Eradication Of Minimal Residual Disease Research Articles

Improved Survival of Adolescents and Young Adults (AYA) Patients Aged 14-40 Years with First Relapse of Acute Lymphoblastic Leukemia Using Pediatric-Inspired Chemotherapy Salvage Protocol (R3 induction protocol)

Background: Although survival of adolescent and young adults (AYA) with acute lymphoblastic leukemia (ALL) has improved using pediatric-inspired protocols, the outcomes of those who relapse remain poor using adult chemotherapy salvage-regimens that have historically incorporated high dose Ara-C based regimen, with long term-survival of less than 10%. The CR rate with blinatumomab for salvage in adult ALL is 34% with a median survival of 7.7 months, with an OS of less than 30% at 18 months. In contrast, pediatric salvage regimens have historically been based on multi-agent therapy and have reported superior outcomes. The ALLR3 protocol for relapsed ALL in patients up to the age of 18 years reported a CR rate of 97% and an overall survival of 72%. We therefore aimed to analyze the outcomes of young adolescents and adults treated on the R3 regimen +/- blinatumomab. Methods: Seventeen AYA patients with Philadelphia-negative ALL aged between 14 and 40 years who relapsed after first-line therapy and treated with ALLR3-protocol were identified. Relapses were classed as very early (<18 months from diagnosis) early (>18m from diagnosis and <6 months from end of therapy) and late (>6 months from end of therapy). The protocol consisted of vincristine (1.5mg/m2 IV D3,10,17,24); mitoxantrone ( 10mg/m2 IV d1 &2); PEG-asparaginase (1000 u/m2 IV d3 & 17); dexamethasone (10mg/m2 BID day d1-5 and d15-20); and intrathecal methotrexate (12mg d1 & d8) were identified. Patient aged 30-40 years received L-Asparaginase instead of PEG-Asparaginase, and 8mg/m2 of dexamethasone instead of 10mg/m2. Patients' characteristics, response rate (RR) and overall survival (OS) were analyzed. Patients who achieved minimal residual disease (MRD) negative CR proceeded with an allogeneic transplant. MRD-positive patients received blinatumomab followed by a transplant. Results: The median age at relapse was 16 years (14-40 years), 88.2% of patients were B-cell ALL and 11.8% were T-cell ALL. Most patient had standard cytogenetics on presentation (76.5%) and were CNS negative (82.4%). Relapses were very early, early or late in 2 (12%) , 5 (29%) , and 7 (41%) of cases, respectively. Relapses were isolated bone marrow (BM), isolated extramedullary (EMD) or combined BM and EMD in 14 (82%),1 (6%) and 2(12%) cases, respectively. Overall complete remission (CR) rate was 60% at the end of R3 induction; CR with negative minimal residual disease (MRD negative, <10−4 cells) at the end of R3-induction was achieved in 47.1% of patients, while 11.8% of patients had CR with positive MRD (≥10−4 cells) who received Blinatumumab thereafter with eradication of MRD. Refractory disease was seen in 41.2% of patients. Almost all patients who responded to R3 proceeded to allogeneic stem cell transplant (88.8%). Eight patients died (47%), but only one patient died because of treatment-related sepsis, while the other 7 patients died because of disease-related causes. At a median follow up of 4 years, OS was 47.3%. Conclusion: Compared to traditional adult-based chemotherapy regimens and antibody therapies used in relapsed ALL, the use of pediatric-inspired protocol (R3) in relapsed AYA-ALL patients showed favorable response rates and overall survival. Further trials are required of pediatric inspired salvage regimens, preferably incorporating antibody therapies in adult patients, especially in 1st relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time-Limited Maintenance with Ibrutinib after First-Line Therapy and the Incremental Impact on Minimal Residual Disease (MRD) for Patients with Chronic Lymphocytic Leukemia (CLL)

