CR Pts Research Articles

Combination Therapy of Eltrombopag and Cyclosporine a Improves Hematopoiesis in Patients with Lower-Risk Myelodysplastic Syndrome

Objective: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal myeloid disorders characterized by ineffective hematopoiesis and cytopenias, with variable risks of progression to acute myelogenous leukemia (AML). Peripheral blood cytopenias are the major sources of morbidity and mortality for lower-risk MDS (LR-MDS) pts.The strategies guided by risk stratification tools are different for HR- and LR-MDS. The treatment options for cytopenias in IST non-responders, especially thrombocytopenia, are limited. Such pts are prone to a high risk of bleeding. Eltrombopag (EPAG) is an orally administered nonpeptide thrombopoietin (TPO) receptor agonist. The single-agent activity of EPAG was demonstrated in 44-47% of pts with LR-MDS . In this study, we investigated the efficacy and safety of the combination of EPAG and CysA in LR-MDS in a non-randomized phase II investigator-initiated trial. Method(s):Pts with a diagnosis of LR-MDS by WHO 2016 classification and IPSS-R as low to intermediate-risk group with hemoglobin (Hb) <9.0 g/dL, or RBC transfusion-dependence (at least four units of RBC at 8 weeks prior to enrollment); platelet count <20×109/L or platelet transfusion dependence; were enrolled. http://www.chictr.org.cn/ identifier: ChiCTR2000035473. The primary objective of this IIT was to evaluate the response to this regimen based on IWG-MDS 2006 criteria. Results All the 31 pts were evaluated for response at the primary endpoint. Among them, 21 (67.7%) pts achieved treatment response in at least one eligible lineage with an objective response rate (ORR), 4 (12.9%) pts achieved a CR, 5 (16.1%) pts achieved bi-lineage responses (HI-PE R), 11 (24.3%) pts achieved platelet lineage responses (HI-P R), and 1 (3.2%) patient achieved erythroid lineage response (HI-E R). ANC did not increase significantly at the primary endpoint compared to the baseline; however, altered ANC was a response of CR pts. The median time to response was 8 (range, 2-24) weeks, irrespective of whether the pts had a platelet or erythroid response.Of the 21 pts eligible for an erythroid lineage response,10 pts (47.6%) had responded by the endpoint and the platelet response rate was 64.5% (20/31). The median increase in Hb levels and platelets was from 60.4±18.2 g/L to 68.0±21.2 g/L (P=0.015) and from 12.3±11.2×109/L to 32.5±37.3×109/L (P=0.003) (Figure 1). The median DORs of HI-E and HI-P were not achieved, but the response rates of erythroid and platelet lineages in 20 months were 80.0% and 70.6%, respectively (Figure 2). The RBC and platelet transfusion-dependent rate decreased from 42.9% (9/21) to 28.6% (6/21) (P=0.334) and from 58.0% (18/31) to 25.8% (8/31)We also performed targeted next-generation exome sequencing of 80 genes associated with myeloid malignancies in 21 pts. Among them, 18 showed a total 19 somatic mutations (Figure 3). TET2,and ANKRD11 were detected in 3 responding pts,and KMT2D was detected in 3 responding pts. Pts with adverse prognostic genes, such as ASXL1, ARSR2, U2AF1, KIT, and ETV6, did not exhibit a hematological response. Somatic mutations in DHX9 and ROBO1 were associated with BM failure, as detected in responding pts. All 31 pts were evaluated for toxicity, and the treatment was found to be well-tolerated. The most commonly reported adverse events (AEs) of any grade were nausea (6/31,19.4%), elevated liver transaminases (4/31,12.9%), and headache (3/31,9.7%); no severe AEs had been reported until the cutoff date. One MDS-SLD patient who received CR at 3 weeks experienced deep venous thrombosis of the lower extremity after 9 months of medication, thereby requiring dose interruption. After anticoagulant therapy, the platelet count was still 65×109/L. One MDS-U case who received HI-P had increased BM blasts from 3.2% to 15.4% for 4 months. Another MDS-U case received HI-E and HI-P, and the chromosome was changed from normal karyotype to -7/del (20q) chimeric karyotype for 9 months after administration of the drugs. However, the hematological response was maintained for 16 months until the cutoff date for data collection. Conclusions: Our results indicated that the addition of Epag to CysA is well-tolerated and is an effective treatment for LR-MDS. These ORR are better than CysA monotherapy, especially HI-P. Also, the hematological responses are durable, although continued Epag administration might be necessary. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Efficacy of the Addition of the Protein Translation Inhibitor Omacetaxine to Induction with Cytarabine and Idarubicin in Newly Diagnosed AML

