Arber, Daniel A.

Abstract Background: The persistence of detectable MRD in complete remission (CR/CRi - CR with incomplete CBC recovery) has been reported to contribute to inferior outcome in younger AML patients (pts) in retrospective studies, however MRD has not been studied prospectively in older adults (age ≥60 yrs) receiving intensive therapy with curative intent. We performed a planned prospective study of MRD status after AML induction therapy in older adults, integrated into the large multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients age ≥60 yrs with AML were randomized 1:1 to receive either 'Standard' 7&3 (Dauno 60mg/m2) induction, with 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior overall survival (OS) with standard therapy despite similar CR/CRi rates using stringent criteria, and similar 30-day induction mortality rates. Submission of diagnostic & remission bone marrow or peripheral blood samples was protocol mandated for prospective MRD assessment, and analysis was performed in the central E-A Leukemia Translational Research Lab (LTL) using 6-color multiparameter flow cytometry. MRD-positive (MRD+) was defined as ≥0.1%. LTL flow cytometric analysis was done blinded to treatment arm and outcome of patients. Only pt samples collected within +/-6 days of CR/CRi confirmation were included in this analysis. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine the MRD effect on OS and disease-free survival (DFS, relapse or death). Results The median follow-up is 47.8 months, and 297 of 685 evaluable patients (43.4%) achieved CR/CRi (Standard 44.6%; CLO 42.0%, p=ns). Remission MRD samples were only available for 147 CR/CRi patients (49.5%), owing to variability in sample viability and AML involvement, collection practices and timing of sample collection at individual sites, and patient/physician decision. 58/147 evaluable CR/CRi patients achieved MRD-negative (MRD-) status (Standard 40.7%, CLO 47.9%, p=0.74). Women (56.9% vs. men 43.1%, p=0.003) were more likely to be MRD-, but there was no other significant difference in MRD status stratified by clinical or disease features. MRD+ status at CR/CRi was associated with significantly inferior OS (p=0.031, Figure 1) and also inferior overall DFS (p=0.02); this was most pronounced for DFS after CLO (Arm B, Figure 2) (p=0.005), but not Standard (Arm A) therapy (p=0.41). The impact of MRD+ was confirmed on multivariate analysis using Cox Model Fitting, for OS: OS for All MRD+ pts, HR 1.64 (95% CI 1.00-2.68) (p=0.05); OS for Standard (Arm A) MRD+ pts, HR 1.06 (95% CI 0.51-2.21) (p=0.87); and OS for CLO (Arm B) MRD+ pts, HR 2.30 (95% CI 1.05-5.06) (p=0.04). There was a similar impact for DFS on multivariate analysis using Cox Model Fitting: DFS for All MRD+ pts, HR 1.86 (95% CI 1.16-2.98) (p=0.01); DFS for Standard (Arm A) MRD+ pts, HR 1.15 (95% CI 0.60-2.19) (p=0.67); and DFS for CLO (Arm B) MRD+ pts, HR 3.45 (95% CI 1.47-8.09) (p=0.004). Post-remission therapy was not stratified by MRD in E2906, and 33% of MRD-evaluable pts underwent allogeneic transplantation (no difference in transplant rate for MRD+ vs. MRD-). Conclusions MRD+ ≥0.1% is common (60.5%) after induction therapy in older adults & is significantly associated with inferior OS and DFS in 1st CR/CRi. However we observed excellent outcomes for MRD- pts in first CR/CRi regardless of induction regimen or post-remission therapy used. MRD+ pts in CR/CRi who went on to receive CLO consolidation had significantly poorer outcomes than those who went on to receive intermediate dose Ara-C consolidation. This observation differs strikingly from younger AML, and suggests that intensified Ara-C may abrogate the adverse impact of MRD in older pts in CR. These results strongly support incorporation of centralized MRD at the time of remission into future studies to guide optimal post-remission strategies in older pts with AML. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Altman:Bayer: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work. Al-Kali:Novartis: Research Funding. Pratz:Millenium/Takeda: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding.

