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Between 2004 and 2017, a total of 1123 adult patients (median age 65 years; 61% males) with newly diagnosed acute myeloid leukemia (AML), not including acute promyelocytic leukemia, were seen at the Mayo Clinic. Treatment included intensive (n = 766) or lower intensity (n = 144) chemotherapy or supportive care (n = 213), with respective median survivals of 22, 9, and 2 months (p p = 0.4). Allogeneic hematopoietic stem cell transplant (AHSCT) was documented in 259 patients and provided the best survival rate (median 55 months; p 60 years (HR 2.2, 1.9–2.6), adverse karyotype (HR 2.9, 1.9–4.9), intermediate-risk karyotype (HR 1.6, 1.02–2.6), post-myeloproliferative neoplasm AML (HR 1.9, 1.5–2.4), and other secondary AML (HR 1.3 (1.1–1.6) as risk factors for shortened survival. These risk factors retained their significance after inclusion of FLT3/NPM1 mutational status in 392 informative cases: FLT3+NPM1− (HR 2.8, 1.4–5.6), FLT3+/NPM+ (HR 2.6 (1.3–5.2), and FLT3−NPM1− (HR 1.8, 1.0–3.0).

Introduction/Objective Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL), defined as CHL and FL occurring simultaneously at the same site, is rare and poorly understood. While both Hodgkin/Reed-Sternberg (HRS) cells and FL are thought to be derived from germinal center B-cells, the relationship between CHL and FL when coexistent is unclear. Here, we present two cases of CHLFL and show that the CHL and FL components have a clonal relationship by FISH. Methods/Case Report Case #1 is a 50-year-old man with abdominal and mediastinal lymphadenopathy. An excised mesenteric lymph node showed two distinct components diagnostic for FL, grade 1-2 and CHL. Case #2 is a 63-year- old woman with a history of FL with transformation to diffuse large B-cell lymphoma. Cytogenetic studies showed a complex karyotype with an add(9p), del(10q), and trisomy 16. Post-treatment imaging revealed left axillary adenopathy. An excised axillary lymph node showed CHL with peripheral areas of FL, grade 3A. Both cases had areas of typical FL with BCL2-positive phenotype and no significant CD30/CD15 expression. HRS cells were CD45/CD20-negative, expressed CD30 (strong), CD15, and PAX5, and were present in a mixed inflammatory background. No EBV RNA was present by in situ hybridization. Interestingly, HRS cells in case #1 expressed both BCL6 and BCL2. FISH was performed in both cases. Case #1 had a BCL2 rearrangement in 48% of FL nuclei and in 100% of HRS cells. In case #2, targeted probes were used based on prior cytogenetic results. Here, 47% of FL nuclei and 44% of HRS cells had a 16p duplication; additionally, 32% of HRS cells had an unbalanced IGH rearrangement with loss of the IGH variable region, suggesting possible clonal evolution. No rearrangement of BCL2 or BCL6 was present. An additional 27 CHLFL cases from the literature were reviewed. CHLFL was mostly nodal and occurred in late adulthood in patients with or without a history of FL. It presented at advanced clinical stage, with a 5-year overall survival of 22%. BCL2 expression in HRS cells was common. Bone marrow involvement was 45% (5/11) and consisted of FL exclusively. Five of six tested cases demonstrated BCL2/IGH rearrangement in both FL and HRS cells. Results (if a Case Study enter NA) NA Conclusion Composite CHL and FL are often clonally related and may share a common progenitor B-cell origin – likely a germinal center B-cell – from which additional genetic abnormalities are acquired to develop two distinct lymphomas.

Purpose: Structural variants (SV) of the MYC gene region are common in multiple myeloma and influence disease progression. However, the prognostic significance of different MYC SVs in multiple myeloma has not been clearly established. Experimental Design: We conducted a retrospective study of multiple myeloma comparing MYC SV subtypes identified by next-generation sequencing (NGS) and FISH to MYC expression and disease survival using 140 cases from Mayo Clinic and 658 cases from the MMRF CoMMpass study. Results: MYC SVs were found in 41% of cases and were classified into nine subtypes. A correlation between the presence of a MYC SV and increased MYC expression was identified. Among the nine MYC subtypes, the non-immunoglobulin (non-Ig) insertion subtype was independently associated with improved outcomes, while the Ig insertion subtype, specifically involving the IgL gene partner, was independently associated with poorer outcomes compared with other MYC SV subtypes. Although the FISH methodology failed to detect approximately 70% of all MYC SVs, those detected by FISH were associated with elevated MYC gene expression and poor outcomes suggesting a different pathogenic role for FISH-detected MYC subtypes compared with other MYC subtypes. Conclusions: Understanding the impact of different MYC SVs on disease outcome is necessary for the reliable interpretation of MYC SVs in multiple myeloma. NGS approaches should be considered as a replacement technique for a more comprehensive evaluation of the multiple myeloma clone.

Acute undifferentiated leukemia (AUL) is a very rare hematologic neoplasm that expresses no markers specific for either myeloid or lymphoid lineages. While commonly observed in several acute leukemias, KMT2A rearrangements in AUL have been rarely reported in the literature. We report the third case to our knowledge of AUL harboring a KMT2A rearrangement. Furthermore, the KMT2A/GIMAP8 gene fusion identified in this case represents a novel KMT2A rearrangement.

Cytogenetic abnormalities are found in most multiple myeloma (MM) patients. Although their prognostic value has been well studied, there are limited data on the association of primary cytogenetic abnormalities with disease characteristics and treatment response. This study was designed to evaluate these associations. This is a retrospective study including 2027 Mayo Clinic patients diagnosed with MM between February 2004 and February 2018 who had cytogenetic testing by FISH at diagnosis. Translocations t(4;14), t(14;16), t(6;14), and t(14;20) were associated with anemia, beta2microglobulin >5.5 µg/ml and ≥50% bone marrow plasma cells; t(4;14) was associated with higher serum monoclonal protein and plasma cell proliferation. Overall response rate to proteasome inhibitor (PI)-based treatment was higher for IgH translocations compared to trisomies (83% vs. 71%, P = 0.002), but was higher for trisomies with immunomodulatory drug (IMiD)-based treatment (87% vs. 75%, P P P = 0.003) treatments. Outcomes were superior with PI + IMiD combinations in all groups. Our results show that t(4;14), t(14;16), t(6;14), and t(14;20) are associated with high-risk disease characteristics, and IgH translocations and trisomies may be associated with better responses to PIs and IMiDs, respectively.