Background: Inhibitors of Bruton's tyrosine kinase (BTKi) are approved and clinically used as indefinite treatments (until disease progression) irrespective of the depth of response in patients (pts) with CLL. Despite impressive, sustained efficacy, their ability (as single agent) to target residual disease clone post induction treatment in CLL is not well established. As indefinite treatment is associated not only with cumulative toxicity but also high cost and compromised quality of life, we investigated the benefit of time-limited maintenance treatment (3 years) with ibrutinib to assess the ability of a BTKi to further deepen antitumor response achieved post induction treatment. Methods: CLL pts (n=35) who had residual disease (by clinical or molecular assessment) after primary induction treatment were enrolled on a prospective phase 2 trial (NCT02649387). MRD assessed in blood (PB)/bone marrow (BM), was determined by 8-color flowcytometry (1x10-4) and defined as ≥1 CLL cell per 10,000 leukocytes or ≥0.01%. Patient were eligible if they had detectable residual (non-progressive) disease within 1 year of completing induction and no prior ibrutinib (or other BTKi) treatment. Ibrutinib 420mg PO QD was given on days 1-28 of a 28-day cycle for up to 36 cycles. Clinical (iwCLL 2008 response criteria) and molecule response MRD (on PB) was done at baseline and then every 3 cycles while on treatment. BM-MRD evaluation was conducted only if PB-MRD was negative (on two separate timepoints 3 months apart). Monitoring of the PB-MRD was continued for 24 months after completing time-limited maintenance with ibrutinib. Cumulative toxicity was assessed using the CTCAE v4.0 and iwCLL criteria. Results: Patient characteristics are summarized in Table 1. In 34 out of 35 (97%) patients, obinutuzumab alone was used as induction therapy. The median follow up is 38.6 months (range 0.9-73.2) and the median number of maintenance cycles completed is 34 (range 1-36). Of the 33 patients assessed for PB-MRD, 8 (24.2%) pts became MRD- on at one assessment. Five patients had BM-MRD assessment with 1 (2.8%) converting to MRD-. The median time to achievement of MRD- was 4.4 months (range 2.7-34.7). We noted that single agent ibrutinib was unable to deliver stringent MRD-negativity (defined as achievement of MRD- status both in PB and BM sustained over 2 consecutive evaluations at least 3 months apart).To assess if pre-maintenance response could impact MRD post-treatment; we note that out of the 8 pts that achieved MRD-, 2 (25%) started with CR and 6 (75%) with nPR/PR at registration. Deepening of response was noted in 5 pts (14.3%) after a median of 14 cycles [3 (8.6%) pts improved nPR to CR and 1(2.9%) went from nPR to CRi and 1 (2.9%) went from a CRi to a CR]. Nine patients proceeded to subsequent treatment with the median time to next treatment (mTTNT) of 32.5 m (range: 12.1 - 61.0). One patient died due to a failure to thrive and acute kidney injury on dialysis and six pts have progressed. The median PFS for the entire cohort was 41.1 m (95% CI: 39.8 - NE). The most commonly reported adverse events (AEs) (seen in >10% pts) regardless of attributions were thrombocytopenia (24 pts; 68.6%), anemia (12 pts; 34.3%), neutropenia (9 pts; 25.7%), lymphopenia (9 pts; 25.7%), hypertension (9 pts; 25.7%), leucopenia (6 pts; 17.1%), fatigue (5 pts; 14.3%), headache (4 pts; 11.4%), and skin infections (4 pts; 11.4%). Atrial fibrillation (AFib) was noted in 3 pts (8.6%). Conclusion: We conclude that BTK targeting with ibrutinib alone although able to clear PB-MRD (24.2%), had limited efficacy to eradicate BM-MRD (2.8%) demonstrating a differential impact in these two disease compartments. While the rate of complete MRD eradication was not necessarily high (when compared to recent data with BTKi/BCL2i combination regimens) MRD-kinetics over time demonstrated progressive decrease in disease burden and response improvement with maintenance treatment. The sequential single agent treatment approach was well tolerated, and the time-limited therapy aimed at minimizing cumulative toxicity seemed to be effective in lowering rate of Afib (compared to historical control ~16%). This data warrants further investigation of time-limited maintenance therapy with newer, more favorably tolerated BTKi and/or Bcl2i post induction treatment(s) to optimize response vs. cumulative toxicity. Further evaluation of sequential time-limited treatments in CLL is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract CT525: GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML

Abstract Background: The presence of minimal residual disease (MRD) in patients that are in complete remission (CR) is associated with an increased risk of relapse and shorter survival in acute myeloid leukemia (AML). Eradication of MRD may improve outcomes for patients with AML; however, to date, therapeutic strategies that target MRD in AML are limited. Vδ1+ γδ T cells are a subset of γδ T cells, that recognize malignant cells through expression of a diverse repertoire of natural cytotoxicity receptors (NCRs) that interact with cognate stress ligands specifically upregulated on diseased cells. Upon target cell recognition, Vδ1+ γδ T cells mediate anti-tumor activity through the direct lysis of transformed cells. The therapeutic potential of human Vδ1+ γδ T cells for the treatment of AML is supported by published preclinical data that show strong and broad antileukemic activity of Vδ1+ γδ T cells in vitro and in vivo (Almeida et al 2016; Di Lorenzo et al 2019). GammaDelta Therapeutics has developed GDX012, a novel allogeneic cell therapy that is enriched for Vδ1+ γδ T cells for the treatment of AML. The cryopreserved drug product is manufactured from a healthy donor leukapheresis that has undergone αβ T cell depletion prior to expansion. GDX012 is a viable (&amp;gt;70% live), pure (CD45 &amp;gt;90%) suspension for IV infusion consisting mainly of Vδ1+ γδ T cells (&amp;gt;60%) expressing a variety of cellular markers that contribute to their function, recognition and targeting of malignant cells. Analysis of the biodistribution of GDX012 in therapeutic murine xenograft models further supports the clinical application of GDX012. When administered systemically, GDX012 shows homing to the bone marrow and is detected for at least 28 days. This suggests that, in addition to high cytotoxic activity against AML blasts, GDX012 also has the capacity to home to and persist in the specific niche where MRD is detected. Study design: This phase 1, open-label, first-in-human study is comprised of two parts 1) Dose Escalation using 3 + 3 design to sequentially evaluate 4 doses of GDX012; 2) Dose Expansion including at least 10 additional patients at the MTD. The primary objective is to determine safety, tolerability, and the MTD of GDX012. The secondary objective is to evaluate the preliminary antileukemic activity of GDX012 based on detection of MRD in bone marrow. Exploratory objectives will evaluate the kinetics of GDX012 and infiltration in bone marrow and assessment of cytokines in blood and bone marrow. Key eligibility criteria include patients aged ≥18 years of age with histologically confirmed AML who are MRD positive by flow cytometry. Patients must be in first or subsequent CR or CR with incomplete hematological recovery. Eligible patients will undergo lymphodepletion with fludarabine for 4 days and cyclophosphamide for 3 days followed by infusion of GDX012. Patients will be followed for safety for at least 100 days post GDX012 infusion. Antileukemic activity will be evaluated from the bone marrow biopsy at Day 30. Up to 34 patients will be enrolled across 6 US sites. Recruitment to Cohort 1 is ongoing. Clinical trial registry number: NCT05001451 Citation Format: Lisa J. Knowles, Mohsan Malik, Oliver Nussebaumer, Alice Brown, Sandra van Wetering, Michael Koslowski. GDX012U-001 A phase 1, open-label, dose escalation, and dose expansion study to assess the safety, tolerability, and preliminary antileukemic activity of GDX012 in patients with MRD positive AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT525.

Panobinostat, a Pan-HDAC Inhibitor, Substantially Decreases the Quiescent Population of Leukemic Cells either in Monoculture or in Co-culture with Bone Marrow Stromal Cells.

Background: It is increasingly evident that interactions between leukemic cells and their niches can have profound effects on clinical outcomes and have been contributed to the failure in treatment and drug shortage in the eradication of minimal residual disease, at least in part, through moving the cells from proliferative state to quiescent state. Objectives: We, therefore, investigated the effects of different bone marrow stromal cells (BMSCs) on the induction of quiescence and tested the advantage of pan-HDAC inhibitor panobinostat in the induction of apoptosis and targeting the quiescence cells of APL-derived (NB4) and CML-derived (K562) cell lines. Methods: We firstly evaluated the effect of BMSCs including mesenchymal stem cell (MSC), osteoblast, and macrophage on the induction of NB4 and K562 cells quiescence in co-culture models. Next, the alterations in mRNA expression of quiescence-related genes and leukemia-driver oncogenes were evaluated in different models. Finally, the anti-leukemic effects of panobinostat were evaluated, using MTT assay and evaluation of apoptosis and G0 population. Results: Upon 10 days of co-culture with stromal cells, we found that leukemic cells significantly accumulated in the G0 phase. The co-cultured cells also depictured an overall overexpression of most quiescence promoter genes. The oncogenes were underexpressed in the majority of co-cultured models. The results also showed that although panobinostat could induce apoptosis in co-cultured cells, its effect on the reduction of the G0 population was more striking. Conclusions: These data propose that leukemia cells' quiescence state induced by stromal cells is reversible by HDAC inhibition and panobinostat could be a potentiate drug for eradication of treatment-resistance quiescence leukemic cells.

Pretransplantation minimal residual disease monitoring by multiparameter flow cytometry predicts outcomes of AML patients receiving allogeneic hematopoietic stem cell transplantation

