Residual Disease In Bone Marrow Research Articles

BELLWAVE-010: A phase 3 study of nemtabrutinib plus venetoclax versus venetoclax plus rituximab (VR) in previously treated patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

TPS7089 Background: VR is a standard of care option for pts with CLL/SLL who have relapsed after ≥1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton tyrosine kinase (BTK) plays an important role in the pathogenesis of CLL. Nemtabrutinib is a BTK inhibitor that targets both wild type and C481-mutant forms of BTK. In the ongoing BELLWAVE-001 study, nemtabrutinib demonstrated manageable safety and durable antitumor activity in pts with R/R CLL/SLL with and without C481 mutations. The randomized, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to evaluate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line or later treatment for pts with R/R CLL/SLL. Methods: Eligible pts are aged ≥18 years with active R/R CLL/SLL after ≥1 prior therapy per iwCLL 2018 criteria and an ECOG PS of 0-2. Approximately 720 pts will be enrolled in 2 parts. Part 1 is an open-label, nonrandomized dose escalation and confirmation phase to evaluate safety and determine the optimal dose of nemtabrutinib + venetoclax. Part 1 will enroll 30 pts to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Pts will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days, followed by nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). Part 2 is an open-label, parallel-group, randomized phase comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 2, approximately 690 pts will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the nemtabrutinib + venetoclax or venetoclax + rituximab (or rituximab biosimilar; 375 mg/m2 at week 6, followed by 500 mg/m2 every 4 weeks starting at week 10 until week 26 [total 6 doses]). Study treatment will continue for approximately 2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). The primary end point for part 2 is progression-free survival by blinded independent central review (BICR) per iwCLL 2018 criteria. Secondary end points for part 2 are undetectable minimal residual disease in bone marrow at month 14 by central laboratory assessment, objective response rate (ORR), and duration of response by BICR per iwCLL 2018 criteria, overall survival, and safety. Exploratory end points are ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life. Recruitment is ongoing. Clinical trial information: NCT05947851 .

Allogeneic Stem Cell Transplantation in Adolescent and Adult Patients with Acute T Cell Lymphoblastic Leukemia / Lymphoma : Single Center Experience of 143 Patients

Background: T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/-LL) is an aggressive hematological neoplasm originates from T-cell progenitors. T-ALL and T-LL are distinguished by the presence of more or <20% marrow blasts, respectively. Allogeneic hematopoietic cell transplantation (SCT) is typically recommended for adults with T-ALL in second or later complete remission (CR2+), but also may be offered to patients in first CR (CR1) with high-risk features. Our center reported previously outcomes of allogeneic HCT (allo-SCT) in 53 adolescent and young adults of T-ALL ( Biol Blood Marrow Transplant. 2012;18(12):1897-1904). Patients and Methods: We analyzed the outcomes of adults (age >14years) with T-ALL who received allo-SCT at King Faisal Specialist Hospital and Research Center between January 1985 and September 2018. Patients eligible for allo-SCT included HR patients in CR1 and any patient in > CR2 or relapse. Patients in CR1 had one or more of the following HR features: WBC count at presentation > 100,000/mm3, residual disease in bone marrow (BM) at day 14 postinduction, central nervous system (CNS) involvement at diagnosis and the need for more than one induction regimen to achieve CR1. Full-intensity conditioning regimens were used for all patients. The majority of patients (95.1%) received cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg), followed by 12 Gy of fractionated total body irradiation (TBI) given in 6 fractions. Seven patients (4.9%) received busulfan 16 mg/kg (1 mg/kg per dose orally every 6 hours over 4 consecutive days) and cyclophosphamide 60 mg/kg once daily i.v. for 2 consecutive days (total dose, 120 mg/kg).Short-course methotrexate plus cyclosporine (MTX/CSA) was the GVHD prophylaxis regimen used, in all patients. Results: 143 patients underwent allo-SCT and were included in this study; some of them were referred in CR for allo- SCT after undergoing induction chemotherapy outside our institution. Median age was 20 years (range, 14-52).Majority of patients were males 116 (80.6%). Extramedullary presentation was reported in 34 patients (23.8 %) with CNS involvement in 15 patients (10.5%). For SCT outcomes, the incidence rates for relapse 27.1%, acute GVHD 45.8%, grade II-IV acute GVHD was 29.9% and that of chronic GVHD was 38.9%, extensive chronic GVHD was 21.5%. GVHD relapse free survival (GRFS) was reported in 27.1%. The majority of relapses occurred within 1 year after SCT. The cumulative incidence of relapse (CIR) at 1 year was 22.4% 95% CI (15.9 - 29.5), at 2 years was 23.8.8% 95% CI (17.2 - 31) and at 5 years was 25.9% 95% CI (19 - 33.3). Other outcomes, Hemorrhagic cystitis (HC) was noted in 9.7%, sinusoidal obstruction syndrome (SOS) 9% The mean time for overall survival (OS) was 166.77 months (95% CI = 136.54 - 197), and the median survival time was 41 months (95% CI = 15 - 266). For the CR1 group was 205.63 months (95% CI = 166.59 - 244.66). At 10 years, OS of the CR1 group was 74.44 months (95% CI = 63.67 - 85.22), and for the > CR2 group was 35.36 months (95% CI = 24.39 - 46.32); p= 0.0001 PFS analysis showed, the overall mean survival time for disease progression at 5 years was 33.16 months (95% CI = 28.77 - 37.54), and the median survival time was 32 months (95% CI = 12 - 55). For the CR1 group was 39.82 months (95% CI = 34.54 - 45.09), and for the >CR2 group was 22.83 months (95% CI = 16.02 - 29.64), p < 0.0001. At 10 years, PFS for the CR1 group was 74.95 months (95% CI = 63.58 - 86.31), and for the >CR2 group was 41.24 months (95% CI = 27.37 - 55.11) with statistically significantly difference, p < 0.0001. On multivariate analysis, chronic GVHD was significantly associated with a lower OS (P=0.006) and PFS (P=0.01).Disease status at SCT remained significantly associated with PFS (P=0.02),but not OS (P=0.07). The presence of extramedullary disease and CNS involvement at diagnosis had no effect on the different outcomes. Conclusions: Allo-SCT could provide better disease control for HR patients with T-ALL/LL in CR1. Dismal outcomes are reported in patients beyond CR1 with early relapses post allo-SCT are almost inevitable. Better understanding of disease's molecular background in addition to MRD applications, could help to identify more patients in CR1 status who might benefit from allo-SCT. Post SCT strategies including maintenance or pre-emptive interventions might be needed to improve SCT outcomes for T-ALL