Siblings diagnosed with B-lymphoblastic leukemia (B-ALL) that share the same driver abnormality have been rarely described in the literature. Herein, we report three pairs of siblings (one non-identical pair, one maternal half-sibling pair, and one identical pair) all diagnosed with ETV6/RUNX1-positive B-ALL. Considering that ETV6/RUNX1 fusion is thought to represent a prenatal event and necessitates additional genomic alterations to result in leukemia, siblings of patient's with known ETV6/RUNX1-positive B-ALL may be at increased risk of ETV6/RUNX1-positive B-ALL due to common exposures (environmental or infectious) or shared germline polymorphisms.

Context.— One goal of the joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee is to ensure the accurate detection and description of chromosomal abnormalities in both constitutional and neoplastic specimens, including hematologic neoplasms. Objective.— To report a 20-year performance summary (1999–2018) of conventional chromosome challenges focusing on hematologic neoplasms. Design.— A retrospective review was performed from 1999 through 2018 to identify karyotype challenges specifically addressing hematologic neoplasms. The overall performance of participants was examined to identify potential recurring errors of clinical significance. Results.— Of 288 total conventional chromosome challenges from 1999–2018, 87 (30.2%) were presented in the context of a hematologic neoplasm, based on the provided clinical history, specimen type, and/or chromosomal abnormalities. For these 87 hematologic neoplasm challenges, 91 individual cases were provided and graded on the basis of abnormality recognition and karyotype nomenclature (ISCN, International System for Human Cytogenomic [previously Cytogenetic] Nomenclature). Of the 91 cases, 89 (97.8%) and 87 (95.6%) exceeded the required 80% consensus for grading of abnormality recognition and correct karyotype nomenclature, respectively. The 2 cases (2 of 91; 2.2%) that failed to meet the 80% consensus for abnormality recognition had complex karyotypes. The 4 cases (4 of 91; 4.4%) that failed to meet the 80% consensus for correct karyotype nomenclature were the result of incorrect abnormality recognition (2 cases), missing brackets in the karyotype (1 case), and incorrect breakpoint designation (1 case). Conclusions.— This 20-year review demonstrates clinical cytogenetics laboratories have been and continue to be highly proficient in the detection and description of chromosomal abnormalities associated with hematologic neoplasms.

The accurate detection of recurrent genetic abnormalities for most hematologic neoplasms is critical for diagnosis, prognosis and/or treatment. Rearrangements involving CCND1 are observed in a subset of mature B-cell neoplasms and can be reliably detected by fluorescence in situ hybridization (FISH) in most cases. However, cryptic and complex chromosomal rearrangements may pose a technical challenge for accurate diagnosis. Herein, we describe two patients with suspected mantle cell lymphoma that lacked obvious CCND1 rearrangements by FISH studies. A next generation sequencing (NGS) based assay, mate-pair sequencing (MPseq), was utilized in each case to investigate potential cryptic CCND1 rearrangements and revealed cryptic insertional events resulting in CCND1/IGH and CCND1/IGK rearrangements. These cases demonstrate that NGS-based assays, including MPseq, are a powerful approach to identify cryptic rearrangements of clinical importance that are not detected by current clinical genomics evaluation.

Patients with a sole del(20q) chromosomal abnormality and without morphologic features of a myeloid neoplasm (MN) have shown variable clinical outcomes. To explore the potential risk stratification markers in this group of patients, we evaluated their genetic mutational landscape by a 35-gene MN-focused next-generation sequencing (NGS) panel and examined the association of mutations to progression of MNs. Our study included 56 patients over a 10-year period with isolated del(20q), of whom 23 (41.1%) harbored at least one mutation. With a median follow-up of 32.6 months (range: 0.1−159.1), 9 of 23 patients with mutation(s) progressed to MNs, while all 33 patients without mutations did not progress to MN. Kaplan−Meier survival analysis demonstrated the presence of mutation(s) as a significant risk factor for progression to MN (P < 0.0001). MN progression was strongly associated with the presence of non-DNMT3A/TET2/ASXL1 epigenetic modifiers and nonspliceosome mutations (P = 0.003). There was no significant difference among patients with and without MN progression with respect to the number of mutations, variant allele frequency, percentage of del(20q), and other clinical/laboratory variables. This study illustrates the underlying genetic heterogeneity and complexity of isolated del(20q), and underscores the prognostic value of NGS mutational analysis in these cases.

In a 28-year period, 39 (7%) patients with chronic myelomonocytic leukemia (CMML) (median age 66 years, 64% male) underwent a splenectomy at our institution. Primary indications for splenectomy were refractory thrombocytopenia (36%), progressive spleen related symptoms (33%), emergent splenectomy for splenic rupture (21%), refractory anemia (8%), and prior to allogeneic stem cell transplant (3%). Eleven (28%) patients had anemia at the time of splenectomy, of which 3 (27%) were autoimmune. The median time to splenectomy from CMML diagnosis was 6 months (0-40); perioperative morbidity and mortality rates were 43% and 13%, while the median postsplenectomy survival was 25 months (11-38). Durable remission in spleen related symptoms, thrombocytopenia, complications from splenic rupture, and anemia were achieved in 85%, 50%, 62%, and 21% of patients, respectively. Perioperative morbidity (n = 30) included infections/sepsis in 6 (20%), intraabdominal bleeding in 4 (13%), venous thromboembolism (VTE) in 3 (10%), and acute lung injury in 2 (7%) patients. The median duration of hospital stay was 6 days (1-25), with 5 deaths occurring secondary to respiratory failure (n = 2), multiorgan dysfunction (n = 2) and hemorrhagic shock (n = 1). There was no difference in overall survival between CMML patients that underwent splenectomy, in comparison to those that did not. Unlike in myelofibrosis, portal hypertension was not an indication for splenectomy and no patients developed post-splenectomy thrombocytosis. In conclusion, apart from being a lifesaving emergent modality in the event of splenic rupture, splenectomy has an important palliative role in patients with CMML, with significant and durable improvements in spleen related symptoms and refractory cytopenias.

