEX. This study was a retrospective, observational analysis of the use of caplacizumab in 60 patients from 29 medical centers in Germany. Immunosuppressive treatment led to a rapid normalization of ADAMTS13 activities (calculated median, 21 days). In 35 of 60 patients, ADAMTS13 activities started to normalize before day 30 after PEX; in 11 of 60 patients, the treatment was extended beyond day 30; and in 5 patients, it was extended even beyond day 58 due to persistent autoimmune activity. In 34 of 60 instances, caplacizumab was stopped before day 30 with a favorable outcome whenever ADAMTS13 activities were >10%. In contrast, 11 of 34 patients with ADAMTS13 activities <10% at the time of stopping caplacizumab treatment developed a nonfavorable outcome (disease exacerbation or relapse). In some cases, prolongation of the treatment interval to every other day was feasible and resulted in a sustained reduction of von Willebrand factor activity. ADAMTS13 activity measurements are central for a rapid diagnosis in the acute setting but also to tailor disease management. An ADAMTS13 activity-guided approach seems safe for identifying the individual time point when to stop caplacizumab to prevent overtreatment and undertreatment; this approach will result in significant cost savings without jeopardizing the well-being of patients. In addition, von Willebrand factor activity may serve as a biomarker for drug monitoring.

Radioimmunotherapy (RIT) has the potential to reduce the incidence of relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with advanced-stage multiple myeloma (MM). In this study, we evaluated the efficacy of RIT in combination with chemotherapy-based reduced-intensity conditioning (RIC). RIT was based on the coupling of an anti-CD66 antibody to the beta emitter 188-rhenium (188-re) for targeted bone marrow irradiation. Between 2012 and 2018, 30 patients with MM, most of them heavily pretreated with various therapies including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and autologous hematopoietic cell transplantation (auto-HCT), were treated with a RIT-RIC combination before allo-HCT. In addition to a fludarabine plus melphalan- or treosulfan-based RIC, a median dose of 18.1 Gy (interquartile range [IQR], 14.6 to 24.1 Gy) was applied to the bone marrow. After a median duration of follow-up for surviving patients of 2.1 years (IQR, 1.3 to 3.0 years), the 2-year progression-free survival and overall survival rates were 43% (95% confidence interval [CI], 26% to 73%) and 55% (95% CI, 38% to 79%), respectively. The 2-year nonrelapse mortality and cumulative incidence of progression were 17% (95% CI, 3% to 30%) and 46% (95% CI, 25% to 67%), respectively. Renal toxicity and mucositis were the most frequent extramedullary side effects. In conclusion, the addition of RIT to RIC was safe and feasible and resulted in promising outcomes compared with those previously reported for RIC-based allo-HCT without the addition of RIT in patients with relapsed/refractory MM. Nevertheless, despite the addition of RIT, relapse after allo-HCT remained a major determinant of therapeutic failure. Therefore, the development of novel RIT strategies (eg, dual targeting strategies or combinations with adapter chimeric antigen receptor T cell-based therapies) is needed.