Background: Omacetaxine mepesuccinate (OM), a semi-synthetic form of homoharringtonine (HHT), mechanistically inhibits aminoacyl-tRNA binding to ribosomal acceptor "A” sites, preventing mRNA translation (Wetzler,Curr Pharm Des 2011, 17:59-64), and causing a rapid decline of short-lived proteins e.g., c-myc, cyclin D, the anti-apoptotic proteins cFLIP, survivin and Mcl-1, an important anti-apoptotic regulator in AML.While HHT added to cytarabine and an anthracycline improved CR and 3-yr EFS in de novo AML patients (pts; Jin et al, Lancet Oncology 2013, 7:599-608), meta-analysis of Chinese studies in elderly pts indicated a CR of 47.5%. Aims: Early analysis of AML-02, a phase Ib trial of escalating doses of OM (an FDA-approved drug) added to a standard 7 + 3 induction regimen was described (NCT02440568; Christian et al., Blood, 2018, 132:5218). Here we report long-term pt outcomes and studies of their correlation with in vitro OM effects on protein translation and apoptosis sensitivity. Methods: From June 2015 to June 2018, 22 pts aged 18-70 yrs with newly diagnosed AML entered AML-02, receiving escalating doses of OM administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and Idarubicin 12mg/m2 IV d1-3. Four OM dose levels were tested starting with cohort #1 at 0.625mg/m2 sc q12h (also 1.25, 2.0, and 3.0mg/m2 q12h cohorts). The primary endpoint, the optimally safe and active dose (OD) was determined using a Bayesian adaptive design, EFFTOX, which considers trade-offs between efficacy and toxicity to establish the OD (Shah et al, Leukemia, 2015; 29:1945). Secondary endpoints included OS, RFS and EFS. Residual disease at d14 was deemed a study failure and pts were taken off study. Hematological toxicity (HT) was defined as incomplete hematologic recovery at d49 with the BM free of leukemia. Post-induction therapy consisted of standard high dose cytarabine consolidation chemotherapy or allogeneic HSCT, based on cytogenetic risk (ELN 2010). Potential correlations of the effects of OM on protein translation rates, measured using the OP-Puro technique, and apoptosis sensitivity, measured using BH3 profiling techniques, on pretreatment AML samples and subsequent patient outcomes were also examined. Follow-up is complete to August 1st, 2022. Results: Median age was 58 yrs, 12 pts had adverse cytogenetics, 6 intermediate and 3 favorable risk (1 unknown due to fibrosis); overall 73% (16) had adverse cytogenetics or secondary AML. Earlier results (Christian et al) indicated no HTs in 21 evaluable pts, and OD was established as 2.0mg/m2. CR was 45.5%, median OS 22.7 months (OS at 4 yrs 45%), and EFS 80 days. The median OS is now 24.2 months (95% CI 18.3-39.7), median EFS is 80 days (95% CI 280-964), and OS at 6 years remains at 45%. There were no new TEAEs. Notably, of 10 pts achieving CR, 1 pt relapsed at D60, 1 was lost to follow-up and 1 died of opiate overdose (in CR). Five of the remaining 7 underwent HSCT and all 7 remain in remission. In pts achieving CR, median RFS is 62.4 months (95% CI 42.6-82.2; Fig.1), suggesting potential LSC impact. Common adverse effects included neutropenia (82%), nausea (64%), vomiting (59%), diarrhea (45%), hyperglycemia (41%), and a transient desquamating skin reaction (27%) that is dose-related and may be due to OM-mediated downregulation of cFLIP levels in sweat glands (Hwang et al, British Journal of Haematology, 2021; 195:e138-e146). In in vitro studies, 3 pretreatment AML pt BM samples were analyzed after a short-term (non-cytotoxic) OM treatment for 4 hours at a dose (75 nM) equivalent to calculated systemic OM levels achieved in cohort#3 (2mg/m2). Responding pt samples (CR;n=2) had a greater reduction in protein translation than the non-responder (NR). With exposure to OM, CR pts also had greater reductions of proteins with a short T1/2, such as anti-apoptotic protein MCL-1, with a marked increase in cytochrome C loss, indicating high mitochondrial priming and sensitivity to apoptosis (Fig.2). Conclusion: This small phase Ib study of the addition of OM to a standard 7 + 3 regimen in a diverse population with predominantly high-risk AML and frequent co-morbidities demonstrates a manageable safety profile, acceptable efficacy and resulted in a prolonged DoR. Studies of pretreatment pt samples suggest that analysis of blast protein translation inhibition and especially BH3 profiling responses to OM may predict susceptibility of LSC to Omacetaxine, and potentially patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcome of 841 Older Patients (>55 yrs) with Newly Diagnosed Ph/BCR-ABL Negative ALL Prospectively Treated According to Pediatric-Based, Age-Adapted GMALL Protocols

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

Updated Results from a Multicenter, Phase 2 Study of Acalabrutinib, Venetoclax, Obinutuzumab (AVO) in a Population of Previously Untreated Patients with CLL Enriched for High-Risk Disease