Abstract Background Activating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients (pts) age ≥60 yrs (n=727) were randomized to 'Standard' therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)]. Results In the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41). Conclusions FLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.

Abstract Background: Induction therapy with daunorubicin (Dauno) & cytarabine (Ara-C) [DA] has been the standard of care for eligible older adults (age ≥ 60 years) with newly diagnosed acute myeloid leukemia (AML) for over 2 decades. Single agent Clofarabine (CLO) induction & consolidation (Consol.) therapy has demonstrated important clinical activity in this age group in large phase II studies. Lower induction mortality (IM) & similar reported complete remission rate (CR) & overall survival (OS), as well as notable activity in those with higher risk disease features [including unfavorable cytogenetics, therapy-related AML (t-AML) & prior antecedent hematologic disorder (AHD)] raises the possibility that a non-Ara-C-based regimen could achieve similar or superior OS with lower toxicity. Methods: We performed a randomized United States Intergroup Phase III trial of single agent CLO [30mg/m2 x 5 days induction; 20 mg/m2 re-induction (if indicated) & 2 cycles Consol.] vs. standard DA therapy [Dauno 60mg/m2 D1-3 & Ara-C 100mg/m2 D1-7 induction x 1-2 cycles; 2 cycles Consol. with Ara-C (1.5g/m2 Q12hrs D1-6 age 60-69; once daily if age 70+)] in patients (pts) age ≥ 60 yrs with newly diagnosed AML. Patients with serum creatinine >1.0 (or GFR <60 mL/min) and those with AML-M3 and ECOG performance status >3 (PS>2 if age 70+ yrs) were excluded. Randomization was stratified by age (60-69 vs. 70+), t-AML, & AHD. Pts with HLA-matched donor were eligible for allogeneic transplantation (AlloHCT) after induction, and those completing Consol. were eligible for randomization #2 (R#2) to maintenance decitabine [20mg/m2 x 3D, monthly x 1 year] versus observation. With a target accrual of 747, E2906 was powered to determine non-inferiority [and possible superiority] of CLO vs. standard DA, and primary endpoint was OS. A weighted statistical analysis was performed to account for confounding impact of R#2. AlloHCT patients were censored at transplant in this analysis. Responses & cytogenetics were confirmed centrally and OS & CR rates were monitored by an independent Data Safety Monitoring Committee (DSMC) at pre-specified time points. Results: As of Feb 23, 2015, 727 pts were randomized. Median age was 68 years (range 60-86); 57% were male, and 38% were age ≥70 yrs. Treatment arms are well balanced for all baselineclinical & AML characteristics, & 30% had unfavorable cytogenetics. Of 659 with complete treatment information reported, 30.4% on DA vs. 40.1% on CLO received 2 cycles of induction (p=0.006). Median follow-up of surviving patients is 7.6 months. Table 1. shows early treatment results (CR, toxicity) for the 686 pts randomized as of Dec 23, 2014 (2 months prior to study end, & excluding 90 with ongoing response evaluation). DA CLO p-value CR/CRi 43.8% 42.8% p=0.87 30-day mortality 8.5% 7.9% p=0.89 60-day mortality 14.9% 13.1% p=0.58 Gr 4-5 Non-Heme Tox.Induction 27% 19% p=0.02 Gr 4-5 Non-Heme Tox.Consol. 20% 7% p=0.001 374 pts have died (174, DA; 200, CLO) & significantly inferior OS was observed for CLO vs. DA [Hazard Ratio (HR) 1.41 (95% CI 1.12-1.78)] (Fig. 1). Planned subgroup analyses were performed (Table 2) demonstrating significant differences in OS after CLO for patients age 60-69 yrs, without AHD, & with intermediate risk cytogenetics; but not for those with Unfav. Cytogen. (Fig. 2) or t-AML. Based on the primary weighted analysis, DSMC recommended suspension of new accrual to E2906 on Feb 23, 2015 & all active patients on CLO were transitioned to DA Arm. Table 2.NHR CLO/Standard (95% CI)*Weighted OS7271.41 (1.12-1.78)Unweighted OS7271.23 (1.00-1.50)Age 60-694491.48 (1.10-1.99)Age 70+2781.34 (0.93-1.93)Intermed. Risk Cytogen.3781.77 (1.27-2.47)Unfav. Risk Cytogen.2160.96 (0.65-1.43)No AHD6041.46 (1.13-1.89)AHD1231.22 (0.74-2.00)De novo AML6271.52 (1.18-1.96)Therapy-related AML1000.94 (0.54-1.61) Conclusions: Despite similar CR & IM, OS after single agent CLO is inferior to standard DA therapy for pts age ≥60 years with newly diagnosed AML who are fit for intensive therapy, and DA remains the standard of care. However no difference in OS was observed after CLO in some pre-specified high risk AML subgroups. R#2 & AlloHCT arms continue in E2906 for pts already enrolled. Embedded prospective minimal residual disease study at CR is being performed to identify pts at higher risk after CLO & DA. Figure 1. Weighted Kaplan-Meier Curves for OS Figure 1. Weighted Kaplan-Meier Curves for OS Figure 2. Unfavorable Cytogenetics OS by Therapy Figure 2. Unfavorable Cytogenetics OS by Therapy Disclosures Off Label Use: Use of clofarabine in AML, and maintenance therapy with decitabine in AML. Claxton:Medimmune: Research Funding; BMS: Consultancy; Astellas: Research Funding; Cyclacel: Research Funding; Merck: Research Funding; Ambit: Research Funding. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy. Altman:Seattle Genetics: Consultancy; BMS: Consultancy; Spectrum: Consultancy; Astellas: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Al-Kali:Novartis: Research Funding.

