Publications by authors named "Sa A Wang"

237 Publications

Venetoclax plus intensive chemotherapy with cladribine, idarubicin, and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome: a cohort from a single-centre, single-arm, phase 2 trial.

Lancet Haematol 2021 Aug;8(8):e552-e561

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

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia.

Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m) and cytarabine (1·5 g/m for patients aged <60 years, 1 g/m for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m) intravenously on days 1-3. Consolidation was cladribine (5 mg/m) and cytarabine (1 g/m for patients aged <60 years and 0·75 g/m for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295.

Findings: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related.

Interpretation: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival.

Funding: MD Anderson Cancer Center.
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http://dx.doi.org/10.1016/S2352-3026(21)00192-7DOI Listing
August 2021

A phase 1b/2 study of azacitidine with PD-L1 antibody avelumab in relapsed/refractory acute myeloid leukemia.

Cancer 2021 Jun 25. Epub 2021 Jun 25.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML.

Methods: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles.

Results: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy.

Conclusions: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML.

Lay Summary: This report describes the results of a phase 1b/2 study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape.
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http://dx.doi.org/10.1002/cncr.33690DOI Listing
June 2021

From the archives of MD Anderson Cancer Center: Concurrent BCR-ABL1 and CRLF2 rearrangements in B-lymphoblast phase of chronic myeloid leukemia.

Ann Diagn Pathol 2021 Aug 5;53:151767. Epub 2021 Jun 5.

Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America.

The t(9;22)(q34;q11.2), also known as the Philadelphia (Ph) chromosome, results in BCR-ABL1 fusion residing on the derivative chromosome 22. This translocation is characteristic of chronic myeloid leukemia, but also can occur in a substantial subset of B acute lymphoblastic leukemia (B-ALL) cases. Ph-like B-ALL has a gene expression profile similar to that of BCR-ABL1 positive/Ph-positive B-ALL, but by definition Ph-like B-ALL does not have the sentinel BCR-ABL1 or the Ph chromosome. About half of Ph-like B-ALL cases carry CRLF2 rearrangements. Rare cases of de novo B-ALL with co-occurrence of BCR-ABL1 and CRLF2 rearrangements have been described. To our knowledge, this is the first report of concurrent BCR-ABL1 and CRLF2 rearrangements in blast phase of chronic myeloid leukemia. In this patient, CRLF2 rearrangement was acquired at the time of disease progression to B-lymphoblast phase of chronic myeloid leukemia. We also review the literature and discuss the distinct clinicopathologic, and genomic characteristics of CRLF2 rearranged B-ALL.
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http://dx.doi.org/10.1016/j.anndiagpath.2021.151767DOI Listing
August 2021

Clonal Dynamics and clinical implications of Post-Remission Clonal Hematopoiesis in Acute Myeloid Leukemia (AML).

Blood 2021 Jun 3. Epub 2021 Jun 3.

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

While clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics and clinical implications of post-remission CH in 164 AML patients who attained complete remission after induction chemotherapies. Post-remission CH was identified in 79 (49%) patients. Post-remission CH persisted long-term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Post-remission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. While patients with post-remission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long-term. Post-remission CH had little impact on relapse risk, non-relapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that while residual clonal hematopoietic stem cells (HSCs) are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes, although larger study is needed to dissect the gene-specific heterogeneity.
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http://dx.doi.org/10.1182/blood.2020010483DOI Listing
June 2021

Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial.

JAMA Oncol 2021 Aug;7(8):1213-1219

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax.

Objective: To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax.

Design, Setting, And Participants: A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older.

Interventions: Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4.

Main Outcomes And Measures: Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.

Results: Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation.

Conclusions And Relevance: The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL.

Trial Registration: ClinicalTrials.gov Identifier: NCT02756897.
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http://dx.doi.org/10.1001/jamaoncol.2021.1649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193546PMC
August 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.
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http://dx.doi.org/10.1038/s41379-021-00817-7DOI Listing
September 2021

CD94 expression patterns in reactive and neoplastic T-cell and NK-cell proliferations.

