ABSTRACT
BACKGROUND: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. METHODS: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. RESULTS: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×106 CAR T cells. At the 450×106 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×106 to 150×106 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×106 to 150×106 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×106 to 150×106 cells. CONCLUSIONS: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).
Subject(s)
Immunotherapy, Adoptive , Multiple Myeloma , Receptors, Chimeric Antigen , Receptors, G-Protein-Coupled , B-Cell Maturation Antigen/therapeutic use , Cytokine Release Syndrome/etiology , Humans , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/etiology , Receptors, Chimeric Antigen/therapeutic use , Receptors, G-Protein-Coupled/therapeutic use , T-LymphocytesABSTRACT
Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms (tMN). Preleukemic clones (ie, clonal hematopoiesis [CH]) are detectable years before the development of these aggressive malignancies, although the genomic events leading to transformation and expansion are not well defined. Here, by leveraging distinctive chemotherapy-associated mutational signatures from whole-genome sequencing data and targeted sequencing of prechemotherapy samples, we reconstructed the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy was revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan were hypermutated and enriched for complex structural variants (ie, chromothripsis), whereas neoplasms with nonmutagenic chemotherapy exposures were genomically similar to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as temporal barcodes linked to discrete clinical exposure in each patient's life, we estimated that several complex events and genomic drivers were acquired after chemotherapy was administered. For patients with prior multiple myeloma who were treated with high-dose melphalan and autologous stem cell transplantation, we demonstrate that tMN can develop from either a reinfused CH clone that escapes melphalan exposure and is selected after reinfusion, or from TP53-mutant CH that survives direct myeloablative conditioning and acquires melphalan-induced DNA damage. Overall, we revealed a novel mode of tMN progression that is not reliant on direct mutagenesis or even exposure to chemotherapy. Conversely, for tMN that evolve under the influence of chemotherapy-induced mutagenesis, distinct chemotherapies not only select preexisting CH but also promote the acquisition of recurrent genomic drivers.
Subject(s)
Antineoplastic Agents , Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Neoplasms, Second Primary , Humans , Melphalan , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation, Autologous/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Neoplasms, Second Primary/chemically induced , Neoplasms, Second Primary/genetics , Antineoplastic Agents/pharmacologyABSTRACT
AIMS: B lymphoblastic leukaemia/lymphoma (B-ALL) is thought to originate from Pro/Pre-B cells and the genetic aberrations largely reside in lymphoid-committed cells. A recent study demonstrated that a proportion of paediatric B-ALL patients have BCR::ABL1 fusion in myeloid cells, suggesting a chronic myeloid leukaemia (CML)-like biology in this peculiar subset of B-ALL, although it is not entirely clear if the CD19-negative precursor compartment is a source of the myeloid cells. Moreover, the observation has not yet been extended to other fusion-driven B-ALLs. METHODS AND RESULTS: In this study we investigated a cohort of KMT2A-rearranged B-ALL patients with a comparison to BCR::ABL1-rearranged B-ALL by performing cell sorting via flow cytometry followed by FISH (fluorescence in situ hybridization) analysis on each of the sorted populations. In addition, RNA sequencing was performed on one of the sorted populations. These analyses showed that (1) multilineage involvement was present in 53% of BCR::ABL1 and 36% of KMT2A-rearranged B-ALL regardless of age, (2) multilineage involvement created pitfalls for residual disease monitoring, and (3) HSPC transcriptome signatures were upregulated in KMT2A-rearranged B-ALL with multilineage involvement. CONCLUSIONS: In summary, multilineage involvement is common in both BCR::ABL1-rearranged and KMT2A-rearranged B-ALL, which should be taken into consideration when interpreting the disease burden during the clinical course.
Subject(s)
Histone-Lysine N-Methyltransferase , Myeloid-Lymphoid Leukemia Protein , Humans , Myeloid-Lymphoid Leukemia Protein/genetics , Histone-Lysine N-Methyltransferase/genetics , Female , Child , Male , Child, Preschool , Adolescent , Fusion Proteins, bcr-abl/genetics , Adult , In Situ Hybridization, Fluorescence , Infant , Gene Rearrangement , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/pathology , Young Adult , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , AgedABSTRACT
Not available.
