Publications by authors named "Robert P Hasserjian"

185 Publications

Myelodysplastic/myeloproliferative neoplasms-unclassifiable with isolated isochromosome 17q represents a distinct clinico-biologic subset: a multi-institutional collaborative study from the Bone Marrow Pathology Group.

Mod Pathol 2021 Nov 13. Epub 2021 Nov 13.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Classification of myeloid neoplasms with isolated isochromosome i(17q) [17p deletion with inherent monoallelic TP53 loss plus 17q duplication] is controversial. Most cases fall within the WHO unclassifiable myelodysplastic/myeloproliferative neoplasms (MDS/MPN-U) category. The uniformly dismal outcomes warrant better understanding of this entity. We undertook a multi-institutional retrospective study of 92 adult MDS/MPN-U cases from eight institutions. Twenty-nine (32%) patients had isolated i(17q) [MDS/MPN-i(17q)]. Compared to MDS/MPN without i(17q), MDS/MPN-i(17q) patients were significantly younger, had lower platelet and absolute neutrophil counts, and higher frequency of splenomegaly and circulating blasts. MDS/MPN-i(17q) cases showed frequent bilobed neutrophils (75% vs. 23%; P = 0.03), hypolobated megakaryocytes (62% vs. 20%; P = 0.06), and a higher frequency of SETBP1 (69% vs. 5%; P = 0.002) and SRSF2 (63% vs. 5%; P = 0.006) mutations that were frequently co-existent (44% vs. 0%; P = 0.01). TP53 mutations were rare. The mutation profile of MDS/MPN-U-i(17q) was similar to other myeloid neoplasms with i(17q) including atypical chronic myeloid leukemia, chronic myelomonocytic leukemia, myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, myelodysplastic syndrome and acute myeloid leukemia, with frequent concomitant SETBP1/SRSF2 mutations observed across all the diagnostic entities. Over a median follow-up of 52 months, patients with MDS/MPN-i(17q) showed a shorter median overall survival (11 vs. 28 months; P < 0.001). The presence of i(17q) retained independent poor prognostic value in multivariable Cox-regression analysis [HR 3.686 (1.17-11.6); P = 0.026] along with splenomegaly. We suggest that MDS/MPN-i(17q) warrants recognition as a distinct subtype within the MDS/MPN-U category based on its unique clinico-biologic features and uniformly poor prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-021-00961-0DOI Listing
November 2021

Combined Phenotype Score Is Associated with the Clinical Outcome of -Mutated Myelodysplastic Syndromes.

Cancers (Basel) 2021 Nov 2;13(21). Epub 2021 Nov 2.

Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

Mutations of are observed in 5-10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the allelic state and variant allele frequency of mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with -mutated MDS. We assessed each mutation according to the phenotypic annotation of mutations (PHANTM) and analyzed the associations between predicted mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01-2.58), = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with -mutated MDS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13215502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8582962PMC
November 2021

Case 33-2021: A 68-Year-Old Man with Painful Mouth Ulcers.

N Engl J Med 2021 Oct;385(18):1700-1710

From the Department of Oral Medicine and Dentistry, Brigham and Women's Hospital (S.-B.W., N.S.T.), the Departments of Radiology (M.Y.W.), Medicine (P.C.A.), Dermatology (D.K.), and Pathology (R.P.H.), Massachusetts General Hospital, and the Departments of Radiology (M.Y.W.), Medicine (P.C.A.), Dermatology (D.K.), and Pathology (R.P.H.), Harvard Medical School - all in Boston.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMcpc2107352DOI Listing
October 2021

Lymph node FNA cytology: Diagnostic performance and clinical implications of proposed diagnostic categories.

Cancer Cytopathol 2021 Oct 18. Epub 2021 Oct 18.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.

Background: Despite widespread clinical use, lymph node fine-needle aspiration cytology (LN-FNAC) lacks universal acceptance for definitively diagnosing lymphomas. This is likely due to reports of lower diagnostic performance, inconsistent terminology use in cytopathology diagnostic reports, and only limited data on the clinical implications of LN-FNAC diagnoses. Recently, a uniform LN-FNAC cytopathological diagnostic reporting system was proposed (the Sydney System). This study evaluated LN-FNAC diagnostic performance and risks of malignancy associated with the proposed diagnostic categories.

Methods: LN-FNAC specimens obtained in 2018-2019, with and without concurrent core biopsy, to evaluate for suspected lymphoma were analyzed (n = 349). LN-FNAC diagnoses were compared with final diagnoses obtained via subsequent tissue biopsy and/or clinical assessment.