Bellwave-010: Phase 3, Open-Label, Randomized Study of Nemtabrutinib Plus Venetoclax Versus Venetoclax Plus Rituximab in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least One Prior Therapy

Background: Venetoclax + rituximab (VR) is a standard therapy among patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who have relapsed after at least 1 line of prior therapy. However, there is an unmet need for more effective treatments. Bruton's tyrosine kinase (BTK) is a critical signaling molecule in the pathogenesis of CLL, and inhibitors of BTK have resulted in significant improvements in survival for patients with CLL. Nemtabrutinib is a noncovalent, reversible, competitive inhibitor of BTK that does not require the C481 residue of BTK for binding and inhibition of kinase activity. As a result, nemtabrutinib can target both wild-type and C481-mutant forms of BTK. Results from the ongoing BELLWAVE-001 study have demonstrated manageable safety and durable antitumor activity of nemtabrutinib in patients with CLL/SLL with and without C481 mutations. The randomized, active-controlled, open-label, phase 3 BELLWAVE-010 study (NCT05947851) is designed to investigate the efficacy and safety of nemtabrutinib + venetoclax versus VR as second-line (2L) or later treatment for patients with relapsed/refractory (R/R) CLL/SLL. Study Design and Methods: Patients aged ≥18 years with active CLL/SLL that is relapsed/refractory to at least 1 prior therapy per the iwCLL 2018 criteria, an ECOG performance status of 0-2, and adequate organ function are eligible. Patients with Richter transformation, active central nervous system involvement, or severe bleeding disorder are excluded. Approximately 720 patients will be enrolled in 2 parts: an open-label, nonrandomized dose escalation and confirmation phase (part 1) to evaluate safety and determine the optimal dose of nemtabrutinib in combination with venetoclax and an open-label, parallel-group, randomized phase (part 2) comparing the efficacy and safety of nemtabrutinib + venetoclax with VR. In part 1, 30 patients will be enrolled to establish the dose of nemtabrutinib using a modified toxicity probability interval design. Patients will receive nemtabrutinib at 2 dose levels (45 mg PO QD starting dose, escalating to 65 mg PO QD) for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks). In part 2, approximately 690 patients will be randomly assigned 1:1 to receive either nemtabrutinib at the recommended dose for 28 days followed by the combination of nemtabrutinib + venetoclax (20-400 mg PO QD ramp up over 4 weeks) or venetoclax (20-400 mg PO QD ramp up over 4 weeks) + rituximab (or rituximab biosimilar; 375 mg/m 2 at week 6 followed by 500 mg/m 2 Q4W starting at week 10 until week 26 [total 6 doses]). Patients will receive study treatment for ~2 years or until unacceptable toxicity, disease progression, or other discontinuation criteria are met. Randomization will be stratified by BTK-C481 mutation status (detected vs not detected; determined by droplet digital PCR with a limit of detection of approximately 0.01%-0.1%), geographic region (US/Canada vs Europe vs rest of world) and risk (high risk [del(17p) and/or TP53-mutated and/or IGHV-unmutated] vs low risk [absence of high-risk factors]). Response will be assessed (including imaging, physical examination, constitutional symptoms, hematological evaluations, and bone marrow biopsy as required) every 12 weeks up to week 97 and every 24 weeks thereafter or more frequently if clinically indicated. Adverse events will be monitored up to 30 days after treatment cessation (90 days for serious adverse events) and will be graded per NCI CTCAE, version 5.0. Hematologic toxicities will be evaluated according to iwCLL 2018 criteria. Patient-reported outcomes will be assessed using the EORTC QLQ-C30, EORTC QLQ-CLL17, and EQ-5D-5L questionnaires. The primary end points for part 1 are safety and tolerability, including dose-limiting toxicities, and to establish the recommended dose of nemtabrutinib in combination with venetoclax. The primary end point for part 2 is PFS as assessed per iwCLL 2018 criteria by blinded independent central review (BICR). Secondary end points for part 2 include undetectable minimal residual disease in bone marrow at month 14 as assessed by central laboratory, ORR, and DOR per iwCLL 2018 criteria by BICR, OS, and safety. Exploratory end points include ORR including partial response with lymphocytosis, pharmacokinetics, and health-related quality of life.

