Guilin Tang

Cytogenetic Abnormalities in a Series of 1029 Patients With Primary Myelodysplastic Syndromes A Report From the US With a Focus on Some Undefined Single Chromosomal Abnormalities

Conventional karyotype has an established role in myelodysplastic syndrome (MDS) and is included in the International Prognostic Scoring System (IPSS) for patient risk stratification and treatment selection. Although some chromosomal abnormalities have been well characterized, the significance of several miscellaneous, infrequent, single chromosomal abnormalities remains to be defined. In addition, the emerging therapeutic agents may change the natural course of disease in patients with MDS and the cytogenetic impact on risk stratification.

Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification

Acute erythroid leukemia (AEL) is a rare type of acute myeloid leukemia (AML) for which diagnostic criteria have been refined in the 2008 World Health Organization (WHO) classification of AML. The relationship of AEL to myelodysplastic syndromes (MDSs) and to AML with myelodysplasia-related changes (AML-MRC) is not clearly defined. We conducted a retrospective, multi-institutional study of patients with AEL and compared them with patients with MDS or AML-MRC with erythroid hyperplasia (> or = 50% erythroid cells). Among a total of 124 patients with AEL, 32% had a history of MDS or chronic cytopenia, 32% had therapy-related disease, and 35% had de novo disease. Sixty-four percent of patients had unfavorable AML risk-group karyotypes. FLT3 and RAS mutations were infrequent, occurring in 6% and 2%, respectively. The median overall survival (OS) of all AEL patients was 8 months, comparable with that of patients with MDS or AML-MRC with erythroid hyperplasia. The OS was related to cytogenetic risk group, but not blast count or morphologic dysplasia. Our findings suggest that AEL is in the continuum of MDS and AML with erythroid hyperplasia, where karyotype rather than an arbitrary blast cutoff represents the most important prognostic factor.

Therapy-related myeloid neoplasms following fludarabine, cyclophosphamide, and rituximab (FCR) treatment in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma

This study is focused on therapy-related myeloid neoplasms after the most promising frontline FCR (fludarabine, cyclophosphamide, and rituximab) therapy in previously untreated chronic lymphocytic leukemia patients. A total of 28 therapy-related myeloid neoplasm patients were identified, including 19 patients from 3 well-controlled FCR frontline trials (n=426 patients), giving an estimated frequency of 4.5% (1.9–8.3%) in a follow-up period of 44 months (range 5–122 months). Clinically, therapy-related myeloid neoplasms could emerge directly from ‘prolonged myelosuppression’ after FCR (10 patients), or after achieving complete hematological recovery (n=18). The overall latency was 35 months (range 3–118 months), with the former group of 23 months and the latter 42 months (P<0.001). In all, 10 cases presented as therapy-related acute myeloid leukemia and 18 as therapy-related myelodysplastic syndromes. Abnormal cytogenetics was present in 26 of 27 (96%) patients, with frequent chromosomes 5 and 7 abnormalities. The median survival was 7 months after therapy-related myeloid neoplasms. Our results indicate that the risk of therapy-related myeloid neoplasms secondary to frontline FCR therapy may not be as high as previously reported after removing the confounding factor of previous cytotoxic exposure, but this risk increased with older age and likely growth factor co-administration. Therapy-related myeloid neoplasms after FCR therapy shares clinicopathological features with therapy-related myeloid neoplasms secondary to other alkylating agents, but has a shorter latency interval indicating possible synergetic effects of the nucleotide analog fludarabine. The fact that therapy-related myeloid neoplasms can directly emerge from ‘prolonged myelosuppression’ warrants a bone marrow examination to rule out therapy-related myeloid neoplasms in this clinical setting.