Abstract Background: The results of the primary endpoint of the E2906 North American Intergroup phase 3 trial - demonstrating significantly inferior OS after single agent clofarabine versus standard intensive daunorubicin & cytarabine induction and consolidation - strongly support the use of intensive therapy for patients age ≥60 years with newly-diagnosed AML who are fit for treatment. This result was achieved despite similar CR rates (including CRi - CR with incomplete blood count recovery) and similar early (30- & 60-day) induction mortality between study arms, raising the question as to the importance of achieving CR as an endpoint. Therefore, we performed a follow-up analysis to address the factors that contribute to early mortality, the necessity for 2nd induction cycle to achieve CR, and to assess the survival impact of the quality of remission. Methods: E2906 design, study population and results for the primary objective were reported previously (ASH 2015, abstr. #217a). We performed this updated analysis to evaluate clinical risk factors for early mortality and re-induction, and to assess the impact of response quality on OS. Univariate comparisons were made with Fisher's exact test (category) and t-test (continuous variable), and logistic regression models were used to examine risk factors associated with early mortality, and with requiring a 2nd cycle of induction therapy. We performed a landmark analysis (beginning Day 60 after initiation of therapy) to determine the impact of response quality (CR/CRi, morphologic leukemia-free-state (MLFS), and treatment failure - i.e. residual/refractory AML) on OS. Survival comparisons were performed with log-rank test. Results: A total of n=727 patients were registered to E2906, the median age is 68 years (range 60-86) and the median follow-up of surviving patients is now 18.3 months. Adjusting for treatment, cytogenetic risk group, FAB subtype, WBC count, and secondary AML, increasing age (p=0.06) and performance status (PS) >1 (p=0.05) were associated with 30-day mortality and only PS >1 (p=0.06) with 60-day mortality. Treatment arm (p=0.003), adverse cytogenetic risk group (p=0.02), increasing age (p=0.03) and baseline WBC <10K (p=0.03) were each independently associated with higher risk of receiving 2nd cycle induction, but there was no difference in CR/CRi (44.2% vs. 42.2%, p=0.58) or in median OS (13.8 versus 12.0 months, p=0.11) for those receiving 1 vs. 2 induction cycles, respectively. We next performed a landmark analysis (day 60, n=608 evaluable patients) to evaluate OS in relation to the quality of response (Table). We observed an advantage in achieving CR and CR/CRi, although the benefit of CRi diminished greatly after 12 months, and OS after MLFS appeared more similar to treatment failure (Figure, p<0.001). The relative adverse impact of CRi and MLFS (vs. CR) was most pronounced for patients treated with clofarabine, where median OS was shorter for those achieving CRi (12.2m vs. 22.6m standard therapy, p=0.007) and MLFS (6.6m vs. 13.4m standard therapy, p=0.15). Conclusion: This follow-up analysis confirms the importance of CR regardless of the number of cycles of induction therapy required to achieve remission, and identifies risk factors associated with early mortality and with requiring re-induction. At longer follow-up the OS after CRi appears to be inferior to true CR, particularly after clofarabine. We hypothesize that this may be due to higher rates of minimal residual disease in CRi, and studies to determine this are being performed. MLFS is not associated with a better overall survival than frank treatment failure (i.e. residual disease) and therefore its value as a response category is uncertain. These results highlight the role of standard intensive remission induction therapy with the intent of achieving CR, which remains the standard of care for fit older adults. Table. Table. Figure 1. Figure 1. Disclosures Foran: karyopharm: Honoraria; novartis: Honoraria; medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Melnick:Janssen: Research Funding. Altman:Novartis: Honoraria; BMS: Honoraria; Janssen: Honoraria; Syros: Honoraria. Al-Kali:Novartis: Research Funding; Celgene: Research Funding.

