Natural history of newly diagnosed myelodysplastic syndrome with isolated inv(3)/t(3;3)
Authors: Koji Sasaki, Guillermo Montalban‐Bravo, Rashmi Kanagal‐Shamanna, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Naval Daver, Naveen Pemmaraju, Marina Konopleva, Gautam Borthakur, Koichi Takahashi, Keyur Patel, Kelly A. Soltysiak, Kelly S. Chien, Kenichi Sakurai, Sherry Pierce, Hagop M. Kantarjian, Guillermo Garcia‐Manero
Journal: American Journal of Hematology (2020)

The MDS1 and EVI1 complex locus (MECOM) rearrangements inv(3) and t(3;3) are adverse cytogenetic abnormalities observed in less than 1% of patients with myelodysplastic syndrome (MDS), and are associated with a high risk for progression to acute myeloid leukemia (AML).1, 2 Both inv(3) and t(3;3) occur within the MECOM complex at genes EVI1 and MDS1 on chromosome 3q26.2 and the RPN1 and GATA2 genes on chromosome 3q21.2 These rearrangements result in overexpression of the oncogenic transcription factor EVI1: EVI1/RPN1 fusion or a longer variant at the MDS1/EVI1 transcript.3 Such overexpression can promote proliferation and impair differentiation of myeloid precursor cells, which leads to leukemogenesis. Given the unique biological process and poor prognosis associated with the MECOM rearrangements, we hypothesized that the presence of inv(3)/t(3;3) warrant a diagnosis of AML regardless of the percentage of blasts in bone marrow. However, MECOM rearrangements are often accompanied with other adverse karyotype abnormalities such as monosomy 7.4, 5 Therefore, the purpose of this study is to evaluate clinical course of patients with MDS and isolated inv(3)/t(3;3). We performed a cytogenetic database search of patients admitted to MD Anderson Cancer Center with MDS and AML from 24 November 1997 to 2 February 2020 for the presence of isolated inv(3) and t(3;3). Patients who had other chromosomal abnormalities at initial diagnosis of MDS other than inv(3) and t(3;3) were excluded from further analysis, as were those who previously received hypomethylating agents (HMAs), cytarabine-based regimens, or intensive chemotherapy. The International Working Group 2006 criteria were used for treatment response evaluation. Complete remission (CR) was defined as <5% blasts with normal maturation of all cell lines, hemoglobin level >11 g/dL, absolute neutrophil count >1 × 109/L, platelet count >100 × 109/L, and 0% blasts in peripheral blood smears. Bone marrow aspirates from patients with newly diagnosed or therapy-related MDS were analyzed via conventional karyotyping and next generation sequencing. We compared the outcome of patients with MDS and isolated inv(3)/t(3;3) to patients with newly diagnosed AML and isolated inv(3)/t(3;3). The 2017 European LeukemiaNet recommendations were used for treatment response evaluation in AML patients. Complete remission was defined as <5% blasts in bone marrow, absence of Auer rods and extramedullary disease, absolute neutrophil count >1 × 109/L, platelet count >100 × 109/L, and absence of blasts in peripheral blood. Outcomes of chemotherapy (HMAs, cytarabine-based regimens, intensive therapy) and allogeneic stem cell transplantation (ASCT) were reviewed. Progression to AML was defined as the presence of ≥20% blasts in bone marrow or peripheral blood following an initial diagnosis of MDS. Baseline patient characteristics were compared with the Fisher's exact, Mann-Whitney U, and chi-square tests to assess differences between patients with MDS and isolated inv(3)/t(3;3) and patients with AML and inv(3)/t(3;3). Progression-free survival (PFS) was measured from the date of diagnosis to the date of progression from MDS to AML, death, or last follow-up; overall survival (OS) was measured from the date of diagnosis to the date of death or last follow-up visit. The Kaplan-Meier method was used to estimate PFS and OS, and was compared by a log-rank test. All reported P values were two-sided, and P values <.05 were considered significant. All statistical analyses were performed using the SPSS software program (version 24). We reviewed 441 bone marrow aspirates with either inv(3) or t(3;3) from 161 patients [inv(3), 182 bone marrow samples from 78 patients; t(3;3), 259 bone marrow samples from 83 patients]. We identified 15 patients with newly diagnosed MDS and either isolated inv(3) or isolated t(3;3) (Figure 1; Table S1; Table S2; Table S3). By IPSS, six patients (40%) were in the intermediate-1, six patients (40%) were in the intermediate-2, and three patients (20%) high risk groups (Table S4). Given the addition of inv(3)/t(3;3) in adverse cytogenetic abnormalities in the IPSS-R risk classification, 14 (93%) patients were in either high or very high risk groups, and one (7%) patient was in the intermediate risk group. Among 15 patients with MDS and isolated inv(3)/t(3;3), nine (60%) patients with MDS received HMA therapy; one (7%), a cytarabine-based regimen; one (7%), intensive chemotherapy (fludarabine, cytarabine, and idarubicin); and four (27%) were untreated due to rapid progression to AML (Table S3). Of the 11 patients who received therapy, four (36%) achieved CR, and underwent subsequent ASCT, and seven (64%) had progressive disease. Among nine patients who received HMA therapy, three (33%) patients achieved CR. The overall median follow-up duration was 55 months (range, 2-55 months). The 5-year PFS rate was 7% with a median PFS of 7 months (Figure S1A); the 5-year OS rate was 7% and the median OS was 12 months (Figure S1B). By IPSS, the 5-year PFS and OS rates in the high risk group were 33% and 33%, respectively; in the intermediate-1 group, 0% and 0%, respectively; in the intermediate-2 group, 0% and 0%, respectively (P = .325; P = .193) (Figure S2A,B). Similarly, by IPSS-R, the PFS and OS rates in the very high risk groups were 14% and 14%, respectively; in the intermediate-1 group, 0% and 0%, respectively; in the intermediate-2 group, 0% and 0%, respectively (P = .500; P = .702) (Figure S2C,D). Among four patients in CR, one patient relapsed 5 months after the CR and died within 3 months after relapse; one patient progressed to AML 3 months after the CR and died within 2 months after relapse; and one patient died of graft-vs-host disease in CR at 5 months following ASCT. One patient achieved CR after intensive chemotherapy (two cycles of fludarabine, cytarabine, and idarubicin) and underwent ASCT. We further compared outcomes of isolated inv(3)/t(3;3) and survival between MDS and AML. Among nine patients with AML and isolated inv(3)/t(3;3), three (33%) achieved CR (Table S5). When we compared the median survival of 5 months in nine patients with newly diagnosed AML and isolated inv(3)/t(3;3), patients with MDS and isolated inv(3)/t(3;3) had a median survival of 12 months (P = .061) (Figure S1B). The only patient who is alive at the completion of this study is a 29-year-old female diagnosed with glioblastoma multiforme in 2012 who underwent treatment with temozolomide, an alkylating agent. She experienced pancytopenia in 2015 (white blood cell count, 1.9 × 109/L; hemoglobin level, 8.6 g/dL; platelet count, 93 × 109/L). Bone marrow examination showed refractory anemia with excess blasts-1 (13% blasts) with isolated inv(3). The patient immediately received the intensive chemotherapy (two cycles of fludarabine, cytarabine, and idarubicin), achieved CR, and underwent subsequent ASCT. The patient had no signs of disease progression for 55 months since the diagnosis of MDS. The prognosis of patients with MDS and isolated inv(3)/t(3;3) is poor, with rapid progression to AML. Given the high incidence of additional adverse cytogenetic abnormalities associated with the MECOM rearrangements in patients with MDS, we confirmed unfavorable prognosis in patients with isolated inv(3)/t(3;3). Notably, 60% of patients progressed to AML within a month after the diagnosis of MDS and isolated inv(3)/t(3;3) without chronic stable cytopenias. The rapid progression to AML can justify the diagnosis of AML in patients with isolated inv(3)/t(3;3) and <20% blasts in bone marrow. Approximately, one-third of patients achieved CR/mCR after either HMA therapy or intensive chemotherapy. However, the response was not durable, with a median time to progression of only 7 months. Proactive early consideration of ASCT should be considered in patients with MDS and isolated inv(3)/t(3;3) regardless of IPSS risk classification. We observed one long-term survivor who received intensive chemotherapy and subsequent stem cell transplant. This is consistent with Halaburda, et al who reported the outcome of 98 patients with AML and inv(3)/t(3;3) who underwent ASCT.6 Patients aged <50 years who proceeded to ASCT in remission had significantly better survival outcomes than those with active disease.6 Given the expected poor survival