Results: The mean patient age was 57.6 years, and 41% were female. LN-FNAC was the initial diagnostic test in 223 (63.9%), and it was used to evaluate for recurrence in 126 (36.1%). LN-FNAC diagnosed 202 hematological malignancies (57.9%), 23 nonhematological malignancies (6.6%), and 124 reactive processes (35.5%). Subsequent tissue biopsy was performed in 42 (12%). The risks of malignancy per diagnostic category were as follows: inadequate, 58.3%; benign, 6.4%; atypical, 69.2%; suspicious, 96.7%; and malignant, 99.3%. LN-FNAC demonstrated up to 96.3% sensitivity, 91.91% specificity, and 87.35% accuracy. Optimal specimen quality and the use of intradepartmental consultation reduced diagnostic error rates in FNA cases without concurrent core biopsy (P = .029 and P = .0002 respectively).

Conclusions: LN-FNAC is accurate and reliable for the diagnosis of lymphoma. Inadequate LN-FNAC samples should be resampled due to a significant associated risk of lymphoma. The diagnostic performance of LN-FNAC may be improved with good specimen quality and reviews by multiple pathologists. Understanding the risks of malignancy associated with LN-FNAC diagnostic categories will help to guide optimal patient management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncy.22523DOI Listing
October 2021

Geographic Variability of Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Am J Clin Pathol 2021 Sep 20. Epub 2021 Sep 20.

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Objectives: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs from classic Hodgkin lymphoma (CHL) in terms of clinicopathologic features, including Epstein-Barr virus (EBV) association. CHL geographic variability is well known, with higher frequencies of mixed-cellularity subtype and EBV positivity in low/middle-income countries (LMICs), but there are few well-characterized series of NLPHL from LMICs.

Methods: We detail clinicopathologic findings of 21 NLPHL cases received in consultation from Kenya and summarize reports of NLPHL with EBV testing published since 2000.

Results: Median age of consultation cases was 36 years, and male/female ratio was 3.2. All cases involved peripheral lymph nodes and showed at least some B-cell-rich nodular immunoarchitecture, with prominent extranodular lymphocyte-predominant (LP) cells and T-cell-rich variant patterns most commonly seen. LP cells expressed pan-B-cell markers, including strong OCT2; lacked CD30 and CD15 expression in most cases; and were in a background of expanded/disrupted follicular dendritic cell meshworks and increased T-follicular helper cells. LP cells were EBV negative in 18 cases. Historical cases showed a low rate of EBV positivity with no significant difference between LMICs and high-income countries.

Conclusions: Unlike CHL, NLPHL shows few geographic differences in terms of clinicopathologic features and EBV association. These findings have implications for diagnosis, prognostication, and treatment of patients with NLPHL in LMICs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqab113DOI Listing
September 2021

The age of the bone marrow microenvironment influences B-cell acute lymphoblastic leukemia progression via CXCR5-CXCL13.

Blood 2021 Nov;138(19):1870-1884

Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt am Main, Germany.

B-cell acute lymphoblastic leukemia (B-ALL) occurs most commonly in children, whereas chronic myeloid leukemia is more frequent in adults. The myeloid bias of hematopoiesis in elderly individuals has been considered causative, but the age of the bone marrow microenvironment (BMM) may be contributory. Using various murine models of B-ALL in young vs old mice, we recapitulated B-ALL preponderance in children vs adults. We showed differential effects of young vs old BM macrophages on B-ALL cell function. Molecular profiling using RNA- and ATAC-sequencing revealed pronounced differences in young vs old BMM-derived macrophages and enrichment for gene sets associated with inflammation. In concordance with the role of C-X-C motif chemokine (CXCL) 13 for disease-associated B-cell chemoattraction, we found CXCL13 to be highly expressed in young macrophages on a translational compared with a transcriptional level. Inhibition of CXCL13 in BM macrophages impaired leukemia cell migration and decreased the proliferation of cocultured B-ALL cells, whereas recombinant CXCL13 increased pAKT and B-ALL cell expansion. Pretreatment of B-ALL-initiating cells with CXCL13 accelerated B-ALL progression. Deficiency of Cxcr5, the receptor for CXCL13, on B-ALL-initiating cells prolonged murine survival, whereas high expression of CXCR5 in pediatric B-ALL may predict central nervous system relapse. CXCL13 staining was increased in bone sections from pediatric compared with adult patients with B-ALL. Taken together, our study shows that the age of the BMM and, in particular, BM macrophages influence the leukemia phenotype. The CXCR5-CXCL13 axis may act as prognostic marker and an attractive novel target for the treatment of B-ALL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011557DOI Listing
November 2021

Distinguishing AML from MDS: a fixed blast percentage may no longer be optimal.