Background While venetoclax (V) plus obinutuzumab (O) is a highly effective frontline CLL regimen, outcomes remain suboptimal for high-risk patients (pts). The efficacy of ibrutinib plus VO in such pts is encouraging, but cardiac and infectious toxicities (tox) are common. We hypothesized that a time-limited triplet with the more selective BTKi acalabrutinib (A) would be active and well-tolerated. We previously published results on an initial cohort unrestricted by genetic risk (Davids et al., 2021), and now report on a new cohort with enrollment restricted to high-risk pts, as well as longer follow-up on the initial cohort. Methods Treatment (tx)-naïve pts with CLL with any genetic risk profile were initially enrolled in this investigator-sponsored, phase 2 study (cohort 1), followed by a multi-center expansion restricted to previously untreated pts with TP53-aberrant CLL (cohort 2). A starts at 100 mg BID for 28 days, followed by 2 cycles of AO (O at standard dosing), and V starts on C4D1 at 20 mg, then 50 mg on C4D2, with weekly ramp-up thereafter to 400 mg QD (total 4 week V ramp-up). AVO continues C5-7 (6 total cycles of O), and AV continues C8-15. If the primary endpoint of undetectable bone marrow MRD (BM-uMRD) CR is reached at C16D1, pts can discontinue therapy (tx); all others continue AV through C24, with the option to discontinue if BM-uMRD at C25D1. Assessments: efficacy by 2018 iwCLL criteria, toxicities (tox) by CTCAE v5, MRD by central 8-color flow (10-4 sensitivity) and NGS clonoSEQ (up to 10-6 sensitivity, Adaptive). BH3 profiling work is ongoing, performed as previously described (Ryan J et al., 2016) on peripheral blood (PB) samples after 1 and 3 cycles. Association of BCL-2 dependence with clinical response was compared by an unpaired t-test. Results As of 13 July 2022, 68 pts were enrolled (cohort 1 all-comers: n=37, cohort 2 TP53-aberrant: n=31) in this ongoing study (NCT03580928), with median follow-up of 35 mos (range 2-45). In all 68 pts, median age 63 yrs (range 36-80); 25% ≥70 yrs; 66% male; 60% TP53-aberrant (del(17p) or mut); 24% complex karyotype (≥3 abnormalities); 74% unmutated IGHV. Of the 56 pts evaluable to date at C16D1, 43% (24/56) achieved the primary endpoint BM-uMRD CR. The best ORR is 98% (48% CR, 50% PR). At C16D1, MRD by flow: 86% PB-uMRD, 86% BM-uMRD (Fig 1A). In a subset of 49 pts with available samples, 59% were PB-uMRD by NGS at 10-5 sensitivity (at 10-6, 59% of pts had indeterminate results due to low cell counts). In the 29 pts with TP53-aberrant disease evaluable at C16D1, the best ORR is 100% (52% CR, 48% PR), and 45% (13/29) achieved BM-uMRD CR, MRD by flow: 86% PB-uMRD, 83% BM-uMRD (Fig 1A). There were no differences in response or MRD based on IGHV status. 79% (19/24) of pts in BM-uMRD CR electively discontinued tx after 15 cycles; median time off tx for these pts is 22.9 mos (range 1-30). 2 of the 19 pts who discontinued tx have had MRD only recurrence, and 1 had CLL disease progression; all 3 restarted tx with AV and achieved PR. 3 pts developed Richter's syndrome: 1 with DLBCL after 15 mos on study, and 2 with Hodgkin transformation (one 13 mos after completing study tx and one 12 mos into study tx; both achieved CR to Hodgkin-directed tx). 93% of all pts (63/68) remain progression-free. In all 68 pts, all-grade heme tox included: neutropenia (75%; 37% Gr3/4), thrombocytopenia (73%; 28% Gr3/4), anemia (49%, 3% Gr3). Non-heme tox: headache (78%, 1% Gr3), fatigue (76%, 1% Gr3), bruising (66%, all Gr1/2), nausea (49%, all Gr1/2), diarrhea (40%, 4% Gr3), infusion-related reaction (30%, 4% Gr3), hypertension (27%; 9% Gr3), increased ALT (27%, 1% Gr3), arthralgia (25%, all Gr1), and infection (6% Gr3; 1 case of Gr5 COVID-19 pneumonia). 