Leuk Res 2021 09 10;108:106614. Epub 2021 May 10.

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

Lymphomas and leukemias of T-cell and NK-cell lineages are highly heterogeneous disorders and lack effective therapeutic strategies. Targeted therapies including anti-CD94 agents are currently under clinical investigation, but studies of CD94 expression on mature T/NK-cell neoplasms are limited. In this study, we investigated the landscape of CD94 protein expression in 15 patients with reactive T/NK-cell proliferations and 124 patients with various T/NK cell neoplasms. CD94 expression was detected at a high level in reactive NK-cells, with a lower level of expression in a subset of reactive CD8 + T-cells; reactive CD4 + T-cells were negative for CD94 expression. All NK-cell neoplasms surveyed had high-level CD94 expression, which was significantly higher than that in T cell neoplasms (p = 0.0174). In neoplastic T-cell proliferations, CD94 expression was positive in all 10 hepatosplenic T-cell lymphoma cases tested, with a high mean fluorescence intensity. Fifty-six percent of T-cell large granular lymphocytic leukemia cases were positive for CD94 expression in a subset of neoplastic cells. All T-cell prolymphocytic leukemia and 97 % of peripheral T-cell lymphoma cases showed no CD94 expression. Our findings demonstrate a broad range of CD94 expression among T/NK-cell neoplasms, in some at levels that suggest therapeutic vulnerability to CD94-targeted therapies.
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http://dx.doi.org/10.1016/j.leukres.2021.106614DOI Listing
September 2021

Concurrent TP53 Mutation and Deletion in Refractory Low-grade Follicular Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 Jul 18;21(7):e626-e629. Epub 2021 Mar 18.

Department of Hematopathology, MD Anderson Cancer Center, Houston, TX. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2021.03.003DOI Listing
July 2021

Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia.

Blood Adv 2021 04;5(7):1876-1883

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

Assessment of measurable residual disease (MRD) provides prognostic information in acute myeloid leukemia (AML). However, the utility of MRD with venetoclax-based lower intensity regimens is unknown. We analyzed the prognostic value of achieving a negative MRD in older/"unfit" patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. MRD was evaluated in bone marrow specimens using multicolor flow cytometry (sensitivity 0.1%). Ninety-seven patients achieving either a complete remission (CR) or CR with incomplete hematologic recovery (CRi) or morphologic leukemia-free state were included. Median age was 72 years (interquartile range, 68-78 years), and 64% had adverse-risk AML. Eighty-three patients achieved CR/CRi, and 52 (54%) became MRD negative. Median time to becoming MRD negative was 2.0 months (interquartile range, 0.9-3.1 months). Patients becoming MRD negative by 2 months had longer relapse-free survival (RFS) compared with those remaining MRD positive (median RFS, not reached vs 5.2 months; hazard ratio [HR], 0.31; 95% confidence interval [CI], 0.12-0.78; P = .004), longer event-free survival (EFS) (median EFS, not reached vs 5.8 months; HR, 0.25; 95% CI, 0.12-0.55; P < .001), as well as longer overall survival (OS) (median OS, 25.1 vs 7.1 months; HR, 0.23; 95% CI, 0.11-0.51; P < .001). Patients achieving an MRD-negative CR had longer OS compared with those with an inferior response (median OS, 25.1 vs 11.6 months; HR, 0.33; 95% CI, 0.19-0.58; P < .0005). Patients becoming MRD negative within 1 month had an improved OS compared with MRD-positive patients (median OS, 25.1 vs 3.4 months; HR, 0.15; 95% CI, 0.03-0.64; P < .0001). Differential impact of MRD status on survival outcomes persisted at a later 4-month time point of evaluation. In conclusion, MRD-negative status at 1, 2, and 4 months after starting therapy confers significantly better survival in older/unfit patients with AML receiving first-line therapy with 10-day decitabine and venetoclax. This trial was registered at www.clinicaltrials.gov as #NCT03404193.
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http://dx.doi.org/10.1182/bloodadvances.2020003717DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045494PMC
April 2021

Clinicopathologic Features of Myelodysplastic Syndromes Involving Lymph Nodes.