Blood 2021 06 10. Epub 2021 Jun 10.

University Hospital Ulm, Ulm, Germany.

Patients with acute myeloid leukemia (AML) have conventionally received more "intense" therapy than patients with myelodysplastic syndromes (MDS). Although less intense therapies are being used more often in AML, the AML-MDS dichotomy remains, with the presence of ≥ 20% myeloblasts in marrow or peripheral blood generally regarded as defining AML. Consequently, patients with 19% blasts are typically ineligible for AML studies, with patients with 21% blasts ineligible for MDS studies. Here we cite biologic and clinical data to question this practice. Biologically, abnormalities in chromosome 3q26,and mutations in NPM1, and FLT3, regarded as AML-associated, also occur in MDS. The genetic signatures of MDS, particularly cases with 10-19% blasts (MDS-EB2), resemble those of AML following a preceding MDS ("secondary AML"). Mutationally, secondary AML appears at least as similar to MDS-EB2 as to de novo AML. Patients presenting with de novo AML but with secondary-type AML mutations, appear to have the same poor prognoses associated with clinically defined secondary AML. Seattle data indicate that after accounting for European LeukemiaNet (ELN) 2017 risk, age, performance status, clinically secondary AML, and treatment including allogeneic transplant, patients with WHO-defined AML (n=769) have similar rates of OS, EFS and CR/CRi as patients with MDS-EB2 (n=202). We suggest defining patients with 10-30% blasts ("AML/MDS") as eligible for either AML or MDS studies. This would permit empirical testing of the independent effect of blast percentage on outcome, allow patients access to more therapies, and potentially simplify the regulatory approval process.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2021011304DOI Listing
June 2021

JAK2 Rearrangements Are a Recurrent Alteration in CD30+ Systemic T-Cell Lymphomas With Anaplastic Morphology.

Am J Surg Pathol 2021 07;45(7):895-904

Department of Pathology, Massachusetts General Hospital, Harvard Medical School.

Peripheral T-cell lymphoma (PTCL) comprises a heterogenous group of rare mature T-cell neoplasms. While some PTCL subtypes are well-characterized by histology, immunophenotype, and recurrent molecular alterations, others remain incompletely defined. In particular, the distinction between CD30+ PTCL, not otherwise specified and anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma can be subject to disagreement. We describe a series of 6 JAK2 rearrangements occurring in a cohort of 97 CD30+ ALK- PTCL (6%), assembled after identifying an index case of a novel PABPC1-JAK2 fusion in a case of ALK- anaplastic large cell lymphoma with unusual classic Hodgkin lymphoma (CHL)-like features. Fusions were identified using a comprehensive next-generation sequencing based assay performed between 2013 and 2020. Five of 6 cases (83%) showed JAK2 rearrangements with 4 novel partners: TFG, PABPC1, ILF3, and MAP7, and 1 case demonstrated a previously described PCM1-JAK2 fusion. By morphology, all cases showed anaplastic large cells and multinucleated Reed-Sternberg-like cells within a polymorphous inflammatory background with frequent eosinophilia reminiscent of CHL. By immunohistochemistry, atypical large cells expressed CD30 with coexpression of at least 1 T-cell marker, aberrant loss of at least 1 T-cell marker and, in 4 of 5 cases stained (80%), unusual CD15 coexpression. These findings suggest that a subset of CD30+ ALK- systemic PTCL with anaplastic morphology carry JAK2 rearrangements, some of which appear to show CHL-like morphologic features. The presence of JAK2 rearrangements in cases of CD30+ PTCL augments current classification and may provide a therapeutic target via JAK2 inhibition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAS.0000000000001708DOI Listing
July 2021

Effect of DNMT3A variant allele frequency and double mutation on clinicopathologic features of patients with de novo AML.

Blood Adv 2021 06;5(11):2539-2549

Department of Pathology, UT Southwestern Medical Center, Dallas, TX.