Background and purposeIs minimal residual disease (MRD) monitoring by multiparameter flow cytometry (MFC) prognostic for acute myeloid leukemia (AML) patients before allogeneic hemopoietic stem cell transplantation (allo-HSCT)? And if so, what level of MRD eradication can be used to help guide the timing of HSCT? Can haplo-HSCT improve the prognosis of AML patients with MRD positive? To figure out these questions, we initiated this retrospective study. Methods96 AML patients were included retrospectively and divided into 5 groups, according to pre-transplantation MRD levels (from 5 × 10−2 to <1 × 10−4), to analyze the overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR). Secondly, we compared the prognosis of MRD-negative (MRDneg) and MRD-positive (MRDpos) AML patients (cutoff value = 1 × 10−3) who underwent allo-HSCT, and further analyzed the prognosis of MRDpos patients after received different transplantation modalities. ResultsIt is found that the 2-year OS and DFS of MRD negative group were better than the MRD positive group, and that the deeper the eradication of MRD before transplantation, the better the prognosis of patients. The CIR in patients received HLA-identical transplantation, was higher in the MRDpos than in the MRDneg. Haploid transplantation reduced the CIR disparity between MRDpos and MRDneg group. Subsequently, in AML patients who remain MRD positive before HSCT, we show that haplo-HSCT offered a better prognosis than HLA-identical transplantation (MSDT and MUDT). ConclusionIt is suggested that achieving MFC-MRD <10−3 (10−4 or even better) before allo-HSCT could reduce the relapse of AML and improve OS and DFS significantly, while haplo-HSCT may be preferred for patients not achieving MRD negativity.

Clinical Value of Measurable Residual Disease in Acute Lymphoblastic Leukemia

Measurable (minimal) residual disease (MRD) status in acute lymphoblastic leukemia (ALL) has largely superseded the importance of traditional risk factors for ALL, such as baseline white blood cell count, cytogenetics, and immunophenotype, and has emerged as the most powerful independent prognostic predictor. The development of sensitive MRD techniques, such as multicolor flow cytometry (MFC), quantitative polymerase chain reaction (PCR), and next-generation sequencing (NGS), may further improve risk stratification and expand its impact in therapy. Additionally, the availability of highly effective agents for MRD eradication, such as blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapies, enabled the development of frontline regimens capable of eradicating MRD early in the treatment course. While long-term follow-up of this approach is lacking, it has the potential to significantly reduce the need for intensive post-remission treatments, including allogeneic bone marrow transplantation, in a significant proportion of patients with ALL.

Treatment of Classic Hairy Cell Leukemia: Targeting Minimal Residual Disease beyond Cladribine.

Simple SummaryStandard treatment with purine analogues facilitates a near normal life expectancy in the majority of patients with classic hairy cell leukemia (HCL), a rare chronic B-cell malignancy. However, nearly all patients ultimately relapse and require retreatment, while drug-induced myelotoxicity accumulates predisposing to infectious complications and, possibly, secondary malignancies. Persistence of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. New insights into disease biology initiated design and investigation of several new, chemotherapy-free, targeted drugs with encouraging efficacy in early clinical trials aimed at enhancing eradication of MRD and optimizing drug tolerability. This review provides an update on recent clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by profound pancytopenia and frequent infectious complications due to progressive infiltration of the bone marrow and spleen. Lacking effective treatment options, affected patients were confronted with a dismal survival prognosis of less than 5 years when the disease was first described in 1958. Tremendous therapeutic advances were accomplished with the introduction of purine analogues such as cladribine in the 1990s, facilitating a near-normal life expectancy in most HCL patients. Nevertheless, nearly all patients eventually relapse and require successive retreatments, while drug-associated myelotoxicity may accumulate and secondary malignancies may evolve. Detection of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. In the last decade, novel biologic insights such as identification of the driver mutation BRAF V600E have initiated the development and clinical investigation of new, chemotherapy-free, targeted drugs in HCL treatment, with encouraging efficacy in early clinical trials aimed at boosting eradication of MRD while optimizing drug tolerability. This review summarizes current clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.

Using Circulating Tumor DNA for Colon Cancer Adjuvant Therapy: To Be or Not to Be?

Detection of circulating tumor DNA (ctDNA) postoperatively is prognostic for recurrence for patients with stage III colon cancer. Those with sustained undetectable ctDNA will likely be cured. Eradication of minimal residual disease (per ctDNA clearance) with chemotherapy did not occur in most ctDNA-positive patients and led to eventual disease relapse.See related article by Henriksen et al., p. 507.

Clofarabine increases the eradication of minimal residual disease of primary B-precursor acute lymphoblastic leukemia compared to high-dose cytarabine without improvement of outcome. Results from the randomized clinical trial 08-09 of the Cooperative Acute Lymphoblastic Leukemia Study Group.

Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia (ALL). To this end, we investigated the therapeutic potential of clofarabine in primary ALL in trial CoALL 08-09 (clinicaltrials gov. identifier: NCT01228331). The primary study objective was the minimal residual disease (MRD)- based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2,500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 versus 79 of 143 randomized patients per arm reaching MRD-negativity (c2 test P=0.03, leftsided P [Fisher’s exact test]=0.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5-year EFS: clofarabine 85.7, SE=4.1 vs. HIDAC 84.8, SE=4.7 [P=0.96]; OS: 95.7, SE=1.9 vs. 92.2, SE=3.2 [P=0.59]), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.

Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy

Initial Results of Ibrutinib Plus Venetoclax in Relapsed, Refractory CLL (Bloodwise TAP CLARITY Study): High Rates of Overall Response, Complete Remission and MRD Eradication after 6 Months of Combination Therapy

Negative Minimal Residual Disease Associated with Extended Response to Moxetumomab Pasudotox in Patients with Relapsed/Refractory Hairy Cell Leukemia: Long-Term Follow-up of Bone Marrow Immunohistochemistry Analyses from a Phase 1 Study

The clinical significance of minimal residual disease (MRD) in patients with relapsed/refractory hairy cell leukemia (r/r HCL) who have achieved complete response (CR) has not been demonstrated. In other hematologic malignancies, MRD eradication may be associated with prolonged clinical response (Hourigan et al. Leukemia 2017;31:1482-90; Lahuerta et al. J Clin Oncol 2017;epub ahead of print). Moxetumomab pasudotox (formerly CAT-8015), a recombinant immunotoxin fusion protein that specifically binds to B lymphocyte-specific surface antigen CD22, has been shown by flow cytometry to eradicate MRD in a significant (P= 0.04) percentage of patients with r/r HCL (Kreitman et al. ASCO 2015). However, a detailed study of MRD by bone marrow immunohistochemistry (IHC) was not previously presented. We analyzed data from a phase 1 dose escalation study of moxetumomab pasudotox in r/r HCL patients to test the hypothesis that eradication of MRD in bone marrow, assessed by IHC, may be associated with prolonged remission.CAT-8015-1001 (NCT00586924) was a phase 1 study evaluating the safety and efficacy of moxetumomab pasudotox in patients with r/r HCL who previously had received at least 2 courses of treatment, at least 1 of which included a purine analog; initial results from the dose escalation phase in 28 patients have been reported (Kreitman et al. J Clin Oncol 2012;30:1822-8). Moxetumomab pasudotox was administered on days 1, 3, and 5 of each 28-day cycle until 2 cycles past complete remission (CR), disease progression, unacceptable toxicity, or neutralizing antibodies. In the dose escalation phase, 28 patients received moxetumomab pasudotox 5, 10, 20, 30, 40, or 50 µg/kg. An additional 21 patients were enrolled in the 50-µg/kg cohort.Bone marrow samples were obtained at baseline and at multiple time points during and after treatment. A central pathology laboratory performed hematoxylin and eosin and IHC staining for HCL/B-cell antigens CD20, CD79a, Annexin A1, DBA.44, and PAX-5. A blinded independent central pathologist reviewed (BICR) and assessed stained slides as IHC MRD+ or IHC MRD− for each time point.The best BICR IHC MRD response was compared with the best investigator-reported (IR) disease response. Duration of CR, duration of response (DOR), progression-free survival (PFS), and overall survival were evaluated for patients with a best response of BICR IHC MRD+ vs MRD−.Thirty-seven patients were evaluated for BICR IHC MRD; posttreatment bone marrow biopsies were not available for 11 patients, and biopsies from one patient were non-evaluable. The BICR IHC MRD status appears to be associated with the IR response; 17 of 18 BICR IHC MRD− patients had a best response of CR vs 9 of 19 MRD+ patients. Among patients found to be BICR IHC MRD− at 1 or more posttreatment evaluations, median duration of CR and median PFS were not reached after 84 months of follow-up vs 13.08 and 82.07 months, respectively, for patients who were consistently MRD+ at all time points. DOR was 82.7 vs 54.7 months for the BICR IHC MRD− and MRD+ groups, respectively.Cladribine monotherapy and cladribine followed by rituximab eliminated IHC MRD in some newly diagnosed HCL patients (Sigal et. al, Blood 2010;115:1893-6; Ravandi et. al Blood 2011;118:3818-23). Although vemurafenib demonstrated 96% to 100% overall response rates and 35% to 42% CR rates in patients with r/r HCL, all CR patients were IHC MRD+, and duration of MRD+ CRs was 19 months (Tiacci et al. N Engl J Med 2015;373:1733-47). Moxetumomab pasudotox is, to our knowledge, the only non-chemotherapy regimen shown to eradicate MRD in a meaningful percentage of patients with r/r HCL. Here, BICR findings confirmed elimination of IHC MRD in 49% of evaluable patients. MRD− patients experienced a statistically significantly longer duration of CR (P=0.0002) and PFS (P=0.0031) vs MRD+ patients.Based on the results of this retrospective analysis, together with observations made in the vemurafenib study, BICR IHC MRD− vs MRD+ status is associated with extended DOR and PFS in patients with r/r HCL treated with moxetumomab pasudotox. If this finding can be replicated in additional clinical studies, including the phase 3 pivotal study of moxetumomab pasudotox, IHC MRD determinations may be useful in evaluating the efficacy of therapies in the r/r HCL population. [Display omitted] DisclosuresKreitman:NIH: Patents & Royalties: Co-inventor on pending Moxetumomab Pasudotox patent owned by NIH. Robak:Akari Therapeutics Plc: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Coutre:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Marshall:MedImmune: Employment. Yang:MedImmune: Employment, Equity Ownership, Other: Travel expenses. Pastan:NIH: Patents & Royalties: Pastan is an inventor on several patents on immunotoxins that have all been assigned to the NIH. Yao:MedImmune: Employment, Equity Ownership.