Systemic mastocytosis with associated clonal hematological non‐mast cell lineage disease: Clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components

Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non‐mast cell lineage disease (SM‐AHNMD). In this study, we analyzed 29 patients with SM‐AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B‐cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM‐AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not‐reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM‐AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence‐in‐situ hybridization performed in four SM‐AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM‐CMML and one patient with SM‐MDS, but not in the mast cells of a case SM‐associated with chronic lymphocytic leukemia with ATM‐deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM‐CMML and SM‐MDS than in pure SM (P < 0.001). Our data indicate that the SM‐AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM‐AHNMD is often dictated by the type of AHNMD. Am. J. Hematol. 88:219–224, 2013.

Erythroid-predominant myelodysplastic syndromes: enumeration of blasts from nonerythroid rather than total marrow cells provides superior risk stratification

In the FAB (French–American–British) and WHO (World Heath Organization) classifications, the blasts in erythroleukemia (M6a) are enumerated from the marrow nonerythroid rather than the total-nucleated cells. However, the method for blast calculation in erythroid-predominant myelodysplastic syndrome (erythroblasts≥50%) is not specified either in the FAB or WHO classifications. We retrieved the files of 74 erythroid-predominant myelodysplastic syndrome patients (17% of all myelodysplastic syndrome) and 192 myelodysplastic syndrome controls (erythroblasts<50%). In erythroid-predominant myelodysplastic syndrome, by enumerating blasts from marrow nonerythroid cells rather than from total nucleated cells, 41 of 74 (55%) cases would be upgraded, either by disease subcategory or International Prognostic Scoring System. Importantly, the patients with <5% blasts demonstrated a superior survival to patients with ≥5% blasts (P=0.002); this distinction was lost when blasts were calculated from total-nucleated cells. Of cases with ≥5% blasts, cytogenetics rather than blast count correlated with survival. We conclude that in erythroid-predominant myelodysplastic syndrome, blast calculation as a proportion of marrow nonerythroid rather than total nucleated cells can better stratify patients into prognostically relevant groups.

Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases

In this study we used a next generation sequencing-based approach to profile gene mutations in therapy-related myelodysplastic syndromes (t-MDS) and acute myeloid leukemia (t-AML); and compared these findings with de novo MDS/AML. Consecutive bone marrow samples of 498 patients, including 70 therapy-related (28 MDS and 42 AML) and 428 de novo (147 MDS and 281 AML) were analyzed using a modified-TruSeq Amplicon Cancer Panel (Illumina) covering mutation hotspots of 53 genes. Overall, mutation(s) were detected in 58.6% of t-MDS/AML and 56.8% of de novo MDS/AML. Of therapy-related cases, mutations were detected in 71.4% of t-AML versus 39.3% t-MDS (p=0.0127). TP53 was the most common mutated gene in t-MDS (35.7%) as well as t-AML (33.3%), significantly higher than de novo MDS (17.7%) (p=0.0410) and de novo AML (12.8%) (p=0.0020). t-AML showed more frequent PTPN11 but less NPM1 and FLT3 mutations than de novo AML. In summary, t-MDS/AML shows a mutation profile different from their de novo counterparts. TP53 mutations are highly and similarly prevalent in t-MDS and t-AML but mutations in genes other than TP53 were more frequent in t-AML than t-MDS. The molecular genetic profiling further expands our understanding in this group of clinically aggressive yet heterogeneous myeloid neoplasms.

Risk stratification of chromosomal abnormalities in chronic myelogenous leukemia in the era of tyrosine kinase inhibitor therapy

Clonal cytogenetic evolution with additional chromosomal abnormalities (ACAs) in chronic myelogenous leukemia (CML) is generally associated with decreased response to tyrosine kinase inhibitor (TKI) therapy and adverse survival. Although ACAs are considered as a sign of disease progression and have been used as one of the criteria for accelerated phase, the differential prognostic impact of individual ACAs in CML is unknown, and a classification system to reflect such prognostic impact is lacking. In this study, we aimed to address these questions using a large cohort of CML patients treated in the era of TKIs. We focused on cases with single chromosomal changes at the time of ACA emergence and stratified the 6 most common ACAs into 2 groups: group 1 with a relatively good prognosis including trisomy 8, -Y, and an extra copy of Philadelphia chromosome; and group 2 with a relatively poor prognosis including i(17)(q10), -7/del7q, and 3q26.2 rearrangements. Patients in group 1 showed much better treatment response and survival than patients in group 2. When compared with cases with no ACAs, ACAs in group 2 conferred a worse survival irrelevant to the emergence phase and time. In contrast, ACAs in group 1 had no adverse impact on survival when they emerged from chronic phase or at the time of CML diagnosis. The concurrent presence of 2 or more ACAs conferred an inferior survival and can be categorized into the poor prognostic group.