Context.— The classification and prognosis determination in acute leukemia (AL) are complex and it is unclear what testing is being performed in practice. Objective.— To survey physicians describing their current practice of test ordering in the diagnosis of AL. Design.— In anticipation of a guideline by the College of American Pathologists (CAP) and the American Society for Hematology on laboratory testing needed for the initial workup of AL, a baseline survey was designed by an expert panel from CAP. Members of professional societies were asked to describe their current practice of test ordering. Results.— Two hundred ninety-four responses were received with 258 respondents analyzed after the first qualifying survey question regarding initial diagnosis of AL. One hundred seventy-six of 249 respondents (70.7%) were board-certified hematopathologists. Flow cytometry and karyotype analysis were routinely performed for acute myeloid leukemia (AML) (99.1% [232 of 234] and 96.2% [225 of 234], respectively) and acute lymphoblastic leukemia (ALL) (98.3% [229 of 233] and 96.6% [225 of 233], respectively). In addition, fluorescence in situ hybridization studies were routinely performed by 81.2% (190 of 234) of respondents for AML and 85.0% (198 of 233) of respondents for ALL; other molecular studies were performed by 78.2% (183) for AML and 54.9% (128) for ALL; immunohistochemistry by 44.9% (105) for AML and 47.6% (111) for ALL; and cytochemistry by 24.8% (58) for AML and 14.2% (33) for ALL. Conclusions.— While flow cytometry and karyotyping are routinely reported as being performed for the diagnosis of AL, there is marked variation in the reporting of testing patterns for other genetic studies, immunohistochemistry, and cytochemistry.

SummaryIntroductionWhile the presence of disseminated intravascular coagulation (DIC) has been implicated in worse clinical outcome in acute leukemia, the relationship between different subtypes of acute leukemia and the clinicopathologic features of DIC has not been systematically well studied.MethodsIn this study, we retrospectively reviewed 149 cases of newly diagnosed acute leukemia and assessed the utility of evaluating red blood cell morphologic features, and coagulation parameters in determining the presence of DIC as well as differentiating subtypes of acute leukemia.ResultsReview of our cohort demonstrates a novel finding, that elevated D‐dimer concentrations ≥19 000 ng/mL fibrinogen equivalent units (FEU) are a sensitive diagnostic indicator of acute promyelocytic leukemia (APL) with moderate specificity, sensitivity 96%, specificity 92% in acute leukemia subtyping. Similar to other studies, APL showed an increased incidence of DIC (P < 0.01) compared to other subtypes of acute leukemia. Surprisingly, the presence of schistocytes on the peripheral blood smear was not a statistically significant indicator of DIC, sensitivity of 36% and specificity of 89%. Finally, the presence of DIC was not a significant indicator of poorer prognosis amongst all patients with AML.ConclusionOverall we identify elevated D‐dimer concentrations ≥19 000 ng/mL FEU are a sensitive indicator of acute promyelocytic leukemia (APL), with a sensitivity of 96% and specificity of 92% in the subtyping of acute leukemias, and that the presence of schistocytes in peripheral blood smears is not a diagnostically sensitive screening test for DIC with a sensitivity of 36%.