2.9% (2/68) pts had afib. 14 pts (21%) required dose-reduction of either only A (4%), only V (9%), or both drugs (7%). BH3 profiling is ongoing, and initial data suggest that pts who later went on to achieve CR may have a greater increase in BCL-2 dependence at C4D1 than pts who achieved PR as best response (p=0.05, Fig 1B). Conclusion AVO is a highly active, well-tolerated triplet in a frontline CLL population enriched for high-risk disease, with 83% of TP53-aberrant pts achieving BM-uMRD after 15 mos of tx. Responses are durable, with 93% PFS in all pts at a median follow-up of nearly 3 yrs. Low rates of cardiac and infectious tox were observed. Our data support continued investigation of the MRD-guided, time-limited AVO triplet. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P368: A PHASE II STUDY OF INOTUZUMAB OZOGAMICIN FOR THE TREATMENT OF MEASURABLE RESIDUAL DISEASE-POSITIVE B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Background: Persistence or re-emergence of measurable residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) is strongly associated with shorter relapse-free survival. Inotuzumab ozogamicin (INO) is an anti-CD22 antibody-drug conjugate with the potential to eradicate MRD in B-ALL. Aims: We aimed to evaluate the efficacy of INO in clearing MRD in patients (pts) with persistent or recurrent MRD positivity after treatment with conventional chemotherapy. Methods: This is a single arm phase II trial of pts with B-ALL in complete remission (CR) who did not achieve MRD negativity (MRD-ve) or had MRD-positive (MRD+ve) relapse after at least 3 months (mos) from the start of frontline therapy (i.e. CR1) or 1 month from the start of any salvage therapy (i.e. ≥ CR2). Eligibility was defined by MRD+ve at ≥ 0.01%. MRD-ve was defined as undetectable MRD by flow cytometry at a minimum sensitivity of 10-4 for Philadelphia (Ph) negative (Ph-) B-ALL and undetectable MRD by both flow and PCR at 10-4 for Ph positive (Ph+) B-ALL. INO was given at a dose of 0.6 mg/m2 on D1 and 0.3 mg/m2 on D8 of C1 and 0.3 mg/m2 on D1 and 8 of subsequent cycles (up to 6 total cycles, given every 21-28 days) along with ursodiol prophylaxis. Pts with Ph+ ALL received concomitant TKI, the choice of which was decided by the treating physician. Results: Between 11/2018 and 1/2022, 20 pts with MRD+ve B-ALL, with a median age of 40 years (range, 19-68) were treated. Twelve pts (60%) had Ph+ B-ALL, 11 of whom received concurrent ponatinib and 1 dasatinib. Eight pts were Ph- (including 3 Ph-like ALL). Fourteen pts (70%) were in CR1, and 6 pts (30%) were in ≥ CR2 (3 in CR2, 2 in CR3 and 1 in CR4). Eleven pts (55%) had received prior blinatumomab (blina) and 4 pts (20%) had prior stem cell transplantation (SCT). The median BCR-ABL1 level in Ph+ B-ALL was 0.58% (range, 0.001-17.5%) and median MRD level by flow cytometry in Ph- B-ALL was 0.2% (range, 0.05-1.24%). Twelve pts (60%) became MRD-ve (responders), 10 after cycle 1 and 2 after cycle 2. In the Ph+ group, 6 pts (50%) responded; another 3 pts attained MMR as best response. Six of 8 (75%) Ph- pts responded. The median number of cycles were 3 (range, 1-6). Seven of 9 pts (78%) without prior blina exposure became MRD-ve, compared with 5/11 (45%) pts with prior blina exposure (p=0.22). Patient disposition is shown in Fig. 1A. Amongst the 12 responders, 5 pts were consolidated with ASCT after a median of 3 cycles (range, 1-3) of INO, all in MRD-ve CR pre-ASCT. Three responders (25%) relapsed (including 1 relapse after ASCT). At a median follow-up of 17 mos, 15 pts (75%) are alive, 8 of whom are in continued MRD-ve CR. The estimated 18 mos RFS and OS were 63% and 73% respectively, for the whole group (Fig. 1B), and the 18 mos OS was 87% and 55% for responders and non-responders, respectively. Outcomes were similar between pts with Ph+ ALL vs. Ph- ALL, prior blina exposure vs. no prior exposure, and pts in CR1 vs. ≥ CR2. INO was overall well-tolerated with no grade 4 non-hematological toxicities. Grade 3 non-hematological toxicities included elevated transaminases in 1 pt and veno-occlusive disease in 1 pt without history of prior ASCT. Ten pts (50%) had grade 3-4 hematological toxicities (primarily neutropenia). Image:Summary/Conclusion: Low-dose, fractionated INO is a well-tolerated option for MRD eradication in Ph+ and Ph- B-ALL pts, including in those with prior blina exposure.

