Biologic features and clinical outcomes in newly diagnosed myelodysplastic syndrome with KMT2A rearrangements.

Myeloid neoplasms with KMT2A (previously called MLL) gene rearrangements result from translocations involving KMT2A located on chromosome 11q23 and various partner genes, most often MLLT3, AF4, ENL, and ELL.1 KMT2Ar AML in adults is inherently chemotherapy resistant and patients have a poor prognosis, although recent clinical trials with menin inhibitors (which regulate aberrant gene expression consequent to KMT2A fusions) have shown promising results. KMT2Ar in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) is extremely rare and most reports have only been in conjunction with studies of KMT2Ar acute leukemias.1 One study reported a small number of KMT2Ar among cases of therapy-related MDS and these cases exhibited a poorer prognosis than expected, given that KMT2A rearrangement is considered intermediate-risk in the IPSS-R cytogenetic risk stratification scheme.2 This is a currently relevant issue, since the International Consensus Classification (ICC) and proposed 5th edition WHO Classification of myeloid neoplasms (WHO2022) now consider KMT2A rearrangement to be AML-defining for myeloid neoplasms with <20% blasts.3, 4 We evaluated the clinicopathologic characteristics and outcomes of patients with KMT2Ar MDS/CMML in comparison to KMT2Ar AML at three tertiary cancer centers. We retrospectively retrieved cases of untreated MDS/CMML (<20% blasts in bone marrow [BM] and blood [PB]) with confirmed 11q23/KMT2A rearrangements from 2005 to 2022. For controls, 100 patients with newly diagnosed AML with 11q23/KMT2A rearrangements were randomly selected over the same time period. Morphological diagnoses were confirmed by five expert hematopathologists (SK, SAW, BT, OP, and RPH): for all cases, promonocytes (but not mature monocytes) were considered as blast equivalents. This study was conducted under approval of the institutional review committees at all participating institutions and in accordance with the declaration of Helsinki. We identified 31 patients with KMT2Ar MDS/CMML and 100 patients with KMT2Ar AML. Patients with KMT2Ar MDS/CMML had similar age and sex distribution, but were less thrombocytopenic (median platelet count 75 × 109/L vs 37 × 109/L, p = .004) than the AML patients. The percentage of BM cells with KMT2A rearrangement by FISH was significantly higher in KMT2Ar AML compared with MDS/CMML (median 92% vs 60.25%, p < .0001). Baseline characteristics of the KMT2Ar MDS/CMML and AML patients are presented in Table 1. Therapy-related disease was more common in the MDS/CMML group compared with the AML group (74% vs 38% p = .0005), with greater latency after prior therapy in KMT2Ar MDS/CMML compared with AML (median 32 months vs 24 months, p = .018). Respective malignancies and their frequencies in individual cohorts are presented in Table S1. KMT2A rearrangement partners were identified in 26 KMT2Ar MDS/CMML and 92 KMT2Ar AML cases (Table S2). 9p21/MLLT3 (AF9) occurred significantly less frequently in KMT2Ar MDS/CMML compared with AML (29% vs 58% p = .007). Data from standard NGS mutation testing were available for 20 of the KMT2Ar MDS/CMML and 66 of the KMT2Ar AML cases. Mutation frequencies are shown in Table S3. Overall, 12 of 20 (60%) KMT2Ar MDS/CMML and 27 of 66 (41%) AML (p > .05) had no detected mutations. The median number of mutations per patient in KMT2Ar MDS/CMML was 0 (range, 0–3), which was borderline lower compared with KMT2Ar AML (median number of mutations 1, range 0–7, p = .08). Mutation distribution was heterogenous in KMT2Ar MDS/CMML and these patients had a significantly lower frequency of mutations in the RAS pathway genes KRAS, NRAS, FLT3, and/or PTNP11 compared with KMT2Ar AML (p < .002). Both cohorts had only rare TP53 mutations, with 1 patient (8%) in the MDS/CMML cohort and 2 patients (3%) in the AML