It is controversial whether acute myeloid leukemia (AML) patients with 20–29% bone marrow (BM) blasts, formerly referred to as refractory anemia with excess blasts in transformation (RAEBT), should be considered AML or myelodysplastic syndrome (MDS) for the purposes of treatment and prognostication. We retrospectively studied 571 de novo AML in patients aged >50 years, including 142 RAEBT and 429 with ≥30% blasts (AML30), as well as 151 patients with 10–19% BM blasts (RAEB2). RAEBT patients were older and had lower white blood count, but higher hemoglobin, platelet count, and karyotype risk scores compared to AML30, while these features were similar to RAEB2. FLT3 and NPM1 mutations and monocytic morphology occurred more commonly in AML30 than in RAEBT. RAEBT patients were treated less often with induction therapy than AML30, whereas allogeneic stem cell transplant frequency was similar. The median and 4‐year OS of RAEBT patients were longer than those of AML30 patients (20.5 vs 12.0 months and 28.6% vs 20.4%, respectively, P = 0.003); this difference in OS was manifested in patients in the intermediate UKMRC karyotype risk group, whereas OS of RAEBT patients and AML30 patients in the adverse karyotype risk group were not significantly different. Multivariable analysis showed that RAEBT (P < 0.0001), hemoglobin (P = 0.005), UKMRC karyotype risk group (P = 0.002), normal BM karyotype (P = 0.004), treatment with induction therapy (P < 0.0001), and stem cell transplant (P < 0.0001) were associated with longer OS. Our findings favor considering de novo RAEBT as a favorable prognostic subgroup of AML. Am. J. Hematol. 89:E193–E199, 2014. © 2014 Wiley Periodicals, Inc.

Abstract A diagnosis of composite lymphoma is typically prompted by the observation of morphologic discordance. We present a case of a spleen revealing histologic features of follicular lymphoma, without any indication of a second lymphoma. Immunohistochemical stains supported this diagnosis and showed the follicular lymphoma to be BCL2–. However, these studies revealed 2 additional unexpected findings: cyclin D1+ mantle zone cells surrounding neoplastic and reactive follicles (indicative of in situ mantle cell lymphoma) and BCL2-bright, histologically nonneoplastic follicles (indicative of in situ follicular lymphoma). ImmunoFISH and microdissection and polymerase chain reaction analysis documented the clonal nature of the cyclin D1+ mantle zones and illustrated clonal independence from the follicular lymphoma. This case illustrates an uncommon and unusual composite follicular and mantle cell lymphoma, with the follicular lymphoma accompanied by an in situ component, whereas the only manifestation of the mantle cell lymphoma was in situ.

Recently the World Health Organization (WHO), in collaboration with the European Association for Haematopathology and the Society for Hematopathology, published a revised and updated edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues. The 4th edition of the WHO classification incorporates new information that has emerged from scientific and clinical studies in the interval since the publication of the 3rd edition in 2001, and includes new criteria for the recognition of some previously described neoplasms as well as clarification and refinement of the defining criteria for others. It also adds entities—some defined principally by genetic features—that have only recently been characterized. In this paper, the classification of myeloid neoplasms and acute leukemia is highlighted with the aim of familiarizing hematologists, clinical scientists, and hematopathologists not only with the major changes in the classification but also with the rationale for those changes.