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

Olutasidenib (FT-2102) in Combination with Azacitidine Induces Durable Complete Remissions in Patients with mIDH1 Acute Myeloid Leukemia

A Phase II Study of Blinatumomab for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia

A Phase II Study of Blinatumomab for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia

Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Fractionated Inotuzumab Ozogamicin Combined with Low-Intensity Chemotherapy Provides Very Good Outcome in Older Patients with Newly Diagnosed CD22+ Philadelphia Chromosome-Negative B-Cell Precursor Acute Lymphoblastic Leukemia: First Results from the EWALL-INO Study

Post-Transplant Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine for Prevention of Relapse

Post-Transplant Vaccination with a Personalized Dendritic Cell/AML Fusion Cell Vaccine for Prevention of Relapse

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study

Efficacy of Tisagenlecleucel in Adult Patients (Pts) with High-Risk Relapsed/Refractory Follicular Lymphoma (r/r FL): Subgroup Analysis of the Phase II Elara Study

Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

Retrospective Comparison between 12-Gray and 8-Gray Total Body Irradiation (TBI) before Allogeneic Hematopoietic Cell Transplantation in Patients with Acute Lymphoblastic Leukemia in First Complete Remission

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

High-Dose Methotrexate Is Not Associated with Reduction in CNS Relapse in Patients with Aggressive B-Cell Lymphoma: An International Retrospective Study of 2300 High-Risk Patients

Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

Long Term Follow-up and Combined Phase 2 Results of Eprenetapopt (APR-246) and Azacitidine (AZA) in Patients with TP53 mutant Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia (AML)

ALL-440: Promising Safety and Efficacy Results from an Ongoing Phase 1/2 Study of Pembrolizumab in Combination with Blinatumomab in Patients (pts) with Relapsed or Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

<h3>Background:</h3> Blinatumomab, a bispecific anti-CD19/CD3 antibody, demonstrated single-agent efficacy with 42% CR/CRh in R/R B-ALL. Upregulation of immune inhibitory molecules has been shown to confer resistance to blinatumomab. Here, we set out to test the combination of pembrolizumab and blinatumomab in a phase 1/2 trial (NCT03512405). <h3>Methods:</h3> Pts [≥18 years old (yo); ECOG <1] with CD19+ R/R B-ALL received blinatumomab 9 mcg/day on days 1–7 and 28 mcg/day on days 8–28 in cycle 1 and on days 1–28 in subsequent cycles. Pembrolizumab was given on day 15 (schedule A) or day 22 (schedule B) in cycle 1 and on days 1 and 22 in subsequent cycles. Cycle length was 42 days, except 35 days for cycle 1 in schedule A. We completed the schedule A phase 1 portion with primary objectives of safety, tolerability, and recommended phase 2 dose (RP2D) using the "3+3" design. <h3>Results:</h3> As of February 1, 2021, 7 pts were enrolled to phase 1, with one unevaluable. Six treated and evaluable pts received a median of 2 (1–5) cycles of treatment. At baseline, the median age was 51 yo (29–74) with median 2 (2–4) prior lines of regimens and median 29% (0–83) BM blasts. Two pts had extramedullary disease. In cycle 1, all 6 pts experienced grade (gr) 1–2 cytokine release syndrome. Neurologic toxicities were all reversible with only 1 ≥ gr3 AE. All-non-hematologic gr3 toxicities, were reversible. No dose-limiting toxicity, ≥ gr4 non-hematologic toxicity, or treatment-related deaths were seen. Five of 6 evaluable pts (83%) achieved MRD-negative CR after a median of 1 (1–2) cycle. Three pts in CR received alloHCT, all engrafted. With a median follow-up of 2.8 (1.1–9.6) months, 4 CRs are ongoing (1 post-transplant), and 5 of 6 pts are still alive at the data cut-off. <h3>Conclusions:</h3> The combination of pembrolizumab and blinatumomab in phase 1 of this study in pts with B-ALL was deemed safe with a manageable side effect profile and encouraging anti-leukemic activity. The study is now open for phase 2 with the primary objective of overall response rate.

AML-212: Treatment Free Remission (TFR) After Ceasing Venetoclax-Based Therapy in Responding Patients with Acute Myeloid Leukemia

<h3>Context:</h3> Ph3 studies confirmed the benefit of adding venetoclax (VEN) to hypomethylating agents (HMA) or low-dose cytarabine (LDAC) in older/unfit patients with newly diagnosed AML with a median response duration of 12-18 months(mo). It is currently unknown whether patients should continue therapy until progression and whether elective therapy cessation could detrimentally impact outcomes. <h3>Objective:</h3> To compare the natural history of patients receiving ≥12mo of VEN-based therapy in first remission. <h3>Design, Setting and Patients:</h3> Retrospective analysis of patients with AML receiving VEN plus HMA or LDAC for ≥12mo and in sustained first remission from three institutions. Two treatment approaches were compared: elective therapy cessation in remission followed by monitoring (STOP) or continued therapy until relapse (CONT). <h3>Main Outcome Measures:</h3> Primary: treatment free remission (TFR), progression free survival (PFS). Secondary: overall survival (OS), molecular correlates of PFS. <h3>Results:</h3> 28 patients were identified: 14 in STOP, 14 in CONT. Median follow-up was 60.9mo. Treatments included VEN-HMA (68%) or VEN-LDAC (32%). Median time on therapy (TOT) was shorter in STOP (19.0mo <i>vs</i> 32.7mo) and fewer cycles were received in STOP (median 17 <i>vs</i> 30). In STOP, treatment cessations were due to patient request (43%) or medical (57%), with a median TFR of 45.8m (95%CI 9.5-not reached). 7/14(50%) have relapsed, with 3 relapsing >31mo of TFR. In CONT, 9/14(64%) have relapsed, with 6 relapsing >24mo of therapy. Cytogenetic evolution was more frequently observed at relapse in CONT (67% <i>vs</i> 43%). A landmark analysis was performed (landmarked at median TOT in STOP to exclude lead-time bias from early relapses in CONT), which revealed no significant difference in PFS (p=0.14) or OS (p=0.24). 10/15 patients with <i>NPM1</i> and/or <i>IDH2</i> mutations remain in remission (6/8 STOP, 4/7 CONT), of which 9/10 achieved undetectable MRD (by flow/qPCR). 1 had detectable <i>IDH2</i> mutation at pre-leukemic levels. Multivariate analysis showed that mutant <i>NPM1</i> is an independent predictor of OS (HR for death 0.002, p=0.037) and PFS (HR for relapse 0.012, p=0.024). <h3>Conclusion:</h3> Durable TFR is highest among patients with <i>NPM1/IDH2</i> mutations and MRD negative after ceasing >12 months of VEN-based treatment. A prospective, randomised, discontinuation study in pts in CR_MRDneg after 12 months of VEN-based therapy should be considered.