ABSTRACT
Comprehensive genomic sequencing is becoming a critical component in the assessment of hematologic malignancies, with broad implications for patient management. In this context, unequivocally discriminating somatic from germline events is challenging but greatly facilitated by matched analysis of tumor:normal pairs. In contrast to solid tumors, conventional sources of normal control (peripheral blood, buccal swabs, saliva) could be highly involved by the neoplastic process, rendering them unsuitable. In this work we describe our real-world experience using cell free DNA (cfDNA) isolated from nail clippings as an alternate source of normal control, through the dedicated review of 2,610 tumor:nail pairs comprehensively sequenced by MSK-IMPACT-heme. Overall, we find nail cfDNA is a robust source of germline control for paired genomic studies. In a subset of patients, nail DNA may have tumor DNA contamination, reflecting unique attributes of the hematologic disease and transplant history. Contamination is generally low level, but significantly more common among patients with myeloid neoplasms (20.5%; 304/1482) compared to lymphoid diseases (5.4%; 61/1128) and particularly enriched in myeloproliferative neoplasms with marked myelofibrosis. When identified in patients with lymphoid and plasma-cell neoplasms, mutations commonly reflected a myeloid profile and correlated with a concurrent/evolving clonal myeloid neoplasm. For nails collected after allogeneic stem-cell transplantation, donor DNA was identified in 22% (11/50). In this cohort, an association with recent history of graft-vs-host disease was identified. These findings should be considered as a potential limitation for the use of nail as normal control but could also provide important diagnostic information regarding the disease process.
ABSTRACT
Somatic mutations in the isocitrate dehydrogenase 2 gene (IDH2) contribute to the pathogenesis of acute myeloid leukaemia (AML) through the production of the oncometabolite 2-hydroxyglutarate (2HG)1-8. Enasidenib (AG-221) is an allosteric inhibitor that binds to the IDH2 dimer interface and blocks the production of 2HG by IDH2 mutants9,10. In a phase I/II clinical trial, enasidenib inhibited the production of 2HG and induced clinical responses in relapsed or refractory IDH2-mutant AML11. Here we describe two patients with IDH2-mutant AML who had a clinical response to enasidenib followed by clinical resistance, disease progression, and a recurrent increase in circulating levels of 2HG. We show that therapeutic resistance is associated with the emergence of second-site IDH2 mutations in trans, such that the resistance mutations occurred in the IDH2 allele without the neomorphic R140Q mutation. The in trans mutations occurred at glutamine 316 (Q316E) and isoleucine 319 (I319M), which are at the interface where enasidenib binds to the IDH2 dimer. The expression of either of these mutant disease alleles alone did not induce the production of 2HG; however, the expression of the Q316E or I319M mutation together with the R140Q mutation in trans allowed 2HG production that was resistant to inhibition by enasidenib. Biochemical studies predicted that resistance to allosteric IDH inhibitors could also occur via IDH dimer-interface mutations in cis, which was confirmed in a patient with acquired resistance to the IDH1 inhibitor ivosidenib (AG-120). Our observations uncover a mechanism of acquired resistance to a targeted therapy and underscore the importance of 2HG production in the pathogenesis of IDH-mutant malignancies.
Subject(s)
Aminopyridines/pharmacology , Drug Resistance, Neoplasm/genetics , Isocitrate Dehydrogenase/antagonists & inhibitors , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Mutant Proteins/genetics , Mutation , Protein Multimerization/genetics , Triazines/pharmacology , Alleles , Allosteric Site/drug effects , Allosteric Site/genetics , Aminopyridines/chemistry , Aminopyridines/therapeutic use , Animals , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Disease Progression , Drug Resistance, Neoplasm/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/therapeutic use , Female , Glutamine/genetics , Glutarates/blood , Glutarates/metabolism , HEK293 Cells , Humans , Isoleucine/genetics , Leukemia, Myeloid, Acute/blood , Leukemia, Myeloid, Acute/drug therapy , Mice , Mice, Inbred C57BL , Models, Molecular , Mutant Proteins/antagonists & inhibitors , Triazines/chemistry , Triazines/therapeutic useABSTRACT
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has become a breakthrough treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, despite the high initial response rate, the majority of adult patients with B-ALL progress after CD19 CAR T-cell therapy. Data on the natural history, management, and outcome of adult B-ALL progressing after CD19 CAR T cells have not been described in detail. Herein, we report comprehensive data of 38 adult patients with B-ALL who progressed after CD19 CAR T therapy at our institution. The median time to progression after CAR T-cell therapy was 5.5 months. Median survival after post-CAR T progression was 7.5 months. A high disease burden at the time of CAR T-cell infusion was significantly associated with risk of post-CAR T progression. Thirty patients (79%) received salvage treatment of post-CAR T disease progression, and 13 patients (43%) achieved complete remission (CR), but remission duration was short. Notably, 7 (58.3%) of 12 patients achieved CR after blinatumomab and/or inotuzumab administered following post-CAR T failure. Multivariate analysis revealed that a longer remission duration from CAR T cells was associated with superior survival after progression following CAR T-cell therapy. In summary, overall prognosis of adult B-ALL patients progressing after CD19 CAR T cells was poor, although a subset of patients achieved sustained remissions to salvage treatments, including blinatumomab, inotuzumab, and reinfusion of CAR T cells. Novel therapeutic strategies are needed to reduce risk of progression after CAR T-cell therapy and improve outcomes of these patients.