Am J Surg Pathol 2021 07;45(7):930-938

Departments of Hematopathology.

Lymph nodes (LNs) involved by a myelodysplastic syndrome (MDS) are rare and uncommonly biopsied. In this study, we report 6 MDS patients who underwent an LN biopsy that showed MDS, and we summarize the clinicopathologic features of this cohort. All patients presented with lymphadenopathy (generalized in 5), 5 patients had splenomegaly, and 3 patients had hepatomegaly. Histologically, the LN architecture was distorted without complete effacement. MDS cells, mostly of the myeloid lineage, produced interfollicular expansion. These myeloid cells exhibited a spectrum of maturation, and immature and atypical forms were common, including eosinophils. Scattered megakaryocytes and nucleated erythroid cells were often present. Concurrent bone marrow aspirate and biopsy specimens in these patients showed persistent/resistant MDS. Following the diagnosis of LN involvement, patients did not respond well to therapy and all died by the time of the last follow-up, with a median survival of 6.7 months (range, 4.5 to 21.6 mo). In summary, patients with MDS uncommonly develop clinically evident lymphadenopathy prompting biopsy as a result of infiltration by MDS. MDS in LNs can be subtle, showing incomplete and sometimes mild distortion of the architecture, and ancillary studies including immunohistochemical and flow cytometric immunophenotypic analysis are often needed to establish the diagnosis. These data also suggest that the emergence of lymphadenopathy attributable to MDS is associated with poor treatment response and prognosis in MDS patients and that aggressive therapy or alternative treatment regimens need to be explored in this context.
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http://dx.doi.org/10.1097/PAS.0000000000001689DOI Listing
July 2021

Patterns of Resistance Differ in Patients with Acute Myeloid Leukemia Treated with Type I versus Type II FLT3 inhibitors.

Blood Cancer Discov 2021 Mar 6;2(2):125-134. Epub 2020 Dec 6.

The Department of Leukemia, MD Anderson Cancer Center, Houston, Texas.

Despite promising results with FLT3 inhibitors (FLT3i), response durations remain short. We studied pretreatment and relapse bone marrow samples from patients with -mutated AML treated with FLT3i-based therapies (secondary resistance cohort), and pretreatment bone marrow samples from patients with no response to FLT3i-based therapies (primary resistance cohort). Targeted next generation sequencing at relapse identified emergent mutations involving on-target , epigenetic modifiers, pathway, and less frequently , and . and D835 mutations emerged most commonly following type I and type II FLT3i-based therapies, respectively. Patients with emergent mutations at relapse had inferior overall survival compared with those without emergent mutations. Among pretreatment mutated patients, pretreatment cohort level variant allelic frequencies for were higher in non-responders, particularly with type I FLT3i-based therapies, suggesting a potential role in primary resistance as well. These data demonstrate distinct pathways of resistance in -mutated AML treated with type I versus II FLT3i.
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http://dx.doi.org/10.1158/2643-3230.bcd-20-0143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935111PMC
March 2021

Flow cytometric immunophenotypic alterations of persistent clonal haematopoiesis in remission bone marrows of patients with NPM1-mutated acute myeloid leukaemia.

Br J Haematol 2021 03 22;192(6):1054-1063. Epub 2021 Feb 22.

