Aleukemic Chronic Myeloid Leukemia Without Neutrophilia and Thrombocytosis: A Report From the BCR::ABL1 Pathology Group.

Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.

Clinical implications of additional chromosomal abnormalities in adult acute myeloid leukemia with inv (16)/t(16;16)/CBFB::MYH11.

OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.

CSF3R mutated myeloid neoplasms: Beyond chronic neutrophilic leukemia.

CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.

Therapy-related myeloid neoplasms with single-hit TP53 mutations share the clinical, molecular, and survival characteristics of their multi-hit counterparts.

Recent updates in the classification of myeloid neoplasms (MNs) recognize the poor prognostic impact of TP53 mutations, with particular emphasis on the TP53 allele status. Studies on the effect of TP53 allele status exclusively in therapy-related MNs (t-MNs) are lacking. We compared the clinicopathologic and survival characteristics of t-MNs with single-hit (SH) and multi-hit (MH) TP53 mutations. A total of 71 TP53-mutated t-MNs were included, including 56 (78.9%) MH and 15 (21.1%) SH. Both groups showed comparable genetic profiles with an excess of high-risk karyotypes and a paucity of other co-mutated genes. TP53 was the sole detectable mutation in 73.3% of SH and 75.0% of MH cases. The overall survival (OS) of SH TP53-mutated t-MNs was not significantly different from MH cases (median survival: 233 vs.273 days, p = 0.70). Our findings suggest that t-MNs with SH TP53 mutations share the poor prognostic and biologic profile of their MH counterparts.