Subject(s)
Antibodies, Bispecific/administration & dosage , Immunotherapy, Adoptive , Inotuzumab Ozogamicin/administration & dosage , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Salvage Therapy , Adult , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/therapy , Survival RateABSTRACT
Plasmacytoid dendritic cells (pDCs) are the principal natural type I interferon-producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN), and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia. The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here, we characterize patients with AML with pDC expansion (pDC-AML), which we observe in â¼5% of AML cases. pDC-AMLs often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, as well as originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells toward pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Dendritic Cells/pathology , Leukemia, Myeloid, Acute/genetics , Adult , Aged , Blast Crisis/genetics , Blast Crisis/pathology , Dendritic Cells/metabolism , Female , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , MutationABSTRACT
Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.
Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Agents/therapeutic use , Glycine/analogs & derivatives , Leukemia, Myeloid, Acute/drug therapy , Pyridines/therapeutic use , Triazines/therapeutic use , Adult , Aged , Aminopyridines/adverse effects , Antineoplastic Agents/adverse effects , Female , Glycine/adverse effects , Glycine/therapeutic use , Humans , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/genetics , Male , Middle Aged , Mutation/drug effects , Pyridines/adverse effects , Treatment Outcome , Triazines/adverse effects , Young AdultABSTRACT
Measurable residual disease (MRD) is a powerful prognostic factor in acute myeloid leukemia (AML). However, pre-treatment molecular predictors of immunophenotypic MRD clearance remain unclear. We analyzed a dataset of 211 patients with pre-treatment next-generation sequencing who received induction chemotherapy and had MRD assessed by serial immunophenotypic monitoring after induction, subsequent therapy, and allogeneic stem cell transplant (allo-SCT). Induction chemotherapy led to MRD- remission, MRD+ remission, and persistent disease in 35%, 27%, and 38% of patients, respectively. With subsequent therapy, 34% of patients with MRD+ and 26% of patients with persistent disease converted to MRD-. Mutations in CEBPA, NRAS, KRAS, and NPM1 predicted high rates of MRD- remission, while mutations in TP53, SF3B1, ASXL1, and RUNX1 and karyotypic abnormalities including inv (3), monosomy 5 or 7 predicted low rates of MRD- remission. Patients with fewer individual clones were more likely to achieve MRD- remission. Among 132 patients who underwent allo-SCT, outcomes were favorable whether patients achieved early MRD- after induction or later MRD- after subsequent therapy prior to allo-SCT. As MRD conversion with chemotherapy prior to allo-SCT is rarely achieved in patients with specific baseline mutational patterns and high clone numbers, upfront inclusion of these patients into clinical trials should be considered.
Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute , Humans , Prognosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Stem Cell Transplantation , Remission Induction , Transplantation, Homologous , Neoplasm, Residual/geneticsABSTRACT
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas include recommendations for the diagnosis and management of pediatric patients with primary mediastinal large B-cell lymphoma (PMBL) and sporadic variants of Burkitt lymphoma and diffuse large B-cell lymphoma. PMBL is now considered as a distinct entity arising from mature thymic B-cells accounting for 2% of mature B-cell lymphomas in children and adolescents. This discussion section includes the recommendations outlined in the NCCN Guidelines for the diagnosis and management of pediatric patients with PMBL.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Adolescent , Humans , Child , Lymphoma, Large B-Cell, Diffuse/pathology , Medical OncologyABSTRACT
Chromosome translocations involving the RUNX1 gene at 21q22 are recurring abnormalities in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), that is, t(8;21) and t(3;21) and in B-cell acute lymphoblastic leukemia with t(12;21). These translocations result in the fusion of RUNX1 with RUNX1T1, MECOM, and ETV6, respectively, and are implicated in leukemogenesis. Here we describe 10 rare RUNX1 fusion gene partners, including six novel fusions, in myeloid neoplasia. Comprehensive molecular testing revealed the partner genes and features of these fusions in all the tested patients, and detected various recurring myeloid related gene mutations in eight patients. In two patients, RUNX1 mutations were identified. Most of these fusions were detected in patients with high-grade MDS and AML with a relatively short survival. Integration of conventional chromosome analysis, FISH testing and molecular genetic studies allow a comprehensive characterization of these rare RUNX1 fusions. Our study may help define myeloid neoplasms with rare and novel RUNX1 translocations and support appropriate patient management.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Myelodysplastic Syndromes/genetics , Oncogene Proteins, Fusion/genetics , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Mutation , Myelodysplastic Syndromes/pathology , Neoplasm Grading , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathologyABSTRACT
BACKGROUND: CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS: We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS: A total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS: In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Receptors, Antigen, T-Cell/therapeutic use , T-Lymphocytes/immunology , Adult , Aged , Cytokines/metabolism , Follow-Up Studies , Humans , Middle Aged , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Recurrence , Remission Induction , Survival AnalysisABSTRACT
Administration of pediatric-inspired chemotherapy to adults up to age 60 with acute lymphoblastic leukemia (ALL) is challenging in part due to toxicities of asparaginase as well as myelosuppression. We conducted a multicenter phase II clinical trial (NCT01920737) investigating a pediatric-inspired regimen, based on the augmented arm of the Children's Cancer Group 1882 protocol, incorporating 6 doses of pegaspargase 2000 IU/m2, rationally synchronized to avoid overlapping toxicity with other agents. We treated 39 adults ages 20-60 years (median, 38 years) with newly-diagnosed ALL (n=31) or lymphoblastic lymphoma (n=8). Grade 3-4 hyperbilirubinemia occurred frequently and at higher rates in patients 40-60 (n=18) vs 18-39 (n=21) years (44 vs 10%, p=0.025). However, 8/9 patients re-challenged with pegaspargase did not experience recurrent grade 3-4 hyperbilirubinemia. Grade 3-4 hypertriglyceridemia and hypofibrinogenemia were common (each 59%). Asparaginase activity at 7-days post-infusion reflected levels associated with adequate asparagine depletion, even among those with antibodies to pegaspargase. Complete response (CR)/CR with incomplete hematologic recovery was observed post-induction in 38/39 (97%) patients. Among patients with ALL, rates of MRD negativity by multiparameter flow cytometry were 33% and 83% following Induction Phase I and Phase II, respectively. Event-free and overall survival at 3 years (67.8 and 76.4%) compare favorably to outcomes observed in other series. These results demonstrate pegaspargase can be administered in the context of intensive multi-agent chemotherapy to adults age ≤60 with manageable toxicity. This regimen may serve as an effective backbone into which novel agents may be incorporated in future frontline studies.
Subject(s)
Asparaginase , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Adult , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Asparaginase/adverse effects , Child , Humans , Middle Aged , Neoplasm, Residual , Philadelphia Chromosome , Polyethylene Glycols/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Young AdultABSTRACT
Autologous stem cell transplantation (ASCT) remains the standard of care for transplantation-eligible patients with multiple myeloma (MM). Bortezomib with lenalidomide and dexamethasone (VRD) is the most common triplet regimen for newly diagnosed MM in the United States. Carfilzomib with lenalidomide and dexamethasone (KRD) has shown promising efficacy and may supplant VRD. We compared stem cell yields and autograft minimal residual disease (MRD)-negativity after VRD and KRD induction. Deeper responses (ie, very good partial response or better) were more common with KRD. Precollection bone marrow (BM) cellularity, interval from the end of induction therapy to start of stem cell collection, and method of stem cell mobilization were similar for the 2 cohorts. Days to complete collection was greater with KRD (2.2 days, versus 1.81 days with VRD), which more often required ≥3 days of apheresis. Precollection viable CD34+ cell content was greater with VRD, as was collection yield (11.11 × 106, versus 9.19 × 106 with KRD). Collection failure (defined as <2 × 106 CD34+ cells/kg) was more frequent with KRD (5.4% versus .7% with VRD). The difference in stem cell yield between VRD and KRD is associated with the degree of lenalidomide exposure. Age ≥70 years predicted poorer collection for both cohorts. Stem cell autograft purity/MRD-negativity was higher with KRD (81.4%, versus 57.1% with VRD). For both cohorts, MRD-negativity was attained in a larger fraction of autografts than in precollection BM. For patients proceeding to ASCT, the time to neutrophil/platelet engraftment was comparable in the 2 study arms. In summary, our data demonstrate that KRD induces deeper clinical responses and greater autograft purity than VRD without compromising stem cell yield or post-transplantation engraftment kinetics.