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

Clonal haematopoiesis (CH) in patients with acute myeloid leukaemia (AML) may persist beyond attaining complete remission. From a consecutive cohort of 67 patients with nucleophosmin 1-mutated (NPM1 ) AML, we identified 50 who achieved NPM1 clearance and had parallel multicolour flow cytometry (MFC) and next generation sequencing (NGS). In total, 13 (26%) cleared all mutations, 37 (74%) had persistent CH frequently involving DNA methyltransferase 3α (DNMT3A,70%), tet methylcytosine dioxygenase 2 (TET2, 27%), isocitrate dehydrogenase 2 (IDH2, 19%) and IDH1 (11%). A small number (<1%) of aberrant CD34 myeloblasts, but immunophenotypically different from original AML blasts [herein referred to as a pre-leukaemic (PL) phenotype], was detected in 17 (49%) patients with CH, but not in any patients with complete clearance of all mutations (P = 0·0037). A PL phenotype was associated with higher mutation burden (P = 0·005). Persistent IDH2 and serine and arginine-rich splicing factor 2 (SRSF2) mutations were exclusively observed in PL CH cases (P = 0·016). Persistent dysplasia was seen exclusively in cases with a PL phenotype (29% vs. none; P = 0·04). The PL phenotype did not correlate with age, intensity of induction therapy or relapse-free survival. Post-remission CH in the setting of NPM1 clearance is common and may result in immunophenotypic changes in myeloid progenitors. It is important to not misinterpret these cells as AML measurable residual disease (MRD).
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http://dx.doi.org/10.1111/bjh.17347DOI 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.
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http://dx.doi.org/10.1038/s41379-021-00739-4DOI Listing
July 2021

Phase 2 study of lenalidomide maintenance for patients with high-risk acute myeloid leukemia in remission.

Cancer 2021 Jun 15;127(11):1894-1900. Epub 2021 Jan 15.

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: New drug combinations have led to significant improvements in remission rates for patients with acute myeloid leukemia (AML). However, many patients with high-risk AML who respond to their initial treatment and are not candidates for allogeneic stem cell transplantation (ASCT) will eventually relapse with poor outcomes.

Methods: In this phase 2 trial, the efficacy of lenalidomide maintenance was evaluated in patients with high-risk AML who had achieved their first or second remission after induction chemotherapy and at least 1 consolidation cycle and who were not candidates for immediate ASCT. Lenalidomide was given orally at 10 to 20 mg daily on days 1 to 28 of a 28-day cycle for up to 24 cycles.

Results: A total of 28 patients were enrolled in this study with a median age of 61 years (range, 24-87 years). The median number of cycles was 8 (range, 1-24 cycles). Ten patients (36%) completed 24 months of maintenance treatment. With a median follow-up of 22.5 months (range, 2.6-55 months), 12 patients (43%) relapsed after a median of 3 months (range, 0.7-23 months). The median duration of remission for all patients was 18.7 months (range, 0.7-55.1 months). The 2-year overall survival and relapse-free survival rates from the time of enrollment were 63% and 50%, respectively. Overall, lenalidomide was well tolerated; serious adverse events of grade 3 or 4, including rash (n = 5), thrombocytopenia (n = 4), neutropenia (n = 4), and fatigue (n = 2), were observed in 13 patients (46%).

Conclusions: Lenalidomide is a safe and feasible maintenance strategy in patients with high-risk AML who are not candidates for ASCT, and it has beneficial effects for patients with negative measurable residual disease.
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http://dx.doi.org/10.1002/cncr.33409DOI Listing
June 2021

Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders.

Am J Clin Pathol 2021 02;155(2):179-210

Division of Hematopathology, Mayo Clinic, Rochester, MN.

Objectives: To report the findings of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop within the categories of reactive eosinophilia, hypereosinophilic syndrome (HES), germline disorders with eosinophilia (GDE), and myeloid and lymphoid neoplasms associated with eosinophilia (excluding entities covered by other studies in this series).

Methods: The workshop panel reviewed 109 cases, assigned consensus diagnosis, and created diagnosis-specific sessions.