Objective To develop a new risk model for primary myelodysplastic syndromes (MDS) that integrates information on mutations, karyotype, and clinical variables. Patients and Methods Patients with World Health Organization–defined primary MDS seen at Mayo Clinic (MC) from December 28, 1994, through December 19, 2017, constituted the core study group. The National Taiwan University Hospital (NTUH) provided the validation cohort. Model performance, compared with the revised International Prognostic Scoring System, was assessed by Akaike information criterion and area under the curve estimates. Results The study group consisted of 685 molecularly annotated patients from MC (357) and NTUH (328). Multivariate analysis of the MC cohort identified monosomal karyotype (hazard ratio [HR], 5.2; 95% CI, 3.1-8.6), "non-MK abnormalities other than single/double del(5q)" (HR, 1.8; 95% CI, 1.3-2.6), RUNX1 (HR, 2.0; 95% CI, 1.2-3.1) and ASXL1 (HR, 1.7; 95% CI, 1.2-2.3) mutations, absence of SF3B1 mutations (HR, 1.6; 95% CI, 1.1-2.4), age greater than 70 years (HR, 2.2; 95% CI, 1.6-3.1), hemoglobin level less than 8 g/dL in women or less than 9 g/dL in men (HR, 2.3; 95% CI, 1.7-3.1), platelet count less than 75 × 109/L (HR, 1.5; 95% CI, 1.1-2.1), and 10% or more bone marrow blasts (HR, 1.7; 95% CI, 1.1-2.8) as predictors of inferior overall survival. Based on HR-weighted risk scores, a 4-tiered Mayo alliance prognostic model for MDS was devised: low (89 patients), intermediate-1 (104), intermediate-2 (95), and high (69); respective median survivals (5-year overall survival rates) were 85 (73%), 42 (34%), 22 (7%), and 9 months (0%). The Mayo alliance model was subsequently validated by using the external NTUH cohort and, compared with the revised International Prognostic Scoring System, displayed favorable Akaike information criterion (1865 vs 1943) and area under the curve (0.87 vs 0.76) values. Conclusion We propose a simple and contemporary risk model for MDS that is based on a limited set of genetic and clinical variables.

We examined the influence of mutations and karyotype on conventional treatment response, specifically hematological improvement in anemia, in primary myelodysplastic syndromes (MDS). Cytogenetic and next generation sequencing (NGS)-derived mutation information was available in 357 patients (median age 74 years; 70% males); the revised international prognostic scoring system risk distribution was very high in 11%, high 15%, intermediate 17%, low 40% and very low 16%. At least one mutation was detected in 81% of patients; most frequent were SF3B1 (32%), ASXL1 (27%), TET2 (24%) and U2AF1 (15%). At median follow-up of 24 months, treatment with hypomethylating agents (HMAs) was documented in 121 (34%) patients, lenalidomide (LEN) in 55 (15%), and erythropoiesis stimulating agents (ESAs) in 136 (38%). ASXL1 mutations adversely affected response to HMAs (27% vs 48%; P = 0.02) and LEN (9% vs 43%; P = 0.04), but not ESAs (P = 0.6). LEN response was also adversely affected by U2AF1 mutations (0% vs 42%; P = 0.02) and high risk karyotype (0% vs 41% in intermediate vs 47% in low risk; P = 0.01). Patients with SF3B1 mutations were more likely to respond to LEN (56% vs 27%; P = 0.04). Contrary to previous reports, we found no association between TET2 mutations and HMA treatment response (40% vs 41%; P = 0.9), even in the absence of ASXL1 mutations (P = 0.4).We conclude that ASXL1 mutations in MDS predict inferior response to treatment with both HMAs and LEN; response to LEN was also compromised by U2AF1 mutations and high risk karyotype; SF3B1 mutations identified patients likely to respond to LEN.

T-lymphoblastic leukemia/lymphoma (T-ALL/LBL) accounts for approximately 15% of pediatric and 25% of adult ALL. While the underlying frequency of KMT2A (MLL) gene rearrangements has been identified in approximately 4-8% of T-ALL/LBL cases, a paucity of literature is available to characterize further the KMT2A rearrangements in pediatric/young adult T-ALL/LBL. A 10-year retrospective review was performed to identify KMT2A rearrangements in specimens sent for T-ALL/LBL fluorescence in situ hybridization studies in patients under the age of 30 years. Of 806 T-ALL/LBL FISH studies performed on unique individuals, 27 (3.3%) harbored KMT2A rearrangements. Nineteen patients were male and eight were female (M:F ratio, 2.4:1) with ages ranging from 1 to 20 years (mean 12, median 12). Of the 27 cases, nine (33%) had KMT2A/MLLT1 fusions, eight (30%) had KMT2A/AFDN fusions, two (7%) had KMT2A/ELL fusions, and one (4%) had a KMT2A/MLLT10 fusion. In addition, five (19%) had KMT2A rearrangements with unidentified gene fusion partners and two (7%) had 3'KMT2A deletions. Our results indicate that MLLT1 and AFDN account for the majority (63%) of KMT2A gene partners in pediatric/young adult T-ALL/LBL, while no KMT2A/AFF1 or KMT2A/MLLT3 fusions were observed despite their common identification in B-ALL and acute myeloid leukemia, respectively. In addition to diagnostic and prognostic value, detecting specific KMT2A fusions may also be of clinical importance in the era of targeted therapies.