Subject(s)
Hematopoietic Stem Cell Transplantation , Multiple Myeloma , Aged , Antineoplastic Combined Chemotherapy Protocols , Autografts , Bortezomib/therapeutic use , Dexamethasone/therapeutic use , Hematopoietic Stem Cell Mobilization , Humans , Multiple Myeloma/drug therapy , Neoplasm, Residual , Transplantation, AutologousABSTRACT
Matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-TOF MS) may soon replace routine electrophoretic methods for monitoring monoclonal proteins in patients with multiple myeloma. To further evaluate the clinical utility of this assay, we compared the performance of MALDI-TOF-MS head-to-head with an established bone marrow-based measurable residual disease assay by flow cytometry (Flow-BM-MRD), using Memorial Sloan Kettering Cancer Center's 10-color, single-tube method. Our results suggest that MALDI-TOF-MS adds value to bone marrow-based MRD testing and may be most useful for early detection of relapse in peripheral blood compared to current electrophoretic methods.
Subject(s)
Bone Marrow Examination/methods , Flow Cytometry/methods , Multiple Myeloma/pathology , Myeloma Proteins/analysis , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Adult , Aged , Female , Humans , Immunoglobulin kappa-Chains/analysis , Male , Middle Aged , Multiple Myeloma/blood , Myeloma Proteins/isolation & purification , Neoplasm, Residual , RecurrenceABSTRACT
Recurrent mutations at R140 and R172 in isocitrate dehydrogenase 2 (IDH2) occur in many cancers, including â¼12% of acute myeloid leukemia (AML). In preclinical models these mutations cause accumulation of the oncogenic metabolite R-2-hydroxyglutarate (2-HG) and induce hematopoietic differentiation block. Single-agent enasidenib (AG-221/CC-90007), a selective mutant IDH2 (mIDH2) inhibitor, produced an overall response rate of 40.3% in relapsed/refractory AML (rrAML) patients with mIDH2 in a phase 1 trial. However, its mechanism of action and biomarkers associated with response remain unclear. Here, we measured 2-HG, mIDH2 allele burden, and co-occurring somatic mutations in sequential patient samples from the clinical trial and correlated these with clinical response. Furthermore, we used flow cytometry to assess inhibition of mIDH2 on hematopoietic differentiation. We observed potent 2-HG suppression in both R140 and R172 mIDH2 AML subtypes, with different kinetics, which preceded clinical response. Suppression of 2-HG alone did not predict response, because most nonresponding patients also exhibited 2-HG suppression. Complete remission (CR) with persistence of mIDH2 and normalization of hematopoietic stem and progenitor compartments with emergence of functional mIDH2 neutrophils were observed. In a subset of CR patients, mIDH2 allele burden was reduced and remained undetectable with response. Co-occurring mutations in NRAS and other MAPK pathway effectors were enriched in nonresponding patients, consistent with RAS signaling contributing to primary therapeutic resistance. Together, these data support differentiation as the main mechanism of enasidenib efficacy in relapsed/refractory AML patients and provide insight into resistance mechanisms to inform future mechanism-based combination treatment studies.