Selecting initial therapy in CLL.

Targeted therapy is a powerful treatment option in chronic lymphocytic leukemia (CLL) that has outperformed conventional chemoimmunotherapy in most clinical settings. Except for selected young, fit patients with a mutated immunoglobulin heavy chain variable region gene, most patients benefit from targeted therapy with either a continuous BTK inhibitor or 1-year fixed-duration venetoclax-obinutuzumab as first-line treatment of CLL. Treatment selection is driven by patient-, treatment-, and disease-related factors, encompassing patient preference, concomitant medications, comorbidities, safety profile of the regimen, and TP53 aberration. Clinical trials are actively investigating the simultaneous inhibition of Bruton's tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) proteins with or without a CD20 monoclonal antibody, which can achieve deep response in most patients (52%-89% undetectable minimal residual disease in bone marrow).

Anti CD19 CAR-T Cell Therapy Can Clear Minimal Residual Disease in Bone Marrow of Patients with Relapsed or Refractory B Cell Non-Hodgkin's Lymphomas

Background: Anti CD19 Chimeric Antigen Receptor T (CAR-T) cell therapy is an effective treatment option for patients with relapsed/refractory B-cell lymphomas. There is limited data on the impact of CAR-T cell therapy on measurable residual disease (MRD) in the bone marrow of these patients. We hereby report CAR-T cell therapy's efficacy to treat bone marrow MRD in patient with relapsed/refractory B-cell lymphomas. Methods: In this retrospective review, patients receiving CAR-T cell therapy for relapsed/refractory B-cell lymphomas who had bone marrow MRD evaluation pre-and post-CAR-T infusion at the University of Arizona Cancer Center (UACC) were analyzed. MRD testing was performed via ClonoSEQ (Adaptive Biotechnologies) on bone marrow aspirates prior to CAR-T cell infusion. Patients with MRD+ (10^6) disease had serial MRD evaluations at day+30, +90, +180, +365 post CAR-T cell infusion. Results: Thirty-three patients with B-cell lymphomas received CAR-T cell therapy at UACC from January 2019 to July 2022. Bone marrow MRD pre-and post-CART was evaluated in ten patients. Baseline characteristics of these patients are outlined in Table 1. Seven (70%) were female, five (50%) had diffuse large B cell lymphoma (DLBCL), two (20%) patients had Richter's syndrome, two patients had transformed DLBCL from follicular lymphoma (FL), one patient had FL grade 3A. Nine (90%) patients were treated with Tisagenlecleucel and one (10%) patient received Axicabtagene ciloleucel CAR-T product. Of the ten patients who had MRD testing done pre-and post-CAR-T, seven (70%) had MRD positive disease prior to treatment. Five of the seven patients converted to MRD negative 10^6 post-CAR-T cell infusion. One patient tested MRD positive below the level of detection on day +30 bone marrow aspirate. One patient is still MRD positive 6 months post-CAR-T infusion but the depth of response continues to improve from MRD positive at 10^4 to MRD negative at 10^5, 6 months post-CAR-T infusion. All MRD positive patients achieved complete metabolic response (CMR) based on the positron emission tomography scans. Conclusion: CAR-T cell therapy has the potential to treat minimal residual disease in patients with B-cell lymphoma. Depth of bone marrow response continues to improve over time. All patients continue to be in CMR. Long term follow-up will help determine if persistent MRD can be used as prognostic marker in B cell lymphomas post CAR-T cell therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (HOVON 139/GiVe): primary endpoint analysis of a multicentre, open-label, randomised, parallel-group, phase 2 trial