This study examines the long-term OS of relapsed AML patients who were enrolled to 9 successive ECOG-ACRIN trials for newly diagnosed AML, during 1984–2008. The objectives were to examine whether there is a trend of improvement in the survival of relapsed AML patients in the more recent studies and to search for prognostic factors that are associated with long-term OS after relapse. A total of 3012 patients were enrolled, 1779 (59.1%) achieved CR1 and of these, 58.9% relapsed. The median follow-up was 9.7 years. The median OS from relapse was 0.5 years and the 5-year OS was 10 (±1)%. These results were similar even for the most recent studies. A multivariate model showed that age, cytogenetics at diagnosis, duration of CR1 and undergoing allogeneic transplantation were significantly associated with OS from relapse. Even among patients who relapsed with better prognostic factors; age < 40 and CR1 > 12 months, there was no significant OS difference between the studies. In conclusion, this large cohort appears to confirm that the survival of AML patients postrelapse continues to be dismal and has not improved during the past quarter of a century.

Metaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

Traditional cytogenetic testing methodologies, including conventional chromosome analysis and fluorescence in situ hybridization (FISH), are invaluable for the detection or recurrent genetic abnormalities in various hematologic malignancies. However, technological advances, including a novel next-generation sequencing technique termed mate-pair sequencing (MPseq), continue to revolutionize the field of cytogenetics by enabling the characterization of structural variants at a significantly higher resolution compared to traditional methodologies. To illustrate the power of MPseq, we present a 27-year-old male diagnosed with chronic myeloid leukemia in myeloid blast crisis with multiple chromosomal abnormalities observed in all 20 metaphases from a peripheral blood specimen, including t(9;22)(q34;q11.2) and t(4;11)(q12;p15). Suspicious of a novel NUP98/PDGFRA fusion [t(4;11)(q12;p15)], break-apart FISH probe sets for the PDGFRA (4q12) and NUP98 (11p15.4) gene regions were performed and were both positive in approximately 86% of 200 interphase nuclei. However, subsequent MPseq testing revealed breakpoints located within the NUP98 gene and within an intergenic region (4q12) located between the CHIC2 and PDGFRA genes, indicating this 4;11 translocation does not result in the predicted NUP98/PDGFRA gene fusion as inferred from FISH and conventional chromosome results. This case demonstrates the clinical utility of MPseq, particularly for characterizing novel gene fusion events which may ultimately identify a false-positive FISH result.

ObjectivesMyeloid sarcoma with CBFB-MYH11 fusion may be enriched in abdominal sites. The clinicopathologic features of 11 cases are reported.MethodsWe collected clinical features, morphology, immunophenotype, and bone marrow (BM) involvement of myeloid sarcoma cases with CBFB-MYH11 fusion.ResultsEleven of 29 total myeloid sarcoma cases were CBFB-MYH11 positive and all 11 involved abdominal sites. The blastic infiltrate was associated with eosinophils in four of 11 cases and plasmacytoid dendritic cell (pDC) nodules in four of six cases. CD34, CD117, and myeloperoxidase were expressed in eight of nine, 10 of 10, and 10 of 10 cases, respectively. Ten of 10 cases showed no BM involvement.ConclusionsOur current series, combined with a literature review, identifies a compelling series of 31 (94%) of 33 cases of myeloid sarcoma with CBFB-MYH11 fusion showing a marked predilection for abdominal sites. In addition, the lack of obvious associated eosinophils, presence of pDC nodules, and lack of concurrent BM involvement suggest that “myeloid sarcoma with CBFB-MYH11 fusion” may represent a unique phenomenon.

Objectives Chromosome (G-banding) and fluorescence in situ hybridization (FISH) serve as the primary methodologies utilized for detecting genetic aberrations in hematologic neoplasms. Chromosomal microarray can detect copy number aberrations (CNAs) with greater resolution when compared to G-banding and FISH, and can also identify copy-neutral loss of heterozygosity (CN-LOH). The purpose of our review is to highlight a preselected group of hematologic neoplasms for which chromosomal microarray has the greatest clinical utility. Methods A case-based approach and review of the literature was performed to identify the advantages and disadvantages of utilizing chromosomal microarray for specific hematologic neoplasms. Results Chromosomal microarray identified CNAs and CN-LOH of clinical significance, and could be performed on fresh or paraffin-embedded tissue and liquid neoplasms. Microarray studies could not detect balanced rearrangements, low-level clones, or distinguish independent clones. Conclusions When utilized appropriately, chromosomal microarray can provide clinically significant information that complements traditional cytogenetic testing methodologies.

Objectives Determine ancillary test utilization for the workup of isolated eosinophilia in otherwise morphologically unremarkable bone marrow (BM). Methods We evaluated BM ancillary testing performed in cases with isolated eosinophilia and otherwise morphologically unremarkable BM. Cases with abnormal morphology (eg, dysplasia, basophilia) and/or findings suggestive of a disorder (eg, unexplained thromboses, lymphoma) are specifically excluded. Results A total of 132 cases met inclusion criteria. Ten cases had an ancillary testing abnormality that warranted a more specific hematologic diagnosis: four cases of lymphocytic variant of hypereosinophilic syndrome, three cases of myeloid neoplasm with PDGFRA rearrangement, and one case each of myeloid neoplasm with PDGFRB rearrangement, chronic eosinophilic leukemia, and morphologically occult systemic mastocytosis. No cases revealed a cryptic PDGFRB or BCR/ABL1 rearrangement or JAK2 V617F mutation. Conclusions Findings from our institutional experience support initial testing in isolated eosinophilia with otherwise unremarkable BM to include PDGFRA rearrangement, tryptase/CD25 immunohistochemistry, cytogenetics, and T-cell flow cytometry/receptor gene rearrangement. This approach achieves diagnostic quality and test utilization efficiency in our clinical practice.