The clinicopathologic features of DNA methyltransferase 3A (DNMT3A)-mutated de novo acute myeloid leukemia (AML), and the significance of variant type, variant allele frequency (VAF), and multiple concomitant DNMT3A mutations, remain poorly defined. We examined 104 DNMT3A-mutated de novo AML patients from 2 major centers. Most (82%) had normal karyotype (NK); R882H variants were frequent(38%). The most commonly comutated genes included nucleophosmin (NPM1; 53%), Fms-related tyrosine kinase 3 (FLT3)-internal tandem duplication (25%), IDH1 (23%), IDH2 (23%), and TET2 (21%). Patients with high DNMT3A VAF at diagnosis (≥44%; DNMT3AHIGH) had more significant leukocytosis and higher blast counts in peripheral blood and bone marrow. DNMT3AHIGH cases were associated with much shorter event-free survival (EFS; 14.1 vs 56.8 months) and overall survival (OS; 18.3 months vs not reached) compared with cases of patients with low DNMT3A (DNMT3ALOW). Thirteen patients had 2 DNMT3A variants and similar VAFs at diagnosis that tracked together at multiple time points after chemotherapy and/or stem cell transplantation (SCT). In multivariable analyses performed in NK patients who received standard induction chemotherapy, presence of 2 DNMT3A mutations (hazard ratio [HR] = 3.192; P = .038) and SCT in first complete remission (HR = 0.295; P = .001) independently affected EFS; increasing marrow blast percentage (HR = 1.026; P = .025), high DNMT3A VAF (HR = 3.003; P = .010), and 2 DNMT3A mutations (HR = 4.816; P = .020) had independent effects on OS. These data support the adverse prognostic significance of DNMT3AHIGH reveal a novel association between 2 concomitant DNMT3A mutations and inferior outcome in DNMT3A-mutated de novo AML with a NK.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2021004250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238486PMC
June 2021

Multiorgan failure in a fatal case of autoimmune hemolytic anemia.

Transfusion 2021 09 27;61(9):2795-2798. Epub 2021 May 27.

Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Background: Autoimmune hemolytic anemia (AIHA) results in red blood cell destruction by auto-antibodies directed against surface antigens and is rarely fatal. Here we describe a case of AIHA, refractory to both standard and experimental therapies, complicated by multiorgan failure, and rapidly leading to death.

Case Report And Results: A 65 year-old man who presented with progressive dyspnea and jaundice was found to have hemolytic anemia. Diagnostic work-up revealed a positive direct antiglobulin test and a strong pan-reactive antibody in the plasma reacting to a titer of 1:1024 with strongest reactivity at 37 °C Coombs' phase with reagent anti-IgG. The red cell eluate contained a pan-agglutinin. The patient received multiple lines of treatment including glucocorticoids, intravenous immunoglobulin, rituximab, eculizumab, splenectomy and etoposide. Despite these interventions, he continued to experience brisk hemolysis and remained transfusion dependent. Repeat testing on day 16 demonstrated persistent high titer IgG auto-antibodies, suggesting minimal suppressive effect of therapy. His course was complicated by acute renal and liver failure, venous thrombosis, and worsening coagulopathy, and he ultimately died from multiorgan failure on day 18.

Conclusion: Severe cases of AIHA can result in multiorgan failure and a fatal outcome. The rapid development of liver failure in this setting has been described in only few case reports to date, and represents an important complication for clinicians to be aware of when treating patients with AIHA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/trf.16513DOI Listing
September 2021

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes.

Am Soc Clin Oncol Educ Book 2021 Mar;41:328-350

Division of Hematology, Department of Internal Medicine, Mayo Clinic, MN.

Myelodysplastic syndromes (MDS) and MDS/myeloproliferative neoplasms (MPNs) are clonal diseases that differ in morphologic diagnostic criteria but share some common disease phenotypes that include cytopenias, propensity to acute myeloid leukemia evolution, and a substantially shortened patient survival. MDS/MPNs share many clinical and molecular features with MDS, including frequent mutations involving epigenetic modifier and/or spliceosome genes. Although the current 2016 World Health Organization classification incorporates some genetic features in its diagnostic criteria for MDS and MDS/MPNs, recent accumulation of data has underscored the importance of the mutation profiles on both disease classification and prognosis. Machine-learning algorithms have identified distinct molecular genetic signatures that help refine prognosis and notable associations of these genetic signatures with morphologic and clinical features. Combined geno-clinical models that incorporate mutation data seem to surpass the current prognostic schemes. Future MDS classification and prognostication schema will be based on the portfolio of genetic aberrations and traditional features, such as blast count and clinical factors. Arriving at these systems will require studies on large patient cohorts that incorporate advanced computational analysis. The current treatment algorithm in MDS is based on patient risk as derived from existing prognostic and disease classes. Luspatercept is newly approved for patients with MDS and ring sideroblasts who are transfusion dependent after erythropoietic-stimulating agent failure. Other agents that address red blood cell transfusion dependence in patients with lower-risk MDS and the failure of hypomethylating agents in higher-risk disease are in advanced testing. Finally, a plethora of novel targeted agents and immune checkpoint inhibitors are being evaluated in combination with a hypomethylating agent backbone to augment the depth and duration of response and, we hope, improve overall survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/EDBK_320113DOI Listing
March 2021

Myeloid/lymphoid neoplasms with FLT3 rearrangement.