Fixed-duration 12 cycles of venetoclax plus obinutuzumab is established as first-line treatment for patients with chronic lymphocytic leukaemia. We aimed to determine the activity and safety of 12 cycles of venetoclax consolidation after fixed-duration venetoclax plus obinutuzumab for previously untreated patients with chronic lymphocytic leukaemia who were unfit for fludarabine-based treatment, and whether this could be guided by minimal residual disease status. We conducted an open-label, randomised, parallel-group, phase 2 trial (HOVON 139/GiVe) at 25 hospitals in the Netherlands. Eligible patients were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, had an ECOG performance status of 0-2, and were unfit for fludarabine-based treatment. All patients received two debulking cycles of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8, 15, and day 1 of cycle two), followed by fixed-duration venetoclax plus obinutuzumab for 12 cycles (six cycles of intravenous obinutuzumab 1000 mg on day 1 and 12 during 28-day cycles of oral venetoclax, starting with a 5-week ramp-up and then 400 mg once daily until completion of cycle 12). Patients were then randomly assigned (1:1) by minimal residual disease status in peripheral blood, to receive either 12 cycles of venetoclax consolidation irrespective of minimal residual disease or venetoclax consolidation only if minimal residual disease was detected at randomisation. The primary endpoint was undetectable minimal residual disease in bone marrow and no progressive disease 3 months after end of consolidation treatment (or corresponding timepoint) by intention-to-treat. Safety was assessed in all patients who received at least one dose of any study drug. This is the primary endpoint analysis of this trial, which is ongoing and is registered with EudraCT (2015-004985-27). Between Oct 28, 2016, and May 31, 2018, 70 patients were enrolled, of whom 67 (47 [70%] men and 20 [30%] women) received fixed-duration treatment and 62 were randomly assigned to receive 12 cycles of venetoclax consolidation (n=32) or minimal residual disease-guided venetoclax consolidation (n=30; one of whom was minimal residual disease positive at randomisation). Median follow-up was 35·2 months (IQR 31·5-41·3). 16 (50% [95% CI 32-68]) of 32 patients in the consolidation group and 16 (53% [34-72]) of 30 in the minimal residual disease-guided consolidation group met the primary endpoint of undetectable minimal residual disease in bone marrow and no progressive disease. 22 (69%) of 32 patients in the venetoclax consolidation group and 11 (37%) of 30 in the minimal residual disease-guided consolidation group had any adverse event (grade 2-4; mainly infections). The most common grade 3 or worse adverse events were infection (two [6%] of 32 patients in the consolidation group and one [3%] of 30 in the minimal residual disease-guided consolidation group) and neutropenia (two [6%] and two [7%]). There were no treatment-related deaths. Consolidation with venetoclax 12-cycle treatment increases the duration of known side-effects and does not prevent the loss of minimal residual disease response and subsequent risk of disease relapse. F Hoffmann-La Roche.

Post-Transplant Blockade of CXCR4 Improves Complete Remission Rates and Donor Stem Cell Engraftment without Aggravating Gvhd

Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematological malignancies, but relapse resulted predominantly from residual disease in bone marrow (BM) remains the major cause of treatment failure. Using immunodeficient mice grafted with laboratory-generated human B-ALL, our previous study suggested that leukemia cells within the BM were resistant to graft-versus-leukemia (GVL) effects, and mobilization with CXCR4 antagonist may dislodge leukemia cells from BM, rendering them destroyed by GVL effects. In this study, we extended this approach to patient-derived xenograft (PDX) and murine T-ALL and AML models for determining its clinical relevance and effects on GVHD and donor hematopoietic engraftment. We found that post-transplant treatment with CXCR4 antagonist AMD3100 significantly improved eradication of leukemia cells in the BM in PDX mice grafted with B-ALL cells from multiple patients. AMD3100 also significantly improved disease-free remission rates in murine T-ALL and AML models, and promoted donor hematopoietic engraftment in mice following non-myeloablative allo-HCT. Furthermore, post-transplant treatment with AMD3100 had no detectable deleterious effect on acute or chronic GVHD. These findings provide important preclinical data supporting the initiation of clinical trials exploring combination therapy with CXCR4 antagonist and allo-HCT. DisclosuresNo relevant conflicts of interest to declare.

The Bloodwise TAP Calibre Feasibility Study to Assess the Mechanism of Action of Idelalisib in B-Cell Receptor Pathway (BCR) Inhibition in Chronic Lymphocytic Leukaemia (CLL)

The Bloodwise TAP Calibre Feasibility Study to Assess the Mechanism of Action of Idelalisib in B-Cell Receptor Pathway (BCR) Inhibition in Chronic Lymphocytic Leukaemia (CLL)

Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.

8010 Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]

T-Acute Lymphoblastic Leukemia Presenting as Bilateral Ovarian Mass in a Toddler.

T-acute lymphoblastic leukemia (T-ALL) generally have nodal presentation while B-cell leukemia and lymphoma may have extra-nodal or visceral involvement. Intra-abdominal presentation of T-ALL is exceedingly rare. Bilateral ovarian involvement at the time of initial presentation of T-ALL has never been described in children, though it may be seen during relapses. The authors describe a toddler with T-ALL who presented with bilateral ovarian mass. Despite complete resolution of ovarian mass post-induction chemotherapy, minimum residual disease in bone marrow was high reaffirming aggressive nature of disease.