Cytogenetic risk stratification of 417 patients with chronic myelomonocytic leukemia from a single institution

Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) have karyotypic abnormalities and this low frequency has made using cytogenetic data for the prognostication of CMML patients challenging. Recently, a three‐tiered cytogenetic risk stratification system for CMML patients has been proposed by a Spanish study group. Here we assessed the prognostic impact of cytogenetic abnormalities on overall survival (OS) and leukemia‐free survival (LFS) in 417 CMML patients from our institution. Overall, the Spanish cytogenetic risk effectively stratified patients into different risk groups, with a median OS of 33 months in the low‐, 24 months in intermediate‐ and 14 months in the high‐risk groups. Within the proposed high risk group, however, marked differences in OS were observed. Patients with isolated trisomy 8 showed a median OS of 22 months, similar to the intermediate‐risk group (P = 0.132), but significantly better than other patients in the high‐risk group (P = 0.018). Furthermore, patients with more than three chromosomal abnormalities showed a significantly shorter OS compared with patients with three abnormalities (8 vs. 15 months, P = 0.004), suggesting possible a separate risk category. If we simply moved trisomy 8 to the intermediate risk category, the modified cytogenetic grouping would provide a better separation of OS and LFS; and its prognostic impact was independent of other risk parameters. Our study results strongly advocate for the incorporation of cytogenetic information in the risk model for CMML. Am. J. Hematol. 89:813–818, 2014.

Immunophenotypic heterogeneity of normal plasma cells: comparison with minimal residual plasma cell myeloma

Plasma cell myeloma (PCM) exhibits immunophenotypic aberrancies that can be used for minimal residual disease (MRD) detection after therapy. The authors sought to determine whether non-neoplastic plasma cells, especially in the bone marrow (BM) post various therapies, would exhibit immunophenotypic variations interfering PCM MRD detection. The authors studied the flow cytometric immunophenotypes of non-neoplastic plasma cells from 50 BM specimens, including 12 untreated BM and 38 BM specimens from patients with non-plasmacytic haematological malignancies undergoing various therapies, and compared with 59 BM specimens positive for PCM MRD. Non-neoplastic plasma cells showed heterogeneous expressions of CD45 (78% (41–100)) and CD19 (80% (52–97)), and were negative for CD20 and CD117. CD56 was observed in a small subset (6% (0–37)) and CD28 in a larger subset (15% (0–59)) of non-neoplastic plasma cells, with the latter more frequently expressed in post-treatment BMs (p=0.01). However, despite a partial immunophenotypic overlap, PCM cells could be reliably discriminated from non-neoplastic plasma cells by the presence of a higher number of aberrancies (3 (1–6) vs 0 (0–2)) and stronger intensity and uniformity of aberrant expression (p<0.001 in each marker using a cut-off value). In addition, simultaneous assessment of cytoplasmic κ/λ with surface markers detected light chain restriction in all 59 PCM cases. In conclusion, non-neoplastic plasma cells in BM are more immunophenotypically heterogeneous than previously understood; however, these immunophenotypic variations differ from those of PCM. With advances in multicolour flow cytometry and application of recently validated markers, PCM MRD may still be reliably distinguished from non-neoplastic plasma cells.

MYC/BCL6 double-hit lymphoma (DHL): a tumour associated with an aggressive clinical course and poor prognosis

Large B cell lymphomas with MYC and BCL6/3q27 rearrangements, designated MYC/BCL6 DHL, are uncommon. Our aim was to better characterize this group of tumours.