TO THE EDITOR: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract (GI TLPD) is a newly recognized entity in the World Health Organization (WHO) classification of lymphoid neoplasms.[1][1] GI TLPD is defined as a clonal T-cell proliferation occurring in the GI tract, most

The International Myeloma Working Group has proposed the Revised International Staging System (R-ISS) for risk stratification of multiple myeloma (MM) patients. There are a limited number of studies that have validated this risk model in the autologous stem cell transplant (ASCT) setting. In this retrospective study, we evaluated the applicability and value for predicting survival of the R-ISS model in 134 MM patients treated with new agents and ASCT at the Mayo Clinic in Arizona and the University Hospital of Salamanca in Spain. The patients were reclassified at diagnosis according to the R-ISS: 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. After a median follow-up of 60 months, R-ISS assessed at diagnosis was an independent predictor for overall survival (OS) after ASCT, with median OS not reached, 111 and 37 months for R-ISS I, II and III, respectively (P

Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with overlapping myeloproliferative and myelodysplastic features and an inherent risk for leukemic transformation [1...

The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.

Among 248 consecutive patients with blast phase myeloproliferative neoplasm (MPN-BP), DNA collected at the time of blast transformation was available in 75 patients (median age, 66 years; 64% men). MPN-BP followed primary myelofibrosis in 39 patients, essential thrombocythemia in 20 patients, and polycythemia vera in 16 patients. A myeloid neoplasm-relevant 33-gene panel was used for next-generation sequencing. Driver mutation distribution was JAK2 57%, CALR 20%, MPL 9%, and triple-negative 13%. Sixty-four patients (85%) harbored other mutations/variants, including 37% with ≥3 mutations; most frequent were ASXL1 47%, TET2 19%, RUNX1 17%, TP53 16%, EZH2 15%, and SRSF2 13%; relative mutual exclusivity was expressed by TP53, EZH2, LNK, RUNX1, SRSF2, and NRAS/KRAS mutations. Paired chronic-blast phase sample analysis was possible in 19 patients and revealed more frequent blast phase acquisition of ASXL1, EZH2, LNK, TET2, TP53, and PTPN11 mutations/variants. In multivariable analysis, RUNX1 and PTPN11 mutations/variants were associated with shorter survival duration; respective hazard ratios (HRs) (95% confidence interval [CI]) were 2.1 (95% CI, 1.1-3.8) and 3.0 (95% CI, 1.1-6.6). An all-inclusive multivariable analysis confirmed the prognostic relevance of RUNX1 mutations (HR, 1.9; 95% CI, 1.5-5.5) and also showed additional contribution from a treatment strategy that includes transplant or induction of complete or near-complete remission (HR, 0.3; 95% CI, 0.2-0.5). The current study points to specific mutations that might bear pathogenetic relevance for leukemic transformation in MPN and also suggest an adverse survival effect of RUNX1 mutations.

Purpose To develop a prognostic system for transplantation-age patients with primary myelofibrosis (PMF) that integrates clinical, cytogenetic, and mutation data. Patients and Methods The study included 805 patients with PMF age ≤ 70 years recruited from multiple Italian centers and the Mayo Clinic (Rochester, MN), forming two independent learning and validation cohorts. A Cox multivariable model was used to select from among a list of 22 variables those that were predictive of overall survival (OS). Integrated clinical and genetic prognostic models with (MIPSS70-plus) or without (MIPSS70) cytogenetic information were developed. Results Multivariable analysis identified the following as significant risk factors for OS: hemoglobin < 100 g/L, leukocytes > 25 × 109/L, platelets < 100 × 109/L, circulating blasts ≥ 2%, bone marrow fibrosis grade ≥ 2, constitutional symptoms, absence of CALR type-1 mutation, presence of high–molecular risk mutation (ie, ASXL1, EZH2, SRSF2, IDH1/ 2), and presence of two or more high–molecular risk mutations. By assigning hazard ratio (HR)–weighted points to these variables, three risk categories were delineated for the MIPSS70 model; 5-year OS was 95% in low-risk, 70% in intermediate-risk, and 29% in high-risk categories, corresponding to median OS of 27.7 years (95% CI, 22 to 34 years), 7.1 years (95% CI, 6.2 to 8.1 years), and 2.3 years (95% CI, 1.9 to 2.7 years), respectively. In the MIPSS70-plus model, which included cytogenetic information, four risk categories were delineated, with 5-year OS of 91% in low-risk, 66% in intermediate-risk (HR, 3.2; 95% CI, 1.9 to 5.2), 42% in high-risk (HR, 6.4; 95% CI, 4.1 to 10.0), and 7% very high–risk categories (HR, 17.0; 95% CI, 9.8 to 29.2). Both models remained effective after inclusion of older patients in the analysis. Conclusion MIPSS70 and MIPSS70-plus provide complementary systems of risk stratification for transplantation-age patients with PMF and integrate prognostically relevant clinical, cytogenetic, and mutation data.

Current cytogenetic risk stratification in primary myelofibrosis (PMF) is two-tiered: ‘favorable’ and ‘unfavorable’. Recent studies have suggested prognostic heterogeneity within the unfavorable risk category. In 1002 consecutive patients, we performed stepwise analysis of impact on survival from individual and prognostically ordered cytogenetic abnormalities, leading to a revised three-tiered risk model: ‘very high risk (VHR)’—single/multiple abnormalities of −7, i(17q), inv(3)/3q21, 12p−/12p11.2, 11q−/11q23, or other autosomal trisomies not including + 8/ + 9 (e.g., +21, +19); ‘favorable’—normal karyotype or sole abnormalities of 13q−, +9, 20q−, chromosome 1 translocation/duplication or sex chromosome abnormality including -Y; ‘unfavorable’—all other abnormalities. Median survivals for VHR (n = 75), unfavorable (n = 190) and favorable (n = 737) risk categories were 1.2 (HR 3.8, 95% CI 2.9–4.9), 2.9 (HR 1.7, 95% CI 1.4–2.0) and 4.4 years and survival impact was independent of clinically derived prognostic systems, driver and ASXL1/SRSF2 mutations. The revised model was also effective in predicting leukemic transformation: HRs (95% CI) were 4.4 (2.0–9.4) for VHR and 2.0 (1.2–3.4) for unfavorable. The impact of driver mutations on survival was confined to favorable and that of ASXL1/SRSF2 mutations to favorable/unfavorable cytogenetic risk categories. The current study clarifies the prognostic hierarchy of genetic risk factors in PMF and provides a more refined three-tiered cytogenetic risk model.