Plasma Exchange to Treat Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome after Anti-CD19 Chimeric Antigen Receptor-T Cell Infusion: A Case Report

Adoptive cell immunotherapy with chimeric antigen receptor-T (CAR-T) cells has shown remarkable clinical outcomes. However, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are the two most significant toxicities during this therapy and can be life-threatening. We described a 12-year-old juvenile who had been diagnosed with relapsed and refractory B-cell acute lymphocytic leukemia (r/r B-ALL). The patient was recruited into our phase I clinical trial concerning ssCAR-T-19 (anti-CD19 CAR-T cells with shRNA targeting IL-6), and 5*106 /kg of engineered ssCAR-T-19 cells were administered. After infusion, the patient underwent a typical CRS reaction, with fever and increased cytokine levels. He was treated with antipyretic drugs, methylprednisolone, and tocilizumab, but the effect was limited. He developed coagulation abnormalities, multiple organ dysfunction, lung infection and ICANS. Apart from the necessary supportive and symptomatic treatment, plasma exchange was performed three times in four days while methylprednisolone pulse was performed for two consecutive days. After that, the body temperature, heart rate, and especially the cytokine levels declined. But digestive tract hemorrhage occurred to him and he was transferred to intensive care unit. To make things worse, he developed acute respiratory failure and received intubation and mechanical ventilation. In addition, symptomatic treatment such as suppression of stomach acid and anti-infection was given. The bleeding was controlled, and his respiratory function improved, and the CRS and ICANS-related symptoms were relieved. He received extubation and was transferred back to the general ward. Additionally, abone marrow smear showed no lymphoblast cells, and minimal residual disease in bone marrow was negative on day +22 and day +30. The patient was eventually discharged in a normal condition. In conclusion, CRS and ICANS as two most common toxicities after CAR-T therapy, which often cause patient death. Several methods such as anti-IL-6 therapy and/or corticosteroids have been adopted in the management guidelines of CRS and ICANS except plasma exchange. This case shows the validity of plasma exchange in a patient with severe CRS and ICANS after receiving ssCAR-T.

Day 0 bone marrow pathology of allogeneic hematopoietic stem cell transplantation is a novel prognostic factor in myeloid malignancies.

Residual disease (RD) is one of the risk factors for relapse after hematopoietic stem cell transplantation (HSCT) in hematological malignancies. Although recent advances in the technology for detecting minimal/measurable RD, such as multiparameter flow cytometry and quantitative PCR, enable risk stratifications of disease relapse, these examinations still have limitations in routine clinical practice. In this study, we assessed RD in bone marrow (BM) specimens on day 0 of allogeneic HSCT by immunostaining of case-specific leukemic blast markers and analyzed the relationship between day 0 BM status and HSCT outcomes. We analyzed 82 adult HSCT recipients with myeloid malignancies. BM histology of day 0 revealed almost empty marrow with a small number of residual BM cells. However, residual blasts could be detected by immunostaining even for only a few cells. When patients were divided into two groups according to the existence of RD on day 0, those with positive RD showed significantly lower overall survival rate (27% vs. 73%, P<0.001) and higher cumulative incidence of relapse (46% vs. 9%, P=0.006) at one year compared to those with negative RD. Furthermore, even if they were not in remission at the point of the pre-conditioning evaluation, the patients who achieved negative RD on day 0 showed comparable prognosis with those who maintained remission before conditioning. This study shows the efficacy of day 0 BM pathology of allogeneic HSCT as a prognostic factor that can contribute to clinical decisions on post-transplant strategies.

T Cells Expressing an Anti-B-Cell Maturation Antigen (BCMA) Chimeric Antigen Receptor with a Fully-Human Heavy-Chain-Only Antigen Recognition Domain Induce Remissions in Patients with Relapsed Multiple Myeloma