Results: The most frequent diagnosis was reactive eosinophilia (35), followed by acute leukemia (24). Myeloproliferative neoplasms (MPNs) received 17 submissions, including chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Myelodysplastic syndrome (MDS), MDS/MPN, and therapy-related myeloid neoplasms received 11, while GDE and HES received 12 and 11 submissions, respectively.

Conclusions: Hypereosinophilia and HES are defined by specific clinical and laboratory criteria. Eosinophilia is commonly reactive. An acute leukemic onset with eosinophilia may suggest core-binding factor acute myeloid leukemia, blast phase of chronic myeloid leukemia, BCR-ABL1-positive leukemia, or t(5;14) B-lymphoblastic leukemia. Eosinophilia is rare in MDS but common in MDS/MPN. CEL, NOS is a clinically aggressive MPN with eosinophilia as the dominant feature. Bone marrow morphology and cytogenetic and/or molecular clonality may distinguish CEL from HES. Molecular testing helps to better subclassify myeloid neoplasms with eosinophilia and to identify patients for targeted treatments.
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http://dx.doi.org/10.1093/ajcp/aqaa244DOI Listing
February 2021

Myeloid/Lymphoid Neoplasms Associated With Eosinophilia and Rearrangements of PDGFRA, PDGFRB, or FGFR1 or With PCM1-JAK2.

Am J Clin Pathol 2021 02;155(2):160-178

MD Anderson Cancer Center, Houston, TX.

Objectives: To summarize cases submitted to the 2019 Society for Hematopathology/European Association for Haematopathology Workshop under the category of myeloid/lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2 rearrangements, focusing on recent updates and relevant practice findings.

Methods: The cases were summarized according to their respective gene rearrangement to illustrate the spectrum of clinical, laboratory, and histopathology manifestations and to explore the appropriate molecular genetic tests.

Results: Disease presentations were heterogeneous, including myeloproliferative neoplasms (MPNs), myelodysplastic syndromes (MDSs), MDS/MPN, acute myeloid leukemia, acute B- or T-lymphoblastic lymphoma/acute lymphoblastic lymphoma (ALL/LBL), or mixed-lineage neoplasms. Frequent extramedullary involvement occurred. Eosinophilia was common but not invariably present. With the advancement of RNA sequencing, cryptic rearrangements were recognized in genes other than PDGFRA. Additional somatic mutations were more frequent in the FGFR1-rearranged cases. Cases with B-ALL presentations differed from Philadelphia-like B-ALL by the presence of an underlying MPN. Cases with FLT3 and ABL1 rearrangements could be potential candidates for future inclusion in this category.

Conclusions: Accurate diagnosis and classification of this category of myeloid/lymphoid neoplasms has important therapeutic implications. With the large number of submitted cases, we expand our understanding of these rare neoplasms and improve our ability to diagnose these genetically defined disorders.
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http://dx.doi.org/10.1093/ajcp/aqaa208DOI Listing
February 2021

Reactive Eosinophil Proliferations in Tissue and the Lymphocytic Variant of Hypereosinophilic Syndrome.

Am J Clin Pathol 2021 02;155(2):211-238

Institute of Pathology and Neuropathology, Eberhard Karls University of Tübingen and Comprehensive Cancer Center, Tübingen University Hospital, Tübingen, Germany.

Objectives: The 2019 Society for Hematopathology and European Association for Haematopathology Workshop reviewed the spectrum of neoplastic, nonneoplastic, and borderline entities associated with reactive eosinophilia in tissue.

Methods: The workshop panel reviewed 46 cases covered in 2 workshop sessions.

Results: The 46 cases were presented with their consensus diagnoses during the workshop. Reactive eosinophilia in lymph nodes and other tissues may be accompanied by or be distinct from peripheral blood eosinophilia. Reactive etiologies included inflammatory disorders such as Kimura disease and IgG4-related disease, which may show overlapping pathologic features and reactions to infectious agents and hypersensitivity (covered in a separate review). Hodgkin, T-cell, and B-cell lymphomas and histiocytic neoplasms can result in reactive eosinophilia. The spectrum of these diseases is discussed and illustrated through representative cases.