Safety and Efficacy of Blinatumomab in Combination with a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-Positive Leukemia

Safety and Efficacy of Blinatumomab in Combination with a Tyrosine Kinase Inhibitor for the Treatment of Relapsed Philadelphia Chromosome-Positive Leukemia

Bendamustine Followed By Ofatumumab and Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BIO Trial of the German CLL Study Group (GCLLSG)

Bendamustine Followed By Ofatumumab and Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): CLL2-BIO Trial of the German CLL Study Group (GCLLSG)

Phase 1 trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox combined with rituximab for relapsed/refractory hairy cell leukemia.

7036 Background: Anti-CD22 recombinant immunotoxin moxetumomab pasudotox (Moxe) is FDA-approved for hairy cell leukemia (HCL) patients who have received at least two prior systemic therapies including a purine nucleoside analog. In phase 3 testing the complete remission (CR) rate was 41%, and response was higher in patients with lower tumor burden and lower titers of antidrug antibodies (ADA). Phase 1 testing indicated that most CRs were without minimal residual disease (MRD) and eradication of MRD was associated with prolonged CR duration. Monoclonal antibody (Mab) rituximab binds to CD20 on HCL cells and induces apoptosis or immune-mediated killing, but as a single-agent achieved only 13% CRs in relapsed HCL requiring therapy. In a phase 1 trial to determine safety, rituximab was combined with Moxe, with the goal to help reduce tumor burden and to prevent or delay ADA by killing normal B-cells. Methods: To allow rituximab sufficient time to accomplish both goals, it was infused 3 days before day 1 of cycle 1 at 375 mg/m2, and Moxe was given by 30-minute infusion on days 1, 3 and 5. On repeat cycles of Moxe days 1, 3 and 5, rituximab was given on day 1. Cycles were generally spaced 4 weeks apart. Moxe was begun at a lower dose, 30 rather than the 40 mcg/kg dose used in phase 3 in case the rituximab would increase its toxicity. Bone marrow aspirate flow cytometry, which can detect 0.002% HCL cells, was the most sensitive test used for MRD detection, much more sensitive than BRAF V600E digital droplet PCR (ddPCR) or bone marrow biopsy immunohistochemistry (IHC). Patients could receive 4 cycles past MRD-free CR, but not more than 8 cycles. Results: Three patients received Moxe at 30 mcg/Kg/dose and 6 received 40 mcg/Kg/dose, all without dose limiting toxicity (DLT). There was no evidence of hemolytic uremic syndrome or capillary leak syndrome. To prevent intravascular hypovolemia due to expected third spacing, patients were encouraged to drink one cup per hour of water or other fluid from days 1 to 8 and take dexamethasone 4 mg orally if headache or nausea prevented good oral hydration. Of the 9 patients, 7 (78%) achieved CR after 2 (n = 6) or 3 (n = 1) cycles, and achieved MRD-free CR after 2 (n = 3), 4 (n = 3) or 6 (n = 1) cycles. No patients became infected with COVID-19. Conclusions: This phase 1 trial met its primary endpoint of determining whether rituximab could be safely combined with Moxe and will enroll 4 additional patients to further access clinical activity. Further testing will determine whether addition of a CD20 Mab to Moxe significantly improves clinical outcome compared to Moxe alone, particularly long-term MRD-free CR rate. Clinical trial information: NCT03805932.

Clofarabine Significantly Increases Eradication of Minimal Residual Disease of B-Precursor ALL Compared to High-Dose Cytarabine in Randomized Trial Coall 08-09