A total of 410 patients with blast phase myeloproliferative neoplasm (MPN-BP) were retrospectively reviewed: 248 from the Mayo Clinic and 162 from Italy. Median survival was 3.6 months, with no improvement over the last 15 years. Multivariable analysis performed on the Mayo cohort identified high risk karyotype, platelet count 65 years and transfusion need as independent risk factors for survival. Also in the Mayo cohort, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35 and 24%, respectively; treatment-specified 3-year/5-year survival rates were 32/10% for patients receiving allogeneic stem cell transplant (AlloSCT) (n = 24), 19/13% for patients achieving CR/CRi but were not transplanted (n = 24), and 1/1% in the absence of both AlloSCT and CR/CRi (n = 200) (p

Myeloid neoplasms with eosinophilia associated with PDGFRA rearrangement are very responsive to tyrosine kinase inhibitors (TKIs). Herein, we report a case of a 53-year-old man with eosinophilia and a well-differentiated extramedullary myeloid tumor with evidence of FIP1L1/PDGFRA rearrangement by fluorescent in situ hybridization in the extramedullary tissue. His bone marrow evaluation revealed a hypercellular marrow with eosinophilia but without evidence of a FIP1L1/PDGFRA rearrangement. The patient was treated with imatinib at a dose of 100 mg daily and responded with normalization of his peripheral eosinophil count. The case raises the possibility that an extramedullary myeloid tumor may represent a primary site for PDGFRA rearrangement, and highlights the importance of performing cytogenetic testing on extramedullary tissue. Detection of the chromosomal rearrangement is critical for initiation of effective targeted therapy that can improve patient outcomes.

Purpose Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse. Patients and methods Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients. Results One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001). Conclusion This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.

Background Cytogenetic abnormalities at diagnosis are relatively uncommon in essential thrombocythemia (ET). In the current study of 818 consecutive patients with ET who were fully annotated for karyotype, we describe the spectrum and prevalence of cytogenetic abnormalities at diagnosis, followed by a comprehensive assessment of phenotypic and molecular correlates and prognostic relevance. Methods The study cohort consisted of 818 consecutive patients with ET that were diagnosed according to the World health Organization 2016 criteria and underwent evaluation between 1967-2021. In order to minimize the inadvertent inclusion of patients with masked polycythemia vera, JAK2 mutated cases with hemoglobin (Hb) level >16 g/dL in women and 16.5 g/dL in men were excluded; similarly, cases with anemia defined by sex adjusted Hb level of Results Prevalence and spectrum of cytogenetic abnormalities Karyotype was normal in 755 patients (92%), showed loss of Y chromosome (-Y) in 16 (2%), and showed abnormalities other than -Y in 47 (5.7%); most common abnormalities included del(20q) (n=10, 21%), trisomy 9 (n=8, 17%), trisomy 8 (n=2, 4%), del(5q) (n=2, 4%), and del(3p) (n=2, 4%). Other sole cytogenetic abnormalities were identified in 18 (38%) patients. Phenotypic and molecular correlates Abnormal karyotype, other than -Y, in comparison with normal karyotype was associated with older age (median age; 63 vs 58 years, p=0.02), lower hemoglobin level (p=0.003), and a higher incidence of arterial thrombosis prior to/at diagnosis (25% vs 13%; p=0.03). 603 patients were annotated for driver mutations; abnormal/normal/-Y frequencies were 78%/60%/71% for JAK2, 22%/26%/14% CALR, 0%/3%/0% MPL and 0%/10% /14% triple negative (p=0.31). NGS information was available in 226 patients and showed absence of ASXL1 mutation in all patients with abnormal karyotype vs 8/211 (4%) with normal karyotype vs 2/4 (50%) with -Y (p At a median follow-up of 9.6 years (range; 0.01-49.4 years), a total of 96 patients (12%) underwent fibrotic transformation: 6 (13%) with abnormal karyotype, 89 (12%) with normal karyotype and 1 (6%) with -Y (p=0.77). Leukemic transformation rates were also similar with respective frequencies of 4%, 3% and 0% (p=0.71). Abnormal karyotype and -Y were associated with inferior survival with median of 12 years (range; 0.1-34) and 9 years (range; 0.01- 19.9), respectively, compared to 21 years (range; 0.01-49.4) for normal karyotype (p60 years (p11 x10 9/L (p60 years (p11 x10 9/L (p=0.001), and male gender (p=0.01) remained significant. Additional analysis suggested individual prognostic impact for del(20q) (p=0.04) and also for trisomy 9 (p=0.09) and other abnormalities (p=0.07), with borderline significance. Conclusion The current study confirms the association of abnormal karyotype in ET with older age, lower hemoglobin level, and history of arterial thrombosis, and its mutual exclusivity with ASXL1 mutations. Our observation regarding the independent adverse impact of abnormal karyotype other than -Y, on overall survival, in the absence of association with fibrotic or leukemic transformation, requires clarification from additional studies, which should also investigate the effect of specific abnormalities. Figure 1 Figure 1. Disclosures Szuber: Novartis: Honoraria.