Conclusions: Reactive eosinophilia in lymph nodes and tissues may be related to both nonneoplastic and neoplastic lymphoid proliferations and histiocytic and nonhematolymphoid processes. Understanding the differential diagnosis of reactive eosinophilia and the potential for overlapping clinical and pathologic findings is critical in reaching the correct diagnosis so that patients can be treated appropriately.
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http://dx.doi.org/10.1093/ajcp/aqaa227DOI Listing
February 2021

Prognostic impact of complete remission with MRD negativity in patients with relapsed or refractory AML.

Blood Adv 2020 12;4(24):6117-6126

Department of Leukemia.

In relapsed/refractory acute myeloid leukemia (AML), the prognostic impact of complete remission (CR) and measurable residual disease (MRD) negativity is not well established. We retrospectively analyzed 141 patients with relapsed/refractory AML who received first salvage therapy and had MRD assessed by multiparameter flow cytometry at the time of response. Patients who achieved CR with full hematologic recovery as best response vs those with incomplete hematology recovery had lower cumulative incidence of relapse (P = .01) and better relapse-free survival (P = .004) but not overall survival (P = .15); a similar trend was observed in patients who achieved MRD negativity vs those who were MRD positive (P = .01, P = .05, and P = .21, respectively). By multivariate analysis, CR and MRD negativity were each independently associated with lower cumulative incidence of relapse (P = .001 and P = .003, respectively) and better relapse-free survival (P < .001 and P = .02) but not overall survival. Patients who achieved CR with MRD negativity had the lowest rates of relapse and best survival (2-year overall survival rate, 37%), which was driven largely by lower rates of early relapse and an increased ability in this group to undergo hematopoietic stem cell transplantation (HSCT); however, post-HSCT outcomes were similar regardless of response to salvage chemotherapy. Overall, in patients with relapsed/refractory AML, CR with MRD negativity was associated with the best outcomes, supporting it as the optimal response in this setting.
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http://dx.doi.org/10.1182/bloodadvances.2020002811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7757010PMC
December 2020

Mastocytosis.

Am J Clin Pathol 2021 02;155(2):239-266

Department of Pathology, University of Utah School of Medicine, Salt Lake City.

Objectives: The 2019 Workshop of the Society for Hematopathology/European Association for Haematopathology received and reviewed cases covering the spectrum of mastocytosis and related diseases, including morphologic mimics, focusing on recent updates and relevant findings for pathologists.

Methods: The workshop panel reviewed 99 cases of cutaneous and systemic mastocytosis (SM) and SM and associated hematologic neoplasms (SM-AHN).

Results: Despite a common theme of KIT mutation (particularly D816V), mastocytosis is a heterogeneous neoplasm with a wide variety of presentations. This spectrum, including rare subtypes and extramedullary organ involvement, is discussed and illustrated by representative cases.

Conclusions: In the age of targeted treatment aimed at KIT, the accurate diagnosis and classification of mastocytosis has major implications for therapy and further interventions. Understanding the clinical, pathologic, and genetic findings of mastocytosis is crucial for selecting the proper tests to perform and subsequent arrival at a correct diagnosis in this rare disease.
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http://dx.doi.org/10.1093/ajcp/aqaa183DOI Listing
February 2021

Next-Generation Scholarship: Rebranding Hematopathology Using Twitter: The MD Anderson Experience.

Mod Pathol 2021 05 20;34(5):854-861. Epub 2020 Nov 20.

