The heterogeneity of AML requires a personalized treatment strategy to achieve a high initial response and translate this response into long-term survival. Based on a possible synergistic effect of azacitidine (AZA) and cytarabine (ARA-C) when AZA is given first through the induction of deoxycytidine kinase by AZA which phosphorylates ARA-C to its active compound, ara-CTP, priming with AZA was integrated with intensive chemotherapy (IC) in a response-based sequential approach in the multicenter RAS-AZIC (DRKS00004519) study for patients (pts) >60 years (y). The safety, the remission rate of 64%, and a low TRM of 10% up to day (d) 90 were previously reported (Jaekel et al, ASH 2017). The final results of outcome at two years are presented. Patients and methods: Pts >60 y with newly diagnosed AML (de novo, secondary, and therapy related) were included (n=109). All received priming with AZA (75 mg/m2/day s.c) for 7 days. Irrespective of baseline bone marrow (BM) blasts, pts with d15 blasts ≥45% received IC (Mitoxantrone 10 mg/m2/day d1-3 and ARA-C 1g/m2/BID d1,3,5,7). If the count was <45%, AZA was continued at d28. The second treatment adaptation was based on d56 response. If CR/CRi were documented, AZA maintenance or allogeneic HCT were given. Otherwise, IC was applied followed by AZA maintenance or allogeneic HCT if a remission was achieved on d90. Response (CR, CRi, PR) on d90 was the primary endpoint. The two-year OS, event-free survival (EFS), and relapse-free survival (RFS) were secondary endpoints. Recruitment was closed on 23.05.2016 and LPLV (last patient last visit) was performed on 25.05.2018. Statistical analysis was planned on an intention-to-treat base. The trial was supervised by an independent Data Monitoring Committee. All pts gave written informed consent. Results: Patient characteristics are shown in table 1. Median age was 70y. Treatment sequels were AZA1+AZA2, n=24 (22%); AZA1+AZA2+IC1, n=30 (27.5%); AZA1+ IC1, n=35 (32.1%); AZA1+ IC1+IC2, n=9 (8.3%)]. The median of days alive and out of hospital till d90 was 41 days. The centrally reviewed response rate was 64.2% [CR/CRi 57.8%; PR 6.4%]. Remissions were achieved with AZA therapy± only one cycle of IC in 91% of responders. Maintenance with AZA was started in 53/70 (76%) responders and 12 (17%) pts received allogeneic HCT. Response translated into an improved survival at two years with a median survival time of 22 months (m) vs 7m only in non-responders (p<0.001). For the entire cohort, the two-year OS was 35.1% with a median survival time of 16m (95% CI, 12.9 to 18.8) (figure 1). Baseline BM blasts, WBC, FLT3 status, and the type of AML had no impact on response or OS. Older age was not associated with an inferior OS [median survival time of 16m in pts ≥75y vs 15m in pts ≤ 64y]. Although statistically not significant, the presence of an NPM1 mutation tended to be associated with a superior response [81% vs 61%; (p=0.08)] and OS [median survival time of 20 vs 16m; (p=0.22)]. Response in favorable, intermediate (int)-I; int-II, and adverse genetics was 73%, 80%, 52%, and 53% respectively (p=0.098). Genetics had a strong impact on OS [median survival times were not reached in favorable and int-I; 15.3 and 11.4m in int-II and adverse risk respectively (p=0.001)]. The two-year EFS was 23% with a median EFS time of 10m (95% CI, 7.7 to 12). Again, genetics had a strong impact on EFS [median EFS times were 20 in favorable, 14 in int-I; 9 in int-II, and 7m in adverse risk (p=0.002)]. EFS correlated with response [median EFS time was 13 m in responders vs 4m only in non-responders (p<0.001)]. Relapse incidence and RFS at two years were 60% and 26% respectively with a median RFS time of 11m (95% CI, 6 to 15.6) (figure 1). Median RFS times were not reached in favorable, 15.5 in int-I; 12.7 in int-II, and only 4m in adverse risk genetics (p=0.003)]. Conclusion: Integrating an epigenetic therapy with IC in elderly pts with AML in an individualized response-based approach is feasible with low TRM and yields responses at least comparable to those achieved with repeated cycles of IC across all cytogenetic risk groups even in pts >70y. Most importantly, response could be translated into an improved survival particularly in pts with favorable and int-I risk genetics. Relapse remains high in adverse genetics. The results might further be improved through mutational profiling which allows the integration of emerging targeted therapies. Disclosures Hänel: Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Sayer:RIEMSER Pharma GmbH: Honoraria. Niederwieser:Novartis: Research Funding; Miltenyi: Speakers Bureau. Al-Ali:Gilead: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Alexion: Honoraria; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding.