Background Since the FDA approval of clofarabine for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) at childhood, several studies have been launched which put clofarabine under scrutiny in combination with other cytostatic drugs as second or third line therapy. As a novel treatment-strategy we introduced the combination of clofarabine with pegylated asparaginase (PEG-ASP) in a randomized fashion in comparison to the standard consolidation course with high dose cytarabine (Hidac) combined with PEG-ASP into the frontline management of ALL within the CoALL 08-09 protocol. The primary objective of the study was to compare the MRD based assessment of the cytotoxic efficacy of the randomized courses in pediatric ALL. Patients and methods CoALL 08-09 was an open, interventional, multi-center, prospective, and randomized clinical trial for patients with newly diagnosed ALL. In March 2010 the trial had been opened for enrollment of patients under 18 years with confirmed diagnosis of acute B- or T-cell precursor leukemia. After a stratified phase I/II, in which patients with high-risk features and high post-induction MRD received the combination of clofarabine and PEG-ASP, the randomized trial started in November 2013. All patients with a measurable MRD at the end of induction (EOI), as measured by RQ-PCR according to EURO-MRD guidelines, were eligible for randomization to receive either the combination of clofarabine 5 x 40 mg/m2 or high dose cytarabine (HIDAC) 4 x 3g/m2 bothin combination with PEG-ASP 2.500 IU/m2 at the beginning of the consolidation phase. Until December 2019 303 study patients were randomized allocating 151 patients towards the clofarabine and 152 patients to the HIDAC arm. Patient characteristics and MRD burden prior to this treatment element were highly comparable. Results The reduction of minimal residual disease was significantly more profound after clofarabine compared to cytarabine (p(Cochran-Armitage)=.01 for BCP-ALL with 93 vs 79 patients reaching MRD negativity (Table 1). MRD status of BCP-ALL after the first randomized consolidation block (day 50) was of prognostic relevance with a statistically significant impact on EFS and relapse rate (Fig. 2a). However, no difference in outcome regarding the event-free and overall survival between the randomized arms was observed (5-year EFS: Clofarabine 85.7, SE=4.1 vs Hidac 84.8, SE=4.7 (p=.96) and OS: 95.7, SE=1.9 vs 92.2, SE=3.2(p=.59) Fig. 2b). This finding was recapitulated independent of gender, age, WBC count at diagnosis, ETV6-RUNX 1 translocation, immunophenotype or overall risk strata). Results for T-ALL patients are in the same range but because of small numbers not statistically significant. No differences in the incidence of severe or persistent toxicity btween randomized treatment elements as well as in the subsequent treatment realization were registered. Conclusion Clofarabine combined with PEG-asparaginase is highly effective and well tolerated in the frontline treatment of ALL. Although the prognostic impact of MRD is still discernible in early consolidation, the greater cytotoxic efficacy of clofarabine reflected by a more frequent eradication of MRD, did not translate into an apparent improvement of outcome likely due to a lack of power in the comparative analysis of randomized patients. Disclosures No relevant conflicts of interest to declare.

Minimal Residual Disease Eradication with Guadecitabine (SGI-110) in the Post-Transplant Setting

Minimal Residual Disease Eradication with Guadecitabine (SGI-110) in the Post-Transplant Setting

Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Minimal Residual Disease Eradication with Venetoclax in Acute Myeloid Leukemia

Clonal Dynamics after Venetoclax-Obinutuzumab Therapy: Novel Insights from the Randomized, Phase 3 CLL14 Trial

Clonal Dynamics after Venetoclax-Obinutuzumab Therapy: Novel Insights from the Randomized, Phase 3 CLL14 Trial

Phase II Study of Blinatumomab and Concurrent Oral Tyrosine Kinase Inhibitor Therapy As Consolidation and Maintenance Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Following Chemotherapy-Sparing Induction