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

Hematopathologists are witnessing very exciting times, as a new era of unsurpassed technological advances is unfolding exponentially, enhancing our understanding of diseases at the genomic and molecular levels. In the evolving field of precision medicine, our contributions as hematopathologists to medical practice are of paramount importance. Social media platforms such as Twitter have helped facilitate and enrich our professional  interactions and collaborations with others in our field and in other medical disciplines leading to a more holistic approach to patient care. These platforms also have created a novel means for instantaneous dissemination of new findings and recent publications, and are proving to be increasingly useful tools that can be harnessed to expand our knowledge and amplify our presence in the medical community. In this Editorial, we share our experience as hematopathologists with Twitter, and how we leveraged this platform to boost scholarly activities within and beyond our subspecialty, and as a powerful medium for worldwide dissemination of educational material and to promote our remote teaching activities during the COVID-19 pandemic.
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http://dx.doi.org/10.1038/s41379-020-00715-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678590PMC
May 2021

CD123 Expression in Philadelphia Chromosome-like B Acute Lymphoblastic Leukemia/Lymphoma.

Clin Lymphoma Myeloma Leuk 2021 04 8;21(4):e317-e320. Epub 2020 Oct 8.

Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address:

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http://dx.doi.org/10.1016/j.clml.2020.09.014DOI Listing
April 2021

International guidelines for the flow cytometric evaluation of peripheral blood for suspected Sézary syndrome or mycosis fungoides: Assay development/optimization, validation, and ongoing quality monitors.

Cytometry B Clin Cytom 2021 03 28;100(2):156-182. Epub 2020 Oct 28.

Division of Hematopathology, Mayo Clinic Arizona, Phoenix, Arizona, USA.

Introducing a sensitive and specific peripheral blood flow cytometric assay for Sézary syndrome and mycosis fungoides (SS/MF) requires careful selection of assay design characteristics, and translation into a laboratory developed assay through development/optimization, validation, and continual quality monitoring. As outlined in a previous article in this series, the recommended design characteristics of this assay include at a minimum, evaluation of CD7, CD3, CD4, CD8, CD26, and CD45, analyzed simultaneously, requiring at least a 6 color flow cytometry system, with both quantitative and qualitative components. This article provides guidance from an international group of cytometry specialists in implementing an assay to those design specifications, outlining specific considerations, and best practices. Key points presented in detail are: (a) Pre-analytic components (reagents, specimen processing, and acquisition) must be optimized to: (i) identify and characterize an abnormal population of T-cells (qualitative component) and (ii) quantitate the abnormal population (semi/quasi-quantitative component). (b)Analytic components (instrument set-up/acquisition/analysis strategy and interpretation) must be optimized for the identification of SS/MF populations, which can vary widely in phenotype. Comparison with expert laboratories is strongly encouraged in order to establish competency. (c) Assay performance must be validated and documented through a validation plan and report, which covers both qualitative and semi/quasi-quantitative assay components (example template provided). (d) Ongoing assay-specific quality monitoring should be performed to ensure consistency.
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http://dx.doi.org/10.1002/cyto.b.21963DOI Listing
March 2021

Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics.

Nat Commun 2020 10 21;11(1):5327. Epub 2020 Oct 21.

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

Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.
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http://dx.doi.org/10.1038/s41467-020-19119-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577981PMC
October 2020

A Cryptic BCR-PDGFRB Fusion Resulting in a Chronic Myeloid Neoplasm With Monocytosis and Eosinophilia: A Novel Finding With Treatment Implications.

J Natl Compr Canc Netw 2020 10 1;18(10):1300-1304. Epub 2020 Oct 1.

Hematopathology, and.

RNA-seq was used to identify the partner gene and confirm the presence of a BCR-PDGFRB fusion. Identification of this fusion product resulted in successful treatment and long-term remission of this myeloid neoplasm. Based on our results, we suggest that despite current WHO recommendations, screening for PDGFRB rearrangement in cases of leukocytosis with eosinophilia and no other etiologic explanation is necessary, even if the karyotype is normal.
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http://dx.doi.org/10.6004/jnccn.2020.7573DOI Listing
October 2020
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