after progression to AML, patients with MDS and inv(3)/t(3;3) may need early intervention with ASCT. Notwithstanding the limitations conferred by the small subsets of patients in the present study, previous studies included additional adverse cytogenetic abnormalities in patients with MDS and inv(3)/t(3;3). We excluded the effect of additional adverse cytogenetic abnormalities to clarify the impact of isolated inv(3)/t(3;3) on survival. In conclusion, patients with MDS and isolated inv(3)/t(3;3) progress to AML without chronic cytopenias. Given the characteristic biological feature and the rapidity of progression, the diagnosis of AML regardless of the percentage of blasts in bone marrow should be warranted. Early intervention with ASCT should be considered, particularly in younger patients. This work was supported in part by the University of Texas MD Anderson Cancer Center Support Grant CA016672, the University of Texas MD Anderson MDS/AML Moon Shot, and Leukemia Texas. Koji Sasaki: Concept and design; administrative support; provision of study materials and patients; data collection, analysis, interpretation; and manuscript writing and final approval. Guillermo Montalban-Bravo, Rashmi Kanagal-Shamanna, Elias Jabbour, Farhad Ravandi, Tapan Kadia, Naval Daver, Naveen Pemmaraju, Marina Konopleva, Gautam Borthakur, Koichi Takahashi, KN, Keyur Patel, Kelly S. Chien, Guillermo Garcia-Manero: Collection and assembly of data; data analysis and interpretation; manuscript writing; and final approval of manuscript. Kenichi Sakurai: data collection, manuscript writing and final approval. Sherry Pierce: Provision of study materials; data collection, and final approval. Kelly A. Soltysiak: Administrative support; data analysis and interpretation; and manuscript writing and final approval. Koji Sasaki: This author declares an advisory role with Pfizer Japan. Guillermo Montalban-Bravo: This author declares no conflict of interest. Rashmi Kanagal-Shamanna: This author declares no conflict of interest. Elias Jabbour: This author declares research support and an advisory role with Adaptive, AbbVie, Amgen, Pfizer, Cyclacel LTD, Takeda, Bristol-Myers Squibb. Farhad Ravandi: This author declares research support and an advisory role with Macrogeni, Selvita, Cyclacel LTD, Menarini Ricerche, Xencor. Tapan Kadia: This author declares research support and an advisory role with Amgen, Bioline RX, Pfizer, Jazz, BMS, Celgene, Genentech, Pharmacyclics, Takeda, AbbVie. Naval Daver: This author declares no conflict of interest. Naveen Pemmaraju: This author declares no conflict of interest. Marina Konopleva: This author declares research support and an advisory role with Eli Lilly, AbbVie, Cellectis, Amgen, F. Hoffman La-Roche, Genentech, Ascentage, Kisoji, Reata. Pharmaceuticals, Ablynx, Astra Zeneca, Agios, Forty-Seven, Stemline Therapeutics, Calithera. Gautam Borthakur: This author declares no conflict of interest. Koichi Takahashi: This author declares an advisory role with Symbio Pharmaceuticals. Keyur Patel: This author declares no conflict of interest. Kelly A. Soltysiak: This author declares no conflict of interest. Kelly S. Chien: This author declares no conflict of interest. Kenichi Sakurai: This author declares no conflict of interest. Sherry Pierce: This author declares no conflict of interest. Guillermo Garcia-Manero: This author declares research support and an advisory role with Bristol Myers Squibb, Astex, and Helsinn, and research support from Amphivena, Novartis, AbbVie, H3 Biomedicine, Onconova, and Merck. Figure S1. Patient outcomes: A) PFS in patients with MDS and isolated inv(3)/t(3;3), and B) OS by disease. Abbreviations: PFS, progression-free survival; OS, overall survival; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia. Figure S2. Overall survival and progression-free survival: (A) PFS by IPSS, (B) OS by IPSS, (C) PFS by IPSS-R, and (D) OS by IPSS-R. Abbreviations: Int-1, intermediate-1; Int-2, intermediate-2; IPSS, International Prognostic Scoring System; IPSS-R, Revised International Scoring System; OS, overall survival; PFS, progression-free survival; MDS, myelodysplastic syndrome; AML, acute myeloid leukemia. Table S1. Patient characteristics Table S2. Karyotypes Table S3. Mutations Table S4. Classification of myelodysplastic syndromes at diagnosis Table S5. Therapy and response Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.