Chimeric antigen receptor (CAR) T cells expressing B-cell maturation antigen (BCMA) can target and kill multiple myeloma (MM). BCMA was chosen as a target for MM because it is expressed by almost all cases of MM but has a restricted expression pattern on normal cells. CAR antigen-recognition domains made up of monoclonal antibody-derived, single-chain-variable fragments (scFv) are potentially immunogenic. To reduce the risk of recipient immune responses against CAR T cells, we used the sequence of a novel anti-BCMA, fully-human, heavy-chain-only binding domain designated FHVH33. The FHVH33 binding domain sequence was from TeneoBio, Inc. FHVH33 is smaller than a scFv. FHVH33 lacks the light chain, artificial linker sequence, and 2 associated junctions of a scFv, so it is predicted to be less immunogenic than a scFv, especially murine-derived scFvs. We constructed a CAR incorporating FHVH33, CD8α hinge and transmembrane domains, a 4-1BB costimulatory domain, and a CD3ζ T-cell activation domain. The CAR, FHVH33-CD8BBZ, is encoded by a γ-retroviral vector. FHVH33-CD8BBZ-expressing T cells (FHVH-BCMA-T) exhibited a full range of T-cell functions in vitro and eliminated tumors and disseminated malignancy in mice (Lam et al, Blood (ASH abstract) 2017 vol 130: 504). We are conducting the first clinical trial of FHVH-BCMA-T. Patients receive conditioning chemotherapy on days -5 to -3 with 300 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine followed by infusion of FHVH-BCMA-T on day 0. This dose-escalation trial has 5 planned dose levels (DL). Twelve patients have received FHVH-BCMA-T on 3 DLs, 0.75x106, 1.5x106 and 3x106 CAR+ T cells/kg of bodyweight. Three patients were enrolled on the trial but not treated. The median age of patients enrolled was 63 (range 52-70); patients received a median of 6 lines of anti-myeloma therapy (range 3-10) prior to treatment with FHVH-BCMA-T. Ten patients out of 12 patients have achieved objective responses (OR). Five patients have obtained CRs or VGPRs to date. One patient achieved a partial remission (PR) 26 weeks after FHVH-BCMA-T infusion through a continued decrease in a measurable plasmacytoma. Five out of 7 patients who had myeloma with high-risk cytogenetics had an OR (Table). ORs occurred in patients with large soft-tissue plasmacytomas. Loss of BCMA expression on myeloma cells after treatment was documented in 2 patients. Two patients who developed progressive MM after CAR T-cell infusion had evidence of minimal residual disease in bone marrow 1-2 months post infusion of CAR T cells (patients 7,8). Eleven out of 12 patients had cytokine release syndrome (CRS); CRS grades ranged from 1-3 (Lee et al. Biol Blood Marrow Transplant 25 (2019) 625-638). The median peak C reactive protein (CRP) of the patients with CRS was 156.3 mg/L. Of 12 patients, 1 received the interleukin-6-receptor antagonist tocilizumab on day +6 to treat grade 3 CRS with hypotension requiring low-dose pressor therapy, grade 2 ejection fraction (EF) decrease and elevation of creatinine kinase (CK). All parameters returned to baseline by day +10. Patient 12 had a grade 3 decrease in EF which resolved by day +29. Two patients had grade 2 neurotoxicity that resolved without intervention: patient 3 had headaches, dysarthria and word-finding difficulties that resolved after 6 days while patient 6 had headaches on day +4. Patient 12 had grade 3 neurotoxicity with confusion on day +2; she was given dexamethasone with improvement in mental status the same day. After attaining a response, patient 6 died from influenza complications 6 weeks after FHVH-BCMA-T infusion. A median of 10.6% (range 1.1-46) of bone marrow T cells were CAR+ when assessed 14 days after FHVH-BCMA-T infusion. We assessed blood CAR+ cells by quantitative PCR. The median peak level of CAR+ cells was 76.5 cells/µl (range 3-347 cells/µl) and the median day post-infusion of peak blood CAR+ cell levels was 13 (range 9-14). The results from this phase 1 trial demonstrate that FHVH-BCMA-T cells can induce responses at low dose levels. Patients who had no CRS or low-grade CRS achieved objective responses. Toxicity was limited and reversible. Accrual to this trial continues. A maximum tolerated dose has not been determined yet. These results encourage further development of FHVH CAR-T. Table Disclosures Manasanch: Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Merck: Research Funding; Skyline Diagnostics: Research Funding; Sanofi: Research Funding; Quest Diagnostics: Research Funding; Celgene: Honoraria. Trinklein:Teneobio, Inc.: Employment, Equity Ownership. Buelow:Teneobio, Inc.: Employment, Equity Ownership. Kochenderfer:Kite and Celgene: Research Funding; Bluebird and CRISPR Therapeutics: Other: received royalties on licensing of his inventions. OffLabel Disclosure: Cyclophosphamide and fludarabine are used in combination for conditioning chemotherapy prior to CAR T-cell infusion

The new international neuroblastoma response criteria.

Over recent years significant advances in histopathology and functional imaging techniques for the diagnosis and restaging of children with neuroblastoma have led to better quantification of disease and assessment of disease response, allowing for better treatment stratification. In this review we summarise recent changes to the International Neuroblastoma Response Criteria including the use of RECIST (Response Evaluation Criteria in Solid Tumours) guidance for measurable soft-tissue disease, replacement of technetium-99m-methylene diphosphonate (MDP) bone scans with metaiodobenzylguanidine (MIBG) scan or [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT scanning, and a new category of minimal residual bone marrow disease.

Abstract 3099: Characterization of bone marrow tumor associated macrophages in patients with chronic lymphocytic leukemia treated with Ibrutinib