Maintenance Rituximab or Observation after Frontline Treatment with Bendamustine-Rituximab (BR) for Follicular Lymphoma: A Real World Analysis Across 13 US Cancer Centers

Maintenance Rituximab or Observation after Frontline Treatment with Bendamustine-Rituximab (BR) for Follicular Lymphoma: A Real World Analysis Across 13 US Cancer Centers

Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia with t(6;9)(p23;q34);dek-NUP214 Is Followed By a Low Relapse Risk and Favorable Outcome in Early Phase- a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

▪Introduction: Allogeneic stem cell transplantation (allo-SCT) is the best post-remission treatment for patients (pts) with acute myeloid leukemia (AML) harboring high-risk genetic features. AML with translocation t(6;9)(p23;q34) (t(6;9) AML) is a rare but well-characterized AML subtype, commonly associated to FLT3 internal tandem duplication (FLT3 -ITD). It constitutes a high-risk cytogenetic entity, with a reported high relapse risk after conventional chemotherapy. Therefore, allo-SCT in first complete remission (CR1) is now commonly recommended in these pts. However, comprehensive studies analyzing the outcome of allo-SCT in this setting are lacking.Patients and methods: We included 182 adult pts with t(6;9) AML who received an allo-SCT from 2000 to 2015, from matched related (MRD), unrelated (MUD), or cord blood donors. Statistical analyses were performed using R v3.0.1 and SPSS v19. Endpoints included leukemia-free survival (LFS), relapse incidence (RI), non-relapse mortality (NRM), overall survival (OS), acute and chronic GVHD, and GVHD-free/relapse-free survival (GRFS). All outcomes were measured from the time of stem cell infusion.Results: Median age was 42 years (18-65 years) and 51% were male. 166 out of 182 pts (91%) presented as de novo AML. An associated cytogenetic abnormality was documented in 20 pts (11%). Among 63 (34%) pts with available information on FLT3 status, 39 (62%) carried a FLT3-ITD mutation. Status at allo-SCT was first CR (CR1) in 130 pts (71%), CR2 in 14 (8%), and non-CR AML in 38 pts (21%), respectively. The type of conditioning regimen was myeloablative in 121 (66%) of the pts. In most pts (n=129, 71%) graft source was peripheral blood. The donor was a MRD in 85 (47%), MUD in 88 (48%) and an unrelated cord blood in 9 (5%) of the pts, respectively (Table 1). With a median follow-up of 28 months, 2-year LFS was 46.7% (95% CI:38.6-54.8), OS 51.9 % (43.7-60.1), RI 26.4% (19.7- 33.6), NRM 26.9 % (20-34.2) and GRFS 33.7% (25.8-41.6). Acute GvHD grade II-IV and 2-year chronic GvHD were 26.3 % (19.9 - 33.1) and 35.7 % (27.8 - 43.6), respectively. In the univariate analysis, disease status at time of allo-SCT was the most important prognostic factor, with the following 2-year outcomes in CR1, CR2, and non-CR: RI of 19.3% (12.3-27.5), 31% (8.6-57.1) and 48.8% (31-64.4, p<0.001); LFS of 55.6% (45.8-65.3), 31.7% (6.3-57.2) and 22.7% (8.5-36.9, p<0.001); OS of 60% (50.2-69.8), 31.4% (6.1-56.8)], and 33.1% (17-49.2, p<0.001); and GRFS of 40.2% (30.2-50.1), 23.8% (0.4-47.2) and 17.2% (4.4-30.1, p<0.001), respectively (Figure 1). Reduced intensity conditioning (RIC) was associated with an increased risk of RI, without impact on LFS or OS. Secondary leukemia was associated with a reduced LFS. A longer interval (i.e., >median value, 4.8 mos.) from diagnosis to allo-SCT was associated with higher NRM. Finally, FLT3 -ITD status and additional cytogenetic abnormalities did not influence prognosis.In pts in CR1, the main causes of death were NRM (infection, n=15; GVHD, n=9), whereas recurrent of the leukemia was the cause of death in only 12 pts. Of note, pts harboring FLT3 -ITD had a relatively favorable outcome, with a 2-year RI, NRM, LFS, OS, and GRFS of 17.2% (3.7-39.1), 27.7% (8.9-50.5), 55.1% (30.8-79.5), 57.5% (32.1-82.8), and 42.9% (19.2-66.5), respectively. In the multivariate analysis for pts in CR1, RIC was the only significant prognostic factor for RI (HR=5.79, 1.82-18.40; p=0.00293), without impact on LFS or OS.Conclusions: Allo-SCT in patients with t(6;9) AML results in a relatively favorable outcome when performed in CR1, with approximately 17% relapse rate, suggesting the existence of a beneficial GvL effect in this context. Notably FLT3 -ITD did not show a negative impact in this entity. This study supports the recommendation to subject pts with t(6;9) AML to allo-SCT while being in CR and emphasize that allo-SCT in CR as the best current therapeutic option for these pts. [Display omitted] DisclosuresSocié:Alexion Pharmaceuticals, Inc.: Consultancy. Mohty:Sanofi: Honoraria, Speakers Bureau.