Mod Pathol 2021 09 14;34(9):1673-1685. Epub 2021 May 14.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Myeloid/lymphoid neoplasms (M/LN) with 13q12/FLT3 rearrangement have been suggested as candidates for possible inclusion in the World Health Organization classification group of M/LN with eosinophilia (M/LN-eo). We report 12 patients with confirmed FLT3 rearrangement, six with t(12;13)/ETV6-FLT3; one with ins(13;22)/BCR-FLT3; and five with an unconfirmed partner gene located on chromosome bands 2p16, 3q27, 5q15, 5q35, and 7q36. Disease presentations were heterogeneous, including lymphoblastic leukemia/lymphoma, myeloid sarcoma, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and myelodysplastic syndrome. However, some common features were observed, such as extramedullary involvement (n = 7, 58%), associated eosinophilia in blood, bone marrow, or tissue (n = 8, 67%), multilineage involvement, either as biphasic myeloid/lymphoid neoplasms (n = 2) or mixed phenotype acute leukemia (n = 2). Mutations were detected in 4/8 (50%) patients by next-generation sequencing. None (0/10) had FLT3 or KIT mutations. Eleven patients received disease-based chemotherapy or hypomethylating agents, three received FLT3 inhibitors, and five patients proceeded to hematopoietic stem cell transplant. Together with a review of 16 cases published in the literature, it is apparent that M/LNs with FLT3 rearrangement show disease features reminiscent of members in the category of M/LN-eo with PDGFRA, PDGFRB, FGFR1, and PCM1/JAK2 rearrangement, characterized by a specific gene rearrangement, frequent eosinophilia, multi-lineage involvement and therapeutic benefit from kinase inhibitors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-021-00817-7DOI Listing
September 2021

Histiocytic and Dendritic Cell Sarcomas of Hematopoietic Origin Share Targetable Genomic Alterations Distinct from Follicular Dendritic Cell Sarcoma.

Oncologist 2021 07 6;26(7):e1263-e1272. Epub 2021 May 6.

Foundation Medicine, Inc., Cambridge, Massachusetts, USA.

Background: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking.

Methods: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes.

Results: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance.

Conclusion: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors.

Implications For Practice: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/onco.13801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8265357PMC
July 2021

Controversies in the recent (2016) World Health Organization classification of acute myeloid leukemia.

Best Pract Res Clin Haematol 2021 03 6;34(1):101249. Epub 2021 Feb 6.

Department of Pathology, WRN 244, Massachusetts General Hospital, Boston, USA. Electronic address:

The current World Health Organization (WHO) Classification of acute myeloid leukemia (AML), developed in 2016 and published in 2017, codifies the defining features of AML and recognizes several subtypes based on clinical, morphologic, and genetic features. This classification is widely used for the purposes of assigning patients to specific therapeutic approaches and entry into clinical trials. Although the WHO Classification ultimately has its origins in the original 1976 French-American-British Classification, it has been periodically updated by the incorporation of a large body of evidence and input from both diagnosticians and clinicians who study and treat AML. Nevertheless, the recent accumulation of genetic data on the molecular underpinnings of myeloid neoplasms as well as numerous recently approved novel therapies have highlighted areas of controversy in how we currently define and classify AML; the 2016 WHO Classification will continually be revised and updated in future versions based on these advances. The purpose of this review is to explore areas of potential refinement in the current WHO Classification of AML, both in terms of its criteria defining the disease as well as the specific disease subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.beha.2021.101249DOI Listing
March 2021

Flow cytometry reveals the nuances of clonal haematopoiesis.

Br J Haematol 2021 03 19;192(6):949-950. Epub 2021 Feb 19.

Department of Pathology-WRN244, Massachusetts General Hospital, Boston, MA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.17348DOI Listing
March 2021

Clinical, immunophenotypic and genomic findings of NK lymphoblastic leukemia: a study from the Bone Marrow Pathology Group.