Abstract Introduction. Complete remission (CR) is observed in 9-26% of patients with chronic lymphocytic leukemia (CLL), with virtually no patient converting to CR beyond 2 years of treatment. Residual bone marrow (BM) disease is typically observed in patients not achieving CR, increasing interest about the specific effects of ibrutinib on the CLL BM microenvironment. Ibrutinib markedly increases the number and function of T cells, and suppresses regulatory B-cell function. However, it may induce M2 polarization of tumor-associated macrophages (TAM), as suggested by limited studies conducted on peripheral blood. Methods. In order to characterize the specific effect of ibrutinib on the CLL BM microenvironment, we identified patients with previously untreated CLL, receiving frontline single agent ibrutinib for more than 2 years, for whom BM biopsy samples were available at baseline and after 1 and 2 years of treatment. All samples were analyzed by immunohistochemistry and the number of positive cells per high power field (HPF)(200X) was assessed; CD68 was used as a general TAM marker, and CD163, PD-L1 and arginase-1 as M2 markers. Negative BM samples, collected as part of lymphoma staging, were used as normal controls. Results. Thirteen patients were included in the study; 85% had unfavorable FISH abnormalities (including deletion 11q and deletion 17p) and 77% had unmutated IGHV. After &amp;gt; 2 years of treatment, 3 (23%) patients had achieved CR, and 10 (77%) partial remission (PR), characterized by residual BM disease. BM samples were available for 11 patients at baseline, 12 patients at 1 year of treatment, and 9 patients at 2 years of treatment. PD-L1 and arginase-1 were negative in BM samples from all patients at all time points and in all 3 normal BMs. The median number of CD68-positive cells/HPF was 3 (range, 3-5) at baseline, 5 (range, 3-20) at 1 year, and 5 (range, 3-10) at 2 years; no differences in CD68 expression was observed between patients who achieved PR and those who achieved CR. All patients with normal BM had five CD68-positive cells/HPF. The median number of CD163-positive cells/HPF was 5 (range, 5-15) at baseline, 15 (range, 10-30) at 1 year, and 20 (range, 15-20) at 2 years; a more pronounced increase in CD163-positive cells was observed among patients who achieved PR as compared to patients who achieved CR. All patients with normal BM had approximatively ten CD163-positive cells/HPF. Conclusions. Ibrutinib increases BM CD68 (TAM) in patients with CLL, reaching a plateau after 1 year of treatment, and BM CD163 (TAM M2), with no plateau observed at 2 years of treatment. The increase in TAM M2 is more pronounced in patients who do not achieve CR after &amp;gt; 2 years of treatment, representing a potential therapeutic target for consolidation strategies. Additional M2 markers, including CSF1R, and digital analysis are being applied, and results will be presented at the meeting. Citation Format: Paolo Strati, Ellen Schlette, Luisa Solis Soto, Daniela Duenas, Ignacio Wistuba, Jan Burger. Characterization of bone marrow tumor associated macrophages in patients with chronic lymphocytic leukemia treated with Ibrutinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3099.

Ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial treatment for younger patients with chronic lymphocytic leukaemia: a single-arm, multicentre, phase 2 trial

Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia. We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m2, days 1-3), cyclophosphamide (250 mg/m2, days 1-3), and rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2-6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov (NCT02251548) and is ongoing. Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50-58). At data cutoff, median follow-up was 16·5 months (IQR 10·6-34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23-0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%). The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients. Pharmacyclics and the Leukemia & Lymphoma Society.

Does Salvage Chemotherapy Regimen Intensity Embark on Clearance of Bone Marrow Neuroblastoma?

Introduction::Neuroblastoma (NBL) is the most common extracranial solid tumor in children. It accounts for 15% of the deaths from cancer in the pediatric age group. Approximately half of the newly diagnosed children are at “high risk” (HR) of treatment failure. This study aim was to evaluate the impact of salvage chemotherapy ICE (ifosfamide, carboplatin, and etoposide) versus TC (topotecan/cyclophosphamide) when administered to NBL HR patients having residual bone marrow disease after primary tumor control on the first line treatment regimen.Materials and Methods:The present retrospective study included two groups of eligible stage 4 NBL patients with persistent bone marrow disease. Group (1), 29 patients, received ICE whereas less intensive TC was administered to Group (2), 32 patients. Data analysis included epidemiological variables, pathology subtype, MYCN gene status, primary tumor response and their correlation with bone marrow disease clearance on each regimen.Results:A higher tendency of complete bone marrow clearance was reported in patients who received ICE compared to TC; 41.4% versus 25.0%, respectively. However, the difference was not statistically significant (p= 0.174).Conclusion:TC regimen appears to be a good alternative to ICE as salvage treatment in an attempt to clear NBL bone marrow residual, with the privilege of being less toxic and can be given on outpatient basis. Further randomized trials of larger study sample size with survival impact analysis are warranted.

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance.

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10−4. Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated vs. unmutated OS: 85.7% alive at 7.2 years vs. 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.

Daratumumab in Combination with Vincristine or Nelarabine As Effective Salvage Therapy for Patients with Acute Lymphoblastic Leukemia at High Risk of Relapse