Purpose: Multiple myeloma (MM) is a plasma cell malignancy characterized by a collection of cytogenetic abnormalities that drive clinical presentation, response to treatment, and prognosis. The most common immunoglobulin heavy chain (IGH) translocation found in MM, t(11;14), results in CCND1 overexpression. Although t(11;14) is considered a standard risk cytogenetic abnormality, heterogeneity in patient outcomes and response to therapy within the t(11;14) group has been reported. In contrast to t(11;14) mantle cell lymphoma, where most cases (73%) have a typical, balanced t(11;14) rearrangement, only 47% of t(11;14) MM have a typical, balanced t(11;14) FISH pattern; the remaining 53% of MM are characterized by an atypical t(11;14) FISH result (Dalland, Genes Chromosomes Cancer, 2021). Here, we compared the genetic characteristics of typical vs. atypical t(11;14) MM and the association with other genomic abnormalities, CCND1 expression, IGH breakpoint location and patient outcomes. Methods: We performed a retrospective study of newly diagnosed t(11;14) MM patients seen at Mayo Clinic (N=411) or enrolled in the MMRF CoMMpass trial (N=167). The t(11;14) FISH results of the Mayo Clinic samples were segmented into two groups: typical CCND1/IGH signal pattern (n=179, 3 red, 3 green, 2 fusion signals) and atypical CCND1/IGH signal pattern (n=232, any FISH pattern deviating from typical). The CoMMpass cases had both RNAseq and long-insert WGS data and were analyzed to detect gene expression, structural and copy number variants and IGH breakpoint locations. These data were used to classify the t(11;14) as typical (n=63) or atypical (n=104) and whether there was a single t(11;14) fusion (n=107) or a gain of the t(11;14) fusion (n=60), and whether these cases were associated with changes in gene expression or breakpoint location. Differences between the groups were measured using χ2 and Wilcoxon tests. Survival curves were estimated using Kaplan Meier and compared using the Log-Rank test. Statistical significance was determined at p Results: Of the Mayo t(11;14) cohort, 232/411 (56%) had an atypical t(11;14) FISH pattern and 179/411 (44%) had a typical t(11;14) FISH pattern. Although an atypical t(11;14) FISH pattern was not significantly associated with monosomy 17/17p deletion, MYC rearrangements, 1q gain or ISS stage III, it was significantly associated with the presence of any trisomy in comparison to typical t(11;14) cases (40/222=18% vs.12/166=7%, p=0.002). Atypical t(11;14) cases had an increase in CCND1 gene expression compared to typical t(11;14) cases (median 375.0 RPKM vs. 266.4 RPKM, p Conclusions: Atypical t(11;14) FISH in MM is found in approximately half of t(11;14) cases, is associated with trisomies, higher CCND1 expression and is more likely to have a breakpoint involving the constant region of the IGH locus. The enrichment of VDJ breakpoints within typical t(11;14) MM is consistent with enrichment of VDJ IGH breakpoints in MCL, which are mostly characterized by typical t(11;14) FISH patterns. While not an independent predictor of outcome with standard therapies, it remains to be evaluated whether patients with typical or atypical t(11;14) have a differential response to novel agents, such as venetoclax. Disclosures Fonseca: Janssen: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Merck: Consultancy; Juno: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy; Aduro: Consultancy; OncoTracker: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; AbbVie: Consultancy; Patent: Prognosticaton of myeloma via FISH: Patents & Royalties; Mayo Clinic in Arizona: Current Employment; Amgen: Consultancy; BMS: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Bayer: Consultancy; Scientific Advisory Board: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Bergsagel: Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse. Kumar: Merck: Research Funding; Carsgen: Research Funding; Roche-Genentech: Consultancy, Research Funding; Beigene: Consultancy; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Sanofi: Research Funding.