Early and Profound Exhausted Phenotype of Central Memory and Memory Stem T Cells in the Bone Marrow of AML Patients Characterizes and Predicts Relapse after Allo-HSCT

Background: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) is the only cure for high-risk acute myeloid leukemia (AML). Unfortunately, relapse remains the major cause of death after HSCT. We investigated if T-cell dysfunction is associated to post-transplant relapse.Patients and Methods: We longitudinally analysed T-cell dynamics in bone marrow (BM) and peripheral blood (PB) of 32 AML patients receiving HSCT from HLA-matched (20 pts) or HLA haploidentical (Haplo, 12 pts) donors. BM and PB samples were collected 60 days after HSCT and at relapse (median 237 days; 16 pts) or, when complete remission was maintained, at 1 year (CR; 16 pts). 10 healthy donors (HD) were used as controls. Samples were analysed by polychromatic flow cytometry for the expression of inhibitory receptors (IR) on CD4 and CD8 T-cell subsets defined by CD45RA, CD62L and CD95 expression. Results were also analysed with BH-SNE, an unbiased dimensionality reduction algorithm. To evaluate T-cell function and specificity, CD107a expression, cytokine profiles and killing of autologous blasts were quantified.Results: After Haplo-HSCT, PD-1, CTLA-4, 2B4 and Tim-3 were expressed in BM and PB T cells at higher percentage when compared to HD and independently from the clinical outcome. Conversely, after HLA-matched HSCT, patients who relapsed displayed a higher frequency of BM-infiltrating T cells expressing PD-1, CTLA-4 and Tim-3 than CR pts (p<0.05) and HD (p<0.01). When investigating each T-cell subset, in both HD and CR pts the IR expression was confined to effector memory and effectors; at relapse, instead, PD-1, 2B4, KLRG1 and Tim-3 were more commonly expressed in BM-infiltrating central memory (TCM) and memory stem T cells (TSCM, p<0.01). Interestingly, at relapse leukemia expressed PD-L1 (9/9 cases) and Galectin-9 (6/9) and the latter linearly correlated with Tim-3+ BM CD8 T-cell percentages, suggesting a preferential role for this immunomodulatory axis after HSCT. Based on phenotype similarities, the BH-SNE algorithm separated HD and HSCT samples in bi-dimensional maps and identified T cell clusters that associated with relapse (32) and were characterized by T cells co-expressing high levels of multiple IRs.Consistent with the exhausted phenotype, BM CD8 T-cells at relapse displayed lower degranulation ability and IL-2 production compared to CR (p<0.05). The ability to degranulate and to produce pro-inflammatory cytokines of BM-T cells expressing at least 1 inhibitory receptor (IR+) could be recovered in five patients upon polyclonal stimulation in vitro with high doses of IL-2, suggesting that T-cell dysfunction can be efficiently reversed. Upon challenge with autologous leukemic blasts, higher proportion of IR+ lymphocytes upregulated HLA-DR (p<0.05), granzyme A and B (p<0.001) and killed blasts (p<0.05) compared to IR- T cells. In addition, IR+ but not IR- cells were efficiently expanded by stimulation with matched Leukemic Antigen-Presenting Cells (fold increase 146 and 3, respectively).Interestingly, we observed that, at day 60 after HLA-matched HSCT, BM CD8 TSCM and TCM cells from patients who shall subsequently relapse already expressed PD-1, Tim-3 and LAG3 at higher percentage when compared to patients who shall maintain long-term CR (p<0.05). Co-expression of at least 3 IR on TSCM and TCM T-cells, but not on effectors, or TEM, at this early time-point was associated with significantly decreased disease free survival.Conclusions: After HSCT, the molecular signature of exhausted CD8 cells in relapsing patients includes PD-1, CTLA-4, 2B4 and Tim-3, expressed on early differentiated T cells. Exhausted BM-T cells are preferentially enriched in specificities directed against leukemic blasts. Taken together, these results highlight a wide, though reversible, immunological dysfunction mediated by AML relapsing blasts. Interestingly, the analysis on early time points suggests that the exhausted phenotype may be predictive of leukemia relapse. [Display omitted] DisclosuresBondanza:TxCell SA: Research Funding; Menarini Biotech: Consultancy; Molmed Spa: Research Funding. Bonini:MolMed: Consultancy.