cohort. Mutations in genes associated with clonal hematopoiesis were infrequent in both cohorts and included ASXL1 (8%), DNMT3A (8%), and TET2 (8%) in KMT2Ar MDS/CMML, frequencies that were not significantly different from KMT2Ar AML (p > .05). There were no NPM1 or in-frame bZIP CEBPA mutations in either cohort. Twenty-nine (94%) MDS/CMML patients and 96 (96%) AML patients received treatment. KMT2Ar MDS/CMML patients were predominantly treated with hypomethylating agents (HMAs) (n = 18, 62%), whereas intensive chemotherapy was the first line of treatment employed for most KMT2Ar AML patients (n = 68, 71%). Among the KMT2Ar MDS/CMML patients, 27 (93%) were treated initially with chemotherapy, of which 13 (48%) attained CR and 8 of these patients (62%) received SCT. The other two treated patients (7%) underwent upfront SCT: one transformed to AML after 5 months while the other remains in CR 15 months after the original diagnosis. In the KMT2Ar AML cohort, intensive chemotherapy was used upfront in 68 (68%) patients; other treatments were low-dose cytarabine or nucleoside analogue with/without venetoclax in 13 (13%) and HMA in 11 (11%) patients (Table S4). CR was attained in 65 (69%) patients and 48 (74%) patients underwent SCT. Overall, 20 of 29 (69%) KMT2Ar MDS/CMML patients progressed to AML with a median progression-free survival (PFS) of 4.5 months (range, 1–27 months). The KMT2A rearrangement identified at the time of diagnosis of MDS persisted in the AML, with an increase in FISH KMT2Ar percentage from 36.5% (range 9–87.5) in the MDS/CMML phase to 87.5% (range, 8.5–100%) in the AML phase of the disease. NGS testing revealed the acquisition of additional mutations at the time of AML progression including NRAS, PTPN11, FLT3, and BRAF. Karyotypes, time to progression, and mutation profile of individual MDS/CMML patients who progressed to AML are shown in Table S5. With a median follow-up of 45 months (range, <1–117 months), the median overall survival (OS) was 12 months for KMT2Ar MDS/CMML patients vs 14.4 months for AML patients (p = .62 [HR 1.13, CI 0.6725–1.922]) (Figure S1A–C). On univariate analysis of the combined MDS/CMML and AML patients, older age (p < .0001), lower platelet count (p = .007), and therapy-related disease (p = .004) were associated with shorter OS, whereas use of SCT (p < .0001) and intensive therapy (p < .0001) were associated with longer OS. There was no significant influence of partner gene, isolated KMT2Ar vs complex/noncomplex karyotypes, or presence of co-mutations on OS. On multivariable analysis including all factors with p < .20 identified in the initial univariate analysis, patient age (HR 1.017 [1.001–1.032], p = .033), platelet count (HR 0.991 [0.000–0.997], p = .005), and use of SCT (HR 0.227 [0.000–0.381], p < .0001) were found to independently significantly influence OS, whereas the effect of therapy-relatedness (HR 1.521 [0.957–2.415], p = .076) was no longer significant. In separate multivariable analyses, there were no significant effects of MDS/CMML vs AML, <10% versus ≥10% BM blasts, or blasts as a continuous variable on OS (data not shown). KMT2A rearrangement represents a distinct cytogenetic subtype of AML and is considered to be a founding and driving event for leukemogenesis. The occurrence of KMT2A rearrangement in MDS/CMML is extremely rare and to our knowledge, this case series is the first to report detailed clinical characteristics of these patients. Despite some differences in the clinical presentation, treatment approaches, and genetic findings, we found no difference in outcomes between KMT2Ar MDS/CMML and AML. We explored a blast cutoff of 10% and found longer survival in cases with <10% blasts (12 months vs 8.5 months, p = .03) in the MDS/CMML cohort (data not shown). However, in multivariable analysis, a 10% blast cutoff did not significantly influence OS. While the t(9,11);KMT2A::MLLT3 is considered