Mod Pathol 2021 07 1;34(7):1358-1366. Epub 2021 Feb 1.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Natural killer (NK) cells are lymphocytes of the native immune system that play a pivotal role in host defense and immune surveillance. While the conceptual view of NK-neoplasms is evolving, little is known about the rare NK lymphoblastic leukemia (NK-LL), which remains as a provisional entity in the 2016 WHO Classification. The goal of this study is to characterize NK-LL cases and compare with other CD56 co-expressing acute leukemias. We identified 105 cases, diagnosed as NK-LL (6), CD56+ acute undifferentiated leukemia (AUL) (6), CD56+ T-lymphoblastic leukemia (T-LL) (51), and CD56+ acute myeloid leukemia (AML) (42). Compared to AUL patients, NK-LL patients were significantly younger (p = 0.021) and presented with higher white blood cell (WBC) (p = 0.037) and platelet counts (p = 0.041). Flow cytometry showed more frequent expression of cytoplasmic CD3 (cCD3, p = 0.064) and CD33, (p = 0.065), while HLA-DR was significantly absent from NK-LL (p = 0.035) compared to AUL. Compared to T-ALL, NK-LL cases showed less frequent cCD3 (p = 0.002), CD4 (p = 0.051), and CD10 expression (p = 0.06). The frequency of abnormal karyotypes was similar between NK-LL, AUL, and T-ALL. The mutational profile differed in four leukemia groups, with a significance enrichment of NOTCH1 (p = 0.002), ETV6 (p = 0.002) and JAK3 (p = 0.02) mutations in NK-LL as compared to AML. As compared to T-ALL, NK-LL cases showed a higher number of total mutations (p = 0.04) and significantly more frequent ETV6 mutations (p = 0.004). Clinical outcome data showed differences in overall survival between all four groups (p = 0.0175), but no difference in event free survival (p = 0.246). In this largest study to date, we find that that NK-LL shows clinical presentation, immunophenotypic and molecular characteristics distinct from AUL, T-ALL, and AML. Our findings suggest NK-LL is a distinct acute leukemia entity and should be considered in the clinical diagnosis of acute leukemias of ambiguous lineage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-021-00739-4DOI Listing
July 2021

Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis.

Blood 2020 12;136(26):3051-3055

Department of Medical Oncology, Dana-Farber Cancer Institute.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2020008206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770567PMC
December 2020

Pan-Cancer Landscape Analysis Reveals Recurrent - Gene Fusion in Aggressive Histologic Subtypes of Thymoma.

JCO Precis Oncol 2020 26;4. Epub 2020 Feb 26.

Foundation Medicine, Cambridge, MA.

Purpose: Thymomas are epithelial neoplasms that represent the most common thymic tumors in adults. These tumors have been shown to harbor a relatively low mutational burden. As a result, there is a lack of genetic alterations that may be used prognostically or targeted therapeutically for this disease. Here, we describe a recurrent gene rearrangement in type B2 + B3 thymomas.

Patients And Methods: A single index case of thymoma was evaluated by an RNA-based solid fusion assay. Separately, tissues from 255,008 unique advanced cancers, including 242 thymomas, were sequenced by hybrid capture-based next-generation DNA sequencing/comprehensive genomic profiling of 186 to 406 genes, including lysine methyltransferase 2A () rearrangements, and a portion were evaluated for RNA of 265 genes. We characterized molecular and clinicopathologic features of the pertinent fusion-positive patient cases.

Results: We identified 11 patients with thymomas harboring a gene fusion of and mastermind-like transcriptional coactivator 2 (). Fusion breakpoints were identified between exon 8, 9, 10, or 11 of and exon 2 of . Fifty-five percent were men, with a median age of 48 years at surgery (range, 29-69 years). Concurrent genomic alterations were infrequent. The 11 thymomas were of B2 or B3 type histology, with 1 case showing foci of thymic carcinoma. The frequency of - fusion was 4% of all thymomas (10 of 242) and 6% of thymomas of B2 or B3 histology (10 of 169).

Conclusion: - represents the first recurrent fusion described in type B thymoma. The fusion seems to be specific to type B2 and B3 thymomas, the most aggressive histologic subtypes. The identification of this fusion offers insights into the biology of thymoma and may have clinical relevance for patients with disease refractory to conventional therapeutic modalities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/PO.19.00288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446345PMC
February 2020

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes.

Nat Med 2020 10 3;26(10):1549-1556. Epub 2020 Aug 3.

Department of Hematology, Democritus University of Thrace Medical School, Alexandroupolis, Greece.

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease, rapid transformation to acute myeloid leukemia (AML), resistance to conventional therapies and dismal outcomes. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R). Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-1008-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8381722PMC
October 2020

Chronic myeloid neoplasms harboring concomitant mutations in myeloproliferative neoplasm driver genes (JAK2/MPL/CALR) and SF3B1.