Background: Combining oral ABL-targeted tyrosine kinase inhibitors (TKIs) with (w/) multi-agent chemotherapy has improved the long-term disease-free survival of adults w/ Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, Ph+ ALL occurs more commonly in older adults, and toxicities of multi-agent chemotherapy, including sequelae of prolonged myelosuppression, are amplified in this population. Others have previously reported rates of morphologic complete response (mCR) approaching 100% among adults w/ Ph+ ALL treated w/ corticosteroids (CS) and dasatinib (DAS) alone as induction therapy, but w/ low rates of minimal residual disease (MRD) negativity by flow cytometry (FACS) and BCR-ABL1 PCR (complete molecular response, CMR) and high rates of relapse in the absence of further consolidation. The bispecific T-cell engager blinatumomab (BLIN) has considerable efficacy in clearing MRD in patients (pts) w/ Ph- B-cell ALL. We have previously reported our institutional experience combining ABL TKIs w/ BLIN in pts w/ Ph+ ALL and MRD, including encouraging safety data and high rates of MRD eradication (King/Geyer et al., Leuk Res, 2019). The ongoing D-ALBA study (GIMEMA LAL2116) is also investigating BLIN + DAS consolidation following 12 weeks of induction (prednisone + DAS followed by DAS), w/out protocol-specified maintenance, and has demonstrated preliminary evidence of efficacy (Chiaretti et al., ASH Meeting, 2019). As such, we designed a phase II study of BLIN as part of a chemotherapy sparing strategy in pts w/ Ph+ ALL (BLISSPHALL), introducing BLIN as early as 6 weeks into treatment for pts in morphologic CR, w/ aim of enhancing early MRD negativity and suppressing resistant clones early in disease course. Study design and methods: Our institution is leading a phase II trial of TKI + BLIN consolidation and maintenance in adults w/ newly-diagnosed Ph+ ALL, w/ potential multicenter expansion (NCT04329325). Pts are eligible if they are ≥18 years-old w/ Ph+ ALL confirmed by cytogenetic or molecular studies, ECOG performance status 0-2, w/out prior therapy for ALL beyond CS, hydroxyurea, or intrathecal chemotherapy, w/out known active extramedullary disease and/or CNS-3 disease, and w/ appropriate organ function. See Figure 1: pts will receive a CS pre-phase (days [d] -6 - 0) followed by modified GIMEMA LAL1205 induction (dexamethasone [DEX] 10 mg/m2 [max 24 mg/d], d1-24, tapered off d25-32) + DAS 140 mg/d (dose adjustments or TKI change permitted per protocol) w/ intrathecal methotrexate (IT MTX) d22, 43 and bone marrow (BM) assessments including FACS and BCR-ABL1 PCR. Pts in mCR on d43 (or optional reassessment ≤ 3 weeks later) will be eligible to proceed to consolidation w/ 3 cycles (C) BLIN 28 mcg/d IVCI, d1-28, concurrent w/ TKI, w/ 14d off BLIN between cycles and BM MRD assessment/IT MTX after each cycle. C1 BLIN + TKI is required to begin inpatient x72 hours. TKI is given continuously including between BLIN cycles. Pts in CMR after consolidation may proceed to maintenance (C4-7 BLIN + TKI, 28d off between cycles). Pts may come off study to proceed to hematopoietic cell transplant (HCT) at any point, though it is recommended such pts receive ≥2C of BLIN + TKI. The primary objective is to determine the proportion of evaluable pts achieving CMR by the end of consolidation (≤ 3C BLIN + TKI). Secondary objectives include safety/toxicity of BLIN + DAS, duration of CMR, incidence of relapse, event-free/overall survival. Exploratory objectives include safety/toxicity of non-DAS TKIs + BLIN, defining patterns/mechanisms of resistance to BLIN+TKI (including ABL kinase mutations), and outcomes among pts not undergoing HCT. The trial utilizes a Simon's minimax two-stage design; 20% CMR rate is considered not promising, a 50% CMR rate is considered promising, and probabilities of type I/II error are set at 0.10/0.10. If ≥ 3 of the first 10 pts achieve CMR we will continue enrollment to max 17 pts. If ≥ 6 pts achieve CMR, then BLIN + TKI will be considered promising for further investigation. The investigators are hopeful this study will add to the currently limited prospective data supporting TKI + BLIN consolidation/maintenance for pts w/ Ph+ ALL and efforts to develop chemotherapy-sparing and immunotherapeutic strategies for older pts w/ ALL. Disclosures Geyer: Amgen: Research Funding. King:Abbvie: Other: advisory board. Park:Novartis: Consultancy; Genentech/Roche: Research Funding; Intellia: Consultancy; Artiva: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Takeda: Consultancy, Research Funding; Servier: Consultancy, Research Funding; AstraZeneca: Consultancy; Allogene: Consultancy; Incyte: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Juno Therapeutics: Research Funding; GSK: Consultancy; Autolus: Consultancy, Research Funding; Minverva: Consultancy; Amgen: Consultancy, Research Funding. OffLabel Disclosure: Blinatumomab is not approved to be given in combination with ABL tyrosine kinase inhibitors for treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia.

Early stage colon cancer: Current treatment standards, evolving paradigms, and future directions.

Colon cancer continues to be one of the leading causes of mortality and morbidity throughout the world despite the availability of reliable screening tools and effective therapies. The majority of patients with colon cancer are diagnosed at an early stage (stages I to III), which provides an opportunity for cure. The current treatment paradigm of early stage colon cancer consists of surgery followed by adjuvant chemotherapy in a select group of patients, which is directed at the eradication of minimal residual disease to achieve a cure. Surgery alone is curative for the vast majority of colon cancer patients. Currently, surgery and adjuvant chemotherapy can achieve long term survival in about two-thirds of colon cancer patients with nodal involvement. Adjuvant chemotherapy is recommended for all patients with stage III colon cancer, while the benefit in stage II patients is not unequivocally established despite several large clinical trials. Contemporary research in early stage colon cancer is focused on minimally invasive surgical techniques, strategies to limit treatment-related toxicities, precise patient selection for adjuvant therapy, utilization of molecular and clinicopathologic information to personalize therapy and exploration of new therapies exploiting the evolving knowledge of tumor biology. In this review, we will discuss the current standard treatment, evolving treatment paradigms, and the emerging biomarkers, that will likely help improve patient selection and personalization of therapy leading to superior outcomes.