as intermediate-risk and the other KMT2A rearrangements are adverse-risk per the 2022 European LeukemiaNet (ELN) classification,5 prognosis was not influenced by translocation partners in our cohort. This result may reflect the heterogeneous treatment approaches to our patients, whereas the ELN risk scheme is intended to predict the outcome for patients treated with intensive chemotherapy. There was a significantly higher proportion of therapy-related disease in KMT2Ar MDS/CMML compared with KMT2Ar AML (74% vs 38%, p = .0005); the most common malignancy in both groups was breast cancer followed by sarcomas, which corresponds to use of topoisomerase II inhibitors, especially anthracyclines, for the treatment of these malignancies. Another key finding in our study is that while KMT2Ar MDS/CMML patients generally had few co-mutations, many patients had acquired new mutations in RAS pathway genes upon transformation to AML. These data suggest that the higher blast counts in AML versus MDS/CMML may be driven in many cases by pro-proliferative mutations, whether present at the time of disease outset or acquired secondarily in progression of KMT2Ar MDS/CMML. The prognosis of patients with KMT2Ar MDS/CMML was extremely poor, with a PFS of 4.5 months and median OS of 12 months, despite lower blast and WBC counts at presentation compared with KMT2Ar AML. Even including patients treated with SCT, 62% of MDS/CMML patients progressed to AML in ≤5 months. This lack of durable responses in KMT2Ar MDS/CMML is similar to MDS with MECOM rearrangements, who also have short survival6 and are considered to represent a high-risk disease that biologically overlaps with its AML counterpart. Our study demonstrates the clinical aggressiveness of KMT2Ar MDS/CMML, despite having less prominent ‘proliferative features’ compared with KMT2Ar AML, such as fewer RAS pathway mutations and lower blast and WBC counts. We hypothesize that KMT2Ar MDS/CMML and AML likely represent the same biologic entity that is driven by their shared KMT2A rearrangement. The recent WHO2022 and ICC consider KMT2Ar to be AML-defining in patients with blast counts of <20%.3, 4 While the ICC requires at least 10% BM or blood blasts to diagnose AML with KMT2Ar, no blast threshold applies in WHO2022; in our series, 11 of 31 of the MDS/CMML patients (35%) would be classified as AML per ICC criteria (data not shown). The results of our study support the AML-defining designation of KMT2Ar in the ICC and WHO2022. Further data are needed to determine whether the 10% blast cutoff applied by the ICC defines a less aggressive disease group within KMT2Ar myeloid neoplasms. There is a clinical need for innovative therapies in these patients and they should be considered for clinical trials enrolling patients with KMT2Ar AML, even if the patients present with blast counts <20%. Maria Siddiqui, Sergej Konoplev, and Robert P. Hasserjian were involved in study design, gathering and analyzing the data, and writing the manuscript. Sergej Konoplev, Olga Pozdnyakova, Robert P. Hasserjian, Guilin Tang, Beenu Thakral, and Sa A. Wang were involved with cytogenetic analysis. Ghayas Issa, Hagop Kantarjian, Naval Daver, Farhad Ravandi, Tapan Kadia, L. Jeffrey Medeiros, Sherry Pierce, Guillermo Montalban-Bravo, Kelly Chien, Danielle Hammond, Koji Sasaki, and Guillermo Garcia-Manero provided suggestions and revisions. All authors read and approved the final manuscript. F.R. has received research funding from Biomea Fusion. The are no other conflicts to declare. The data that support the findings of this study are available from the corresponding author upon reasonable request. Data S1: Table S1. Antecedent malignancies in cohorts. Table S2. KMT2A partners. Table S3. Mutation distribution in KMT2Ar MDS/CMML and KMT2Ar AML patients. Table S4. Treatment regimens of KMT2Ar MDS/CMML and AML. 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