Mod Pathol 2021 01 21;34(1):20-31. Epub 2020 Jul 21.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

JAK2, CALR, and MPL are myeloproliferative neoplasm (MPN)-driver mutations, whereas SF3B1 is strongly associated with ring sideroblasts (RS) in myelodysplastic syndrome (MDS). Concomitant mutations of SF3B1 and MPN-driver mutations out of the context of MDS/MPN with RS and thrombocytosis (MDS/MPN-RS-T) are not well-studied. From the cases (<5% blasts) tested by NGS panels interrogating at least 42 myeloid neoplasm-related genes, we identified 18 MDS/MPN-RS-T, 42 MPN, 10 MDS, and 6 MDS/MPN-U cases with an SF3B1 and an MPN-driver mutation. Using a 10% VAF difference to define "SF3B1-dominant," "MPN-mutation dominant," and "no dominance," the majority of MDS/MPN-RS-T clustered in "SF3B1-dominant" and "no dominance" regions. Aside from parameters as thrombocytosis and ≥15% RS required for RS-T, MDS also differed in frequent neutropenia, multilineage dysplasia, and notably more cases with <10% VAF of MPN-driver mutations (60%, p = 0.0346); MPN differed in more frequent splenomegaly, myelofibrosis, and higher VAF of "MPN-driver mutations." "Gray zone" cases with features overlapping MDS/MPN-RS-T were observed in over one-thirds of non-RS-T cases. This study shows that concomitant SF3B1 and MPN-driver mutations can be observed in MDS, MPN, and MDS/MPN-U, each showing overlapping but also distinctively different clinicopathological features. Clonal hierarchy, cytogenetic abnormalities, and additional somatic mutations may in part contribute to different disease phenotypes, which may help in the classification of "gray zone" cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0624-yDOI Listing
January 2021

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1-KMT2A-YAP1 and VIM-KMT2A fusions.

Mod Pathol 2020 11 27;33(11):2307-2317. Epub 2020 May 27.

Foundation Medicine, Inc., 150 Second Street, Cambridge, MA, 02141, USA.

Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1-KMT2A-YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1-KMT2A-YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20-66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM-KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1-KMT2A-YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM-KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-020-0582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581494PMC
November 2020

How I Diagnose Low-Grade Myelodysplastic Syndromes.

Am J Clin Pathol 2020 06;154(1):5-14

Department of Pathology, Massachusetts General Hospital, Boston.

Objectives: Myelodysplastic syndromes (MDS) are a group of myeloid neoplasms that are often difficult to diagnose due to their pathologic and clinical heterogeneity. The key features of MDS are peripheral blood cytopenias, ineffective hematopoiesis manifesting as morphologic dysplasia, and clonal genetic abnormalities. The most difficult diagnostic dilemmas often arise in low-grade MDS cases (lacking excess blasts), which can be difficult to distinguish from other causes of cytopenia. This distinction requires the integration of information from the peripheral blood (both CBC parameters and morphology), bone marrow morphology, genetic studies, and interrogation of the clinical record to exclude secondary causes.

Methods: We discuss the approach to the diagnosis of low-grade MDS (cases lacking increased blasts), including a diagnostic algorithm and two illustrative cases.

Results: The appropriate use of ancillary studies is important to support or dispute the likelihood of low-grade MDS in conjunction with the findings of morphologic dysplasia. Interpreting the results of cytogenetics and next-generation sequencing can be challenging and must incorporate the emerging knowledge of clonal hematopoiesis of indeterminate potential.

Conclusions: The role of pathologists in integrating data from multiple sources in the diagnosis of low-grade MDS is evolving and becoming increasingly complex; in this challenging diagnostic setting, it is important to feel comfortable with uncertainty and maintain a conservative approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcp/aqaa046DOI Listing
June 2020

Concordance among hematopathologists in classifying blasts plus promonocytes: A bone marrow pathology group study.

Int J Lab Hematol 2020 Aug 16;42(4):418-422. Epub 2020 Apr 16.

Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, Texas.

Enumeration of blasts and promonocytes is essential for World Health Organization (WHO) classification of myelomonocytic neoplasms. The accuracy of distinguishing blasts, promonocytes and monocytes, including normal vs abnormal monocytes, remains controversial. The objective of this analysis is to assess concordances between experienced hematopathologists in classifying cells as blasts, promonocytes, and monocytes according to WHO criteria. Each of 11 hematopathologists assessed glass slides from 20 patients [12 with chronic myelomonocytic leukemia (CMML) and 8 with acute myeloid leukemia (AML)] including blood and BM aspirate smears, and limited nonspecific esterase (NSE) stains. All cases were blindly reviewed. Fleiss' extension of Cohen's kappa for multiple raters was used on these variables, separately for peripheral blood (PB) and bone marrow (BM). Spearman's rank correlation was used to assess correlations between each pair of hematopathologists for each measurement. For the classification based on the sum of blasts and promonocytes in the BM, Fleiss' kappa was estimated as 0.744. For PB, categorizing patients according to the sum of blasts and promonocytes, Fleiss' kappa was estimated as 0.949. Distinction of abnormal monocytes from normal monocytes in PB did not achieve a good concordance and showed strong evidence of differences between hematopathologists (P < .0001). The hematopathologists achieved a good concordance rate of 74% in CMML vs AML classification and a high k rate, confirming that criteria for defining the blasts equivalents (blasts plus promonocytes) could be applied consistently. Identification of monocyte subtypes (abnormal vs normal) was not concordant. Our results support the practice of combining blasts/promonocytes into a single category.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ijlh.13212DOI Listing
August 2020

Comparison of therapy-related and de novo core binding factor acute myeloid leukemia: A bone marrow pathology group study.