Purpose: Multiple myeloma (MM) is a plasma cell (PC) malignancy with an increasing incidence in the United States. Fluorescence in situ hybridization (FISH) is currently the gold-standard diagnostic assay to detect recurrent genomic abnormalities of prognostic and therapeutic significance in MM. Hyperdiploid MM, a standard risk abnormality, is characterized by gains of odd-numbered chromosomes including chromosome 15. While gains of chromosome 15 have been reported in approximately 53% of standard risk MM patients (Chretien, Blood, 2015), losses of chromosome 15 are rarely reported. Enumeration of chromosome 15 centromere is detected using the alpha satellite FISH probe. We previously discovered ~9% of cases had false-negative chromosome 15 FISH results when compared to Mate Pair Sequencing (MPseq) (Smadbeck, BCJ, 2019). To our knowledge, no previous studies have reported a reduced performance of the alpha satellite D15Z4 FISH probe in PC FISH studies. A false-negative result for D15Z4 could result in an underreporting of trisomy 15 and overreporting of monosomy 15. Here, we investigated the incidence of false-negative D15Z4 FISH results by examining the presence of monosomy 15 from patients with a monoclonal gammopathy. Methods: We identified 1231 samples from patients with a monoclonal gammopathy who had undergone uniform testing to identify MM-specific cytogenetic abnormalities. DNA from bone marrow samples was genotyped on the Precision Medicine Research Array and biogeographical ancestry was assessed using the Geographic Population Structure Origins tool (Elhaik, Nat Commun, 2014; Home DNA 2016). FISH of immunoglobulin (cIg)-stained PCs was performed as described (Baughn, BCJ, 2018). Chromosome 15 centromere probe (Vysis CEP 15 D15Z4, Abbott Molecular, Abbott Park, IL) was used for chromosome 15 enumeration. Samples were divided into two groups: Cases with or without evidence of monosomy 15 by FISH. Mann-Whitney U test was applied to compare difference between groups for data deviating from normal distribution. A Chi-squared test evaluating the differences across these two groups was used. Results: We identified monosomy 15 in 31 cases (2.5% of cohort). Monosomy 15 was observed in nearly 100% of both the PC (cIg+) and non-PC (cIg-) populations, by contrast to the other recurrent PC-specific genomic abnormalities which were restricted to only the PC population. All samples with a banded analysis revealed most metaphases had two normal chromosome 15s demonstrating that the D15Z4 FISH probe failed to correctly enumerate the number of chromosome 15 centromere signals. Of the samples with a monosomy 15 result, the median African ancestry was 76.2% (95% percentiles: 77.5%-89.0%), while the median African ancestry of the non-monosomy 15 cohort was 2.3% (95% percentiles: 0%-87.7%) (). Although not all patients with >50% African ancestry had evidence of monosomy 15, 26/31 (83.9%) of patients with monosomy 15 had >50% African ancestry. Accordingly, patients with African ancestry (similarity ≥ 0.70) had 8.02-fold (95% confidence interval: 3.73-17.25, P = 9.92 X10 -8) increased possibility to have monosomy 15. Of cases with monosomy 15, 22 (71.0%) had an IGH rearrangement with the most prevalent IGH partner being CCND1. The incidence of t(11;14) was greater in the monosomy 15 group (13/31:41.9%), in contrast to the non-monosomy 15 group (330/1200=27.5%) (P = 0.12). Conclusions: We report a polymorphic variant of the chromosome 15 centromere resulting in a false-negative FISH result using the D15Z4 FISH probe. Surprisingly, the false-negative FISH result was not uniformly distributed among patients and was highly enriched in individuals of African ancestry. This may be due to a variation of the chromosome 15 alpha satellite in some individuals that prevents the D15Z4 FISH probe from sufficiently binding (O'Keefe, Genome Research, 2000). Although this study focused on identification of monosomy 15, the incidence of a false-negative result is likely greater than we have reported in this study since we did not evaluate cases that had a true trisomy 15 that was reported as normal chromosome 15 enumeration by FISH. This study highlights a critical need to ensure diagnostic reagents have equal performance for all patients independent of their ancestry. Evaluation of genomic events using unbiased approaches such as whole genome sequencing may circumvent some of these limitations. Disclosures Elhaik: DDC: Consultancy. Baird: DDC: Current Employment. Kumar: Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Beigene: Consultancy; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Carsgen: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Background: Therapy-related acute myeloid leukemia (AML) is a well-described entity and known to carry a worse prognosis, compared to de novo AML. In the current study, we sought to describe the presenting features and outcome of patients with AML, in the setting of previous history of cancer with or without exposure to chemotherapy or radiotherapy. Methods: A Mayo Clinic database of patients with AML was queried to identify patients with a previous history of cancer, both hematologic and solid tumors. A comparative analysis of presenting features, treatment details and survival were performed between patients with therapy-related AML (Group A) and those with AML and a history of cancer that had been managed with surgery alone (Group B). Results: A total of 250 patients (median age 68 years, range 19-90; 60% males) with AML and a previous history of cancer (both hematologic and solid) were identified; 182 (73%) cases were determined to be therapy-related AML (Group A) while the remaining 68 (27%) did not receive chemotherapy or radiotherapy for their antecedent cancer (Group B) (Table). Among group A patients 106 (58%) were exposed to chemotherapy, 37 (20%) to radiotherapy and 39 (22%) to combination chemotherapy and radiotherapy for their cancer. At the time of AML diagnosis, adverse karyotype was noted in 91 (51%) group A and 12 (19%) group B patients (p Treatment and outcome in Groups A and B: Intensive and less intensive AML-directed chemotherapy were given to 100 (55%) and 44 (24%) patients in group A and 38 (56%) and 14 (21%) patients in group B (P=0.8). 79 (65%) remissions (complete remission (CR) 42 (29%) and CR with incomplete count recovery (CRi) 37 (26%) were documented in Group A and 37 (71%) remissions (CR: 21 (40%) and CRi=16 (31%) in Group B (P=0.2). After a median follow-up of 8.4 months (range: 0.9-217), 184 deaths were documented: 132 (72.5%) in Group A and 52 (76.5%) in Group B (P=0.5). 52 (36%) patients from Group A and 25 (48%) from Group B relapsed (P=0.1). The median (range) overall survival (OS) rates of patients from Group A was 13 (9-17) months and that of Group B was 14 (10-35) months (P=0.6). The 1-, 3- and 5-year OS rates were 52%, 28%, and 24% in Group A; and 62%, 33%, and 24% in Group B patients (Fig 1). Multivariable analysis identified relapse (HR 2.8, 95% CI 1.7-4.7) and failure to achieve CR/CRi (HR 2.8 95% CI 1.9-4.7) as risk factors for inferior survival (Fig 2a and 2b). The median (range) relapse free survival of patients in Group A was 28 (17 -81) and that of Group B was 27 (14 - 76) months (P=0.9) (Fig 2c). 28 patients underwent allogenic stem-cell transplant (25 in CR1 and 3 in CR2), 23 in Group A and 5 in Group B; the 1-, 3-, and 5-year OS of patients who underwent allogenic stem cell transplant were 88%, 72%, and 72% regardless of the group (Fig 2d). Conclusion: The current study did not find significant differences between AML patients with previous history of cancer with or without exposure to chemo/radiotherapy, in terms of either response to AML-directed therapy or overall or relapse-free survival, despite a higher prevalence of adverse karyotype in therapy-related AML. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee.

Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome. Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response. Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05). CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented. Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2). Conclusion :In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.

The t(11;14)(q13;32)-positive plasma cell neoplasms (PCNs) are common. In light of their lymphoplasmacytoid features and CD20 expression, we speculated that they may share laboratory features with B-cell lymphomas with plasmacytic differentiation (BCL-PCDs). We investigated flow cytometric CD19 and CD45 expression, DNA ploidy index and M-protein subtype in 416 t(11;14)-positive PCNs, as well as control groups (88 BCL-PCDs and 81 t(11;14)-negative PCNs). The plasma cells from the t(11;14)-positive PCNs were largely CD19-/CD45-, similar to the t(11;14)-negative PCNs and unlike the BCL-PCD plasma cells (p .0001). 79% of the t(11;14)-positive PCNs were diploid, which was significantly more than in t(11;14)-negative PCNs (p .0001) and significantly less than in the BCL-PCDs (p .001). Although IgM secretion was common in BCL-PCDs (80%) and rare in PCNs (3%), most IgM PCNs (92%) were t(11;14)-positive. These findings may be helpful in evaluating specimens with clonal plasma cells in the reference laboratory setting.