Acute lymphoblastic leukemia (ALL) relapsing after allogeneic stem cell transplantation (allo-SCT) is usually associated with poor outcome. T-ALL patients relapsing early post-allo-SCT or relapsed B-ALL patients who have failed currently available targeted and immunotherapies need an effective salvage therapy.We herein describe 3 cases where minimal residual disease (MRD) negative remission was achieved in very high-risk relapsing ALL patients with the use of daratumumab with or without nelarabine.Patient 1: A 24-year-old male diagnosed in May 2016 with T lymphoblastic lymphoma. Following ECOG 2993-based induction, his PET became negative. Additional 3 high-dose methotrexate and 3 consolidation cycles were prescribed followed by maintenance therapy. In August 2017, he relapsed in the bone marrow (BM) and central nervous system, and a second remission (CR2) was achieved after therapy with mitoxantrone + cytarabine. He underwent allo-SCT from his matched brother in CR2. Three and a half months after the transplant he experienced a third relapse. Two cycles of nelarabine were administrated followed by daratumumab 16mg/kg in a “myeloma like” protocol. BM at the end of 2 nelarabine cycles demonstrated remission but with 0.09% residual disease cells on flow cytometry. After the first 2 months of daratumumab, BM confirmed MRD eradication. One dose of 5x105/kg donor lymphocyte infusion (DLI) was also prescribed.Patient 2: A 43-year-old female diagnosed with T-ALL in February 2017. Her disease was refractory to ECOG 2993-based induction and remission was achieved only after a second-line therapy with mitoxantrone + cytarabine. She was referred to allo-SCT from her matched sister, engrafted well and developed grade 2-3 acute graft-versus-host disease which responded well to steroids. Five months post-transplant an extra-medullary relapse was diagnosed in her eye and skin, while MRD was identified in her BM. The same regimen of 2 cycles of nelarabine followed by daratumumab 16mg/kg was prescribed. Extra-medullary disease was eliminated and so was the residual BM disease. One dose of 5x105/kg DLI was also prescribed.The case of patient 3 has just been published (Ganzel C, et al. Haematologica, June 2018). In brief, this is a 21-year-old man diagnosed 7 years ago with Ph+ B-ALL. Daratumumab was prescribed to treat his 7th relapse after he had been treated with multiple TKIs, including ponatinib, underwent two allo-SCTs and received immunotherapy with 2 different anti CD19 and anti CD22 CAR-T cell agents. In parallel to daratumumab, vincristine was administered every 4 weeks as well as daily ponatinib. Molecular remission following daratumumab was confirmed by PCR for BCR/ABL.Kinetics of response and duration of follow-up: For the patient with Ph+ ALL, daratumumab was prescribed while overt disease was present in the BM but peripheral counts were low (WBC=2,000, ANC=1,000, PLT=95,000). Hematologic remission was confirmed after 1 month and molecular remission after 4 months. Unfortunately, 6 months after the first infusion of daratumumab he relapsed again and now (one year post-daratumumab administration) he is alive and treated with bortezomib and gemtuzumab ozogamicin.Both T-ALL patients achieved morphologic remission with nelarabine and received one DLI. MRD was identified in BM examination following nelarabine cycles and its elimination was confirmed in the BM at the end of the first 2 months of daratumumab (a total of 8 weekly infusions). Currently, these patients are 20 and 22 weeks following relapse and are alive and in molecular remission. In all 3 patients we noticed no significant side effects that could be related to daratumumab infusion. Peripheral WBC and PLT count dynamics are shown in figure 1.Treatment of ALL patients who relapse with high-risk features is a great challenge. Herein we report three consecutive patients who achieved MRD negativity with daratumumab. Daratumumab can be combined with other effective agents in a simple and safe protocol that may be delivered even to heavily pre-treated patients. Although larger studies with longer follow-up are required, this novel approach may offer new hope for patients with a devastating disease such as relapsed ALL. DisclosuresOfran:Novartis: Other: Served on a Novartis advisory board.

Abstract 55: Intrinsic molecular characteristics of bone marrow-disseminated tumor cells

Abstract Dormant or slow-cycling disseminated tumor cells (DTC) in bone marrow (BM) are known to persist in patients with various types of cancer including head and neck squamous cell carcinoma (HNSCC). BM-DTC has been thought to have possible metastatic stem cell traits although functional and clonal analysis of BM-DTC remain elusive. Recently, we reported that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis was crucial for drug resistance dependent on a slow-cycling state in BM-DTC but not in lung metastatic cells. This study aimed to elucidate intrinsic molecular characteristics in BM-DTC. We used the human HNSCC cell line HEp3-originated sublines [i.e. parental line (P-HEp3), BM-DTC-derived (BM-HEp3), and lung metastases-derived sublines (Lu-HEp3)]. Our transcriptome analyses for these sublines revealed that slow-cycling and drug-resistant BM-HEp3 cells had unique gene expression signatures. In addition, our investigation for phosphorylation of 39 kinases associated with tumor progression showed enhanced activation of only Src in BM-HEp3 compared with P- and Lu-HEp3. Importantly, Src inhibition by dasatinib in these sublines led to a remarkable reduction in cell viability only in BM-HEp3. These data suggest that intrinsic molecular characteristics of BM-DTC are distinct from primary and lung metastatic tumor cells. Src activation may be important for survival of dormant or slow-cycling BM-DTC. Further studies should contribute to better understanding of biology of minimal residual disease in BM and metastatic initiation. Citation Format: Manabu Maeshiro, Satoru Shinriki, Takuya Nakamura, Hirofumi Jono, Hideki Nakayama, Yukio Ando, Hirotaka Matsui. Intrinsic molecular characteristics of bone marrow-disseminated tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 55.