Am J Hematol 2020 07 20;95(7):799-808. Epub 2020 Apr 20.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.

This multi-institutional study retrospectively evaluated clinicopathologic and genetic characteristics in 351 patients with core-binding-factor acute myeloid leukemia (CBF-AML), comprising 69 therapy-related (t-CBF-AML) and 282 de novo cases. The T-CBF-AML patients were older, had lower WBC counts, and slightly higher hemoglobin than patients with de novo disease. Secondary cytogenetic abnormalities were more frequent in patients with de novo disease than t-CBF-AML (57.1% vs 41.1%, P = .026). Patients with secondary cytogenetic abnormalities had longer overall survival (OS) than those without abnormalities (median 190 vs 87 months, P = .021); trisomy 8, trisomy 22, and loss of the X or Y chromosome were associated with longer OS. In the 165 cases performed of targeted gene sequencing, pathogenic mutations were detected in 75.7% of cases, and were more frequent in de novo than in therapy-related disease (P = .013). Mutations were found in N/KRAS (37.0%), FLT3 (27.8%), KIT (17.2%), TET2 (4.9%), and ASXL1 (3.9%). The TET2 mutations were associated with shorter OS (P = .012) while N/KRAS mutation was associated with longer OS in t(8;21) AML patients (P = .001). The KIT mutation did not show prognostic significance in this cohort. Although they received similar therapy, t-CBF-AML patients had shorter OS than de novo patients (median 69 vs 190 months, P = .038). In multivariate analysis of all patients, older age and absence of any secondary cytogenetic abnormalities were significant predictors of shorter OS. Among the t-CBF-AML subset, age and hemoglobin were significant on multivariate analysis. This study demonstrated that although de novo and t-CBF-AML patients share many features, t-CBF-AML patients have worse clinical outcome than de novo patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.25814DOI Listing
July 2020

Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia.

Blood 2020 05;135(20):1729-1738

Dana-Farber Cancer Institute, Boston, MA.

Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient's original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019004770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225688PMC
May 2020

Genomic alterations in patients with somatic loss of the Y chromosome as the sole cytogenetic finding in bone marrow cells.

Haematologica 2021 02 1;106(2):555-564. Epub 2021 Feb 1.

Department of Pathology, Boston Children Hospital, Boston, USA.

Loss of the Y chromosome (LOY) is one of the most common somatic genomic alterations in hematopoietic cells in men. However, due to the high prevalence of LOY as the sole cytogenetic finding in the healthy older population, differentiating isolated LOY associated with clonal hematologic processes from aging-associated mosaicism can be difficult in the absence of definitive morphological features of disease. In the past, various investigators have proposed that a high percentage of metaphases with LOY is more likely to represent expansion of a clonal myeloid disease-associated population. It is unknown whether the proportion of metaphases with LOY is associated with the incidence of myeloid neoplasia-associated genomic alterations. To address this question, we identified marrow samples with LOY as isolated cytogenetic finding and used targeted next generation sequencing-based molecular analysis to identify common myeloid neoplasia-associated somatic mutations. Among 73 patients with median age of 75 years (range 29-90), the percentage of metaphases with LOY was <25% in 23 patients, 25-49% in 10, 50-74% in 8 and ≥75% in 32. A threshold of ≥75% LOY was significantly associated with morphologic diagnosis of myeloid neoplasm (p = 0.004). Further, ≥75% LOY was associated with a higher lifetime incidence of diagnosis of myelodysplastic syndromes (MDS; p < 0.0001), and in multivariate analysis ≥75% LOY was a statistically significant independent predictor of myeloid neoplasia [OR 6.17; 95% CI = 2.15-17.68; p = 0.0007]. Higher LOY percentage (≥75%) was associated with greater likelihood of having somatic mutations (p = 0.0009) and a higher number of these mutations (p = 0.0002). Our findings indicate that ≥75% LOY in marrow is associated with increased likelihood of molecular alterations in genes commonly seen in myeloid neoplasia and with morphologic features of MDS. These observations suggest that ≥75% LOY in bone marrow should be considered an MDS-associated cytogenetic aberration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3324/haematol.2019.240689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7849577PMC
February 2021
-->