Subject(s)
Aminopyridines/therapeutic use , Antineoplastic Agents/therapeutic use , Glutarates/metabolism , Hematopoiesis/drug effects , Isocitrate Dehydrogenase/genetics , Leukemia, Myeloid, Acute/drug therapy , Mutation , Triazines/therapeutic use , Aminopyridines/pharmacology , Antineoplastic Agents/pharmacology , Female , Gene Frequency , Glutarates/antagonists & inhibitors , Humans , Isocitrate Dehydrogenase/antagonists & inhibitors , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Male , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Triazines/pharmacologySubject(s)
Chromosome Deletion , Chromosomes, Human, Pair 5 , Mutation , Phosphoproteins , RNA Splicing Factors , Thrombocytosis , Humans , RNA Splicing Factors/genetics , Thrombocytosis/genetics , Thrombocytosis/diagnosis , Phosphoproteins/genetics , Chromosomes, Human, Pair 5/genetics , Anemia, Sideroblastic/genetics , Anemia, Sideroblastic/diagnosis , Male , Female , Middle Aged , AgedABSTRACT
Measurable residual disease is associated with inferior outcomes in patients with acute myeloid leukemia (AML). Measurable residual disease monitoring enhances risk stratification and may guide therapeutic intervention. The European LeukemiaNet working party recently came to a consensus recommendation incorporating leukemia associated immunophenotype-based different from normal approach by multi-color flow cytometry for measurable residual disease evaluation. However, the analytical approach is highly expertise-dependent and difficult to standardize. Here we demonstrate that loss of plasmacytoid dendritic cell differentiation after 7+3 induction in AML is highly specific for measurable residual disease positivity (specificity 97.4%) in a uniformly treated patient cohort. Moreover, loss of plasmacytoid dendritic cell differentiation as determined by a blast-to-plasmacytoid dendritic cell ratio >10 was strongly associated with inferior overall and relapse-free survival (RFS) [Hazard ratio 2.79, 95% confidence interval (95%CI): 0.98-7.97; P=0.077) and 3.83 (95%CI: 1.51-9.74; P=0.007), respectively), which is similar in magnitude to measurable residual disease positivity. Importantly, measurable residual disease positive patients who reconstituted plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) showed a higher rate of measurable residual disease clearance at later pre-transplant time points compared to patients with loss of plasmacytoid dendritic cell differentiation (blast/ plasmacytoid dendritic cell ratio <10) (6 of 12, 50% vs 2 of 18, 11%; P=0.03). Furthermore pre-transplant plasmacytoid dendritic cell recovery was associated with superior outcome in measurable residual disease positive patients. Our study provides a novel, simple, broadly applicable, and quantitative multi-color flow cytometry approach to risk stratification in AML.
Subject(s)
Dendritic Cells/pathology , Leukemia, Myeloid, Acute/mortality , Neoplasm Recurrence, Local/mortality , Neoplasm, Residual/mortality , Adult , Aged , Case-Control Studies , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm, Residual/pathology , Neoplasm, Residual/therapy , Prognosis , Retrospective Studies , Survival RateABSTRACT
CD99(MIC2) is a widely expressed cell surface glycoprotein and functions as a tumor suppressor involved in downregulation of SRC family of tyrosine kinase. CD99 expression is tightly regulated through B-cell development. The principal aims of this study were to investigate the clinical utility of CD99 expression (i) in distinguishing normal plasma cells from primary plasma cell neoplasms; (ii) in detection of minimal residual disease in primary plasma cell neoplasms; and (iii) in distinguishing plasma cell component of B-cell lymphomas from primary plasma cell neoplasms. We analyzed expression of CD99 by flow cytometry and immunohistochemistry in lymph nodes, peripheral blood, and bone marrow samples. CD99 showed stage-specific expression with highest expression seen in precursor B and plasma cells. In contrast to the uniform bright expression on normal plasma cells, CD99 expression on neoplastic plasma cells was lost in 39 out of 56 (69.6%) cases. Furthermore, 8 out of 56 samples (14%) showed visibly (>10-fold) reduced CD99 expression. Overall, CD99 expression was informative (absent or visibly dimmer than normal) in 84% of primary plasma cell neoplasm. In the context of minimal residual disease detection, CD99 showed superior utility in separating normal and abnormal plasma cells over currently established antigens CD117, CD81, and CD27 by principal component analysis. Preservation of CD99 expression was strongly associated with cyclin D1 translocation in myeloma (p < 0.05). B-cell lymphomas with plasma cell component could be distinguished from myeloma by CD99 expression. In summary, we established that tumor suppressor CD99 is markedly downregulated in multiple myeloma. The loss is highly specific for identification of abnormal cells in primary plasma cell neoplasms, and can be exploited for diagnostic purposes. The role of CD99 in myeloma pathogenesis requires further investigation.