Thiotepa-Busulfan-Fludarabine in Comparison to Busulfan-Cyclophosphamide As Myeloablative Conditioning Regimen Pre Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia: A Study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)

Background. Busulfan plus Cyclophosphamide (BuCy) is the traditional myeloablative conditioning (MAC) regimen pre allogeneic stem cell transplantation (SCT) for acute myelogenous leukemia (AML). The Thiotepa, Busulfan, Fludarabine (TBF) protocol was initially developed for cord blood SCT and subsequently employed in haploidentical SCT; however, there is limited data assessing the TBF regimen in SCT from sibling (MSD) and unrelated donor (URD) for AML and no comparison between the two preparative protocols has been performed.Patients and methods. We analyzed transplantation outcomes of 2523 adult patients (pts) with AML in remission (CR1, CR2+) aged 18-50 years that underwent a first SCT from MSD or URD between 2007 and 2015 and reported to the ALWP of the EBMT. One hundred and three patients received TBF and 2370 pts received BuCy. Pts who received oral busulfan, manipulated grafts, or transplant from <=8/10 HLA-matched donor were excluded. All pts received MAC regimen (defined by Busulfan dose>=9.6 mg/kg). As compared to BuCy, the TBF group included significantly older pts, who were transplanted more recently, had longer interval from diagnosis to transplant, and were more likely to have received BM as stem cell source and URD as donor type. In order to minimize the bias due to differences in pts characteristics, a 1:3 pair-matched analysis was performed. One hundred and forty-six pts receiving TBF were compared with 438 pts receiving BuCy; matching factors included age, year of SCT, disease status at SCT, interval from diagnosis to SCT, donor type, CMV serostatus of both the donor and patient, stem cell source, GVHD prophylaxis and use of anti-thymocyte globulin.Results. With a median follow-up of 22 months, incidence of grade II-IV and III-IV aGVHD after TBF vs BuCy was 29% vs 23% (p=0.23) and 15% vs 8% (p=0.04), respectively. The 5-year cumulative incidence of cGVHD and severe cGVHD was 36% vs 43% (p=0.66) and 16% vs 22% (p=0.72) for TBF vs BuCy, respectively. The 1-year and 5-year non-relapse mortality (NRM) rates were 10% and 22% for TBF vs 9% and 13% for BuCy, respectively (p=0.36). The 1-year and 5-year relapse incidence (RI) rates were 17% and 25% for TBF vs 21% and 37% for BuCy, respectively (p=0.32). No significant difference was observed in leukemia-free survival (LFS), being the 1-year and 5-year LFS rates 73% and 53% for TBF vs 70% and 50% for BuCy, respectively (p=0.56). Overall survival (OS) was also similar, being 80% and 54% for TBF vs 79% and 59% for BuCy, respectively (p=0.88). The composite endpoint graft-vs-host disease-free, relapse-free survival (GRFS) at 5 years was 48% for TBF and 40% for BuCy (p=0.48). Notably, when the analysis was restricted to pts in CR1, a significant difference in RI rate was observed (1-year and 5-year RI: 10% and 18% for TBF vs 20% and 38% for BuCy, respectively, p=0.003) leading to a trend for better LFS for TBF as compared to BuCy (1-year and 5-year LFS: 78% and 57% for TBF vs 72% and 50% for BuCy, respectively, p=0.07), with no difference in OS. When examining separately pts receiving SCT from MSD or URD, no significant difference was observed between TBF and BuCy regimens in terms of transplant outcome. In multivariate analysis, TBF was associated with lower RI compared to BuCy (HR 0.6, p=0.02), while no difference was observed in terms of NRM, LFS, OS and GRFS (HR 0.8, p=0.12 for GRFS). TBF was also associated with lower incidence of cGVHD (HR 0.7, p=0.04) and a trend for lower incidence of severe cGVHD (HR 0.6, p=0.1); on the contrary we observed a trend for higher incidence of grade III-IV aGVHD following TBF as compared to BuCy (HR 1.79, p=0.06).Conclusions. These results suggest that TBF is a valid myeloablative conditioning pre MSD or URD SCT for AML pts < 50 years of age and in remission, with similar transplantation outcome as compared to the traditional BuCy preparative regimen. These data may serve as the scientific background for a well designed randomized two arm study comparing TBF to BuCy as MAC pre SCT in AML pts below the age of 50 years in CR. [Display omitted] DisclosuresSavani:Jazz Pharmaceuticals: Speakers Bureau.