Introduction: Differential diagnosis of polyglobulia/erythrocytosis which is caused by deregulated erythropoiesis with an overproduction of red blood cells resulting in elevated hemoglobin and hematocrit levels is a diagnostic challenge. Case Report: A 31-year-old man was referred to us with a suspected diagnosis of polycythemia vera (a clonal myeloproliferative neoplasm) because of erythrocytosis. One year before, he suffered from an ischemic central retinal vein occlusion of unknown cause. Aspirin treatment was initiated. His mother was diagnosed with a JAK2V617F negative polycythemia vera years earlier and treated with phlebotomies as well as aspirin. Apart from erythrocytosis, laboratory analysis showed a normal white blood cell and platelet counts. The differential blood picture and lactate dehydrogenase were within the normal ranges. Molecular testing for BCR-ABL, JAK2V617F and Calreticulin gene mutations by PCR was negative. Bone marrow biopsy was normal without signs for a myeloproliferative neoplasm. As almost all patients with polycythemia vera carry the phenotype-driver mutation JAK2V617F, further genetic testing for congenital causes of erythrocytosis was conducted. Mutations in the EPO-receptor gene were not found, but a very rare heterozygous point mutation in the beta-globin-chain [exon 2 (c.119A>C) leading to a change in codon 40 (CAG>CCG)] was detected by next generation sequencing. This rare variant belongs to the high oxygen affinity hemoglobinopathies leading to a reduction of oxygen supply in tissues and an increase in red cell production. Conclusion: The diagnosis of a JAK2 mutation negative polycythemia vera must always be questioned and congenital causes of erythrocytosis excluded as the therapeutic and prognostic consequences are immense. Rare variants of hemoglobinopathies, particularly those with high oxygen affinity need to be excluded by molecular testing.
The 2016 WHO classification integrates clinical, bone marrow (BM)-morphology, and molecular features to define disease entities. This together with the advancements in molecular detection and standardization of BM features enable an accurate diagnosis of myeloproliferative neoplasms (MPN) in the majority of patients. Diagnostic challenges remain due to phenotypic mimicry of MPN, failing specificity of BM-morphology, and the fact that phenotype-driver mutations, such as JAK2V617F, are not exclusive to a particular MPN, and their absence does not preclude any of these. We present a series of cases to illustrate themes to be considered in complex cases of MPN, such as triple-negative (TN)-MPN or MPN-unclassifiable (MPN-U). Eleven patients labelled as TN-MPN or MPN-U were included. Serum tryptase and NGS were part of a systematic/sequential multidisciplinary evaluation. Results were clustered into four categories based on diagnostic entities and/or how these diagnoses were made: (A) With expanding molecular techniques, BCR-ABL1 and karyotyping should not be missed; (B) systemic mastocytosis is underdiagnosed and often missed; (C) benign non-clonal disorders could mimic MPN; and (D) NGS could prove clonality in some “TN”-MPN cases. The prognostic/therapeutic consequences of an accurate diagnosis are immense. In TN-MPN or MPN-U cases, a multidisciplinary re-evaluation integrating molecular results, BM-morphology, and clinical judgment is crucial.
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