scholarly journals Acute Myeloid Leukemia and Myelodysplastic Syndromes After Radiation Therapy Are Similar to De Novo Disease and Differ From Other Therapy-Related Myeloid Neoplasms

2012 ◽  
Vol 30 (19) ◽  
pp. 2340-2347 ◽  
Author(s):  
Valentina Nardi ◽  
Karen M. Winkfield ◽  
Chi Young Ok ◽  
Andrzej Niemierko ◽  
Michael J. Kluk ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
De Novo ◽  
External Beam Radiation ◽  
Beam Radiation ◽  
Myeloid Neoplasms ◽  
Acute Myeloid

Purpose Therapy-related myeloid neoplasms (t-MN) represent a unique clinical syndrome occurring in patients treated with chemotherapy and/or external-beam radiation (XRT) and are characterized by poorer prognosis compared with de novo disease. XRT techniques have evolved in recent years and are associated with significantly reduced bone marrow exposure. The characteristics of post-XRT t-MN in the current era have not been studied. Patients and Methods We analyzed patients who developed acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) after XRT alone (47 patients) or cytotoxic chemotherapy/combined-modality therapy (C/CMT, 181 patients) and compared them with patients with de novo MDS or AML (222 patients). We estimated bone marrow exposure to radiation and compared the clinical, pathologic, and cytogenetic features and outcome of the XRT patients with the C/CMT patients and with patients with de novo MDS and AML. Results Patients with t-MN after XRT alone had superior overall survival (P = .006) and lower incidence of high-risk karyotypes (P = .01 for AML and < .001 for MDS) compared with patients in the C/CMT group. In contrast, there were no significant differences in survival or frequency of high-risk karyotypes between the XRT and de novo groups. Conclusion AML and MDS diagnosed in the past decade in patients after receiving XRT alone differ from t-MN occurring after C/CMT and share genetic features and clinical behavior with de novo AML/MDS. Our results suggest that post-XRT MDS/AML may not represent a direct consequence of radiation toxicity and warrant a therapeutic approach similar to de novo disease.

scholarly journals Long-Term Durability of Eltrombopag Clinical Benefit for Advanced Myelodysplastic Syndromes or Acute Myeloid Leukemia and Severe Thrombocytopenia (ASPIRE Part 3)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3740-3740
Author(s):  
Moshe Mittelman ◽  
Uwe Platzbecker ◽  
Boris Afanasyev ◽  
Sebastian Grosicki ◽  
Maria Socorro O Portella ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Febrile Neutropenia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Double Blind ◽  
Grade 3 ◽  
Acute Myeloid

Thrombocytopenia is a common complication in patients (pts) with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) that is associated with significant morbidity, a clinically significant bleeding risk, and early death. There are only limited treatment options for this high-risk population. Previous trials (Frey et al. ASH 2012) of thrombopoietin receptor agonists (TPO-RAs) for thrombocytopenia treatment in these pts suggested reduced thrombocytopenia-associated bleeding. ASPIRE (NCT01440374) was a multicenter, phase 2 trial. Eligible pts were ≥18 years, with high-risk MDS or AML, thrombocytopenia (platelets ≤25 x 109/L) due to bone marrow insufficiency, bone marrow blasts ≤50%, and an Eastern Cooperative Oncology Group status of 0-2. Exclusion criteria included platelets ≤10 x 109/L for reasons other than bone marrow insufficiency; leukocyte count ≥25 x 109/L; previous TPO-RA treatment. Pts were severely ill, on no other anti-MDS/AML therapy, with an expected median survival of ~6 months on treatment. Part 1 was an 8-week open-label study of eltrombopag 100 mg/day with dose escalation up to 300 mg/day (Mittelman et al. ASH 2012). Part 2 was a 12-week randomized, double-blind trial, during which pts received eltrombopag or placebo (Mittelman et al. Lancet Haematol 2018). Pts who completed both parts continued to Part 3, an extension phase of 10 months (for pts from Part 1) and 9 months (for pts from Part 2) (Fig. 1A). In ASPIRE Part 2, eltrombopag reduced the frequency of clinically relevant thrombocytopenic events (CRTEs) (one or more ≥Grade 3 hemorrhagic adverse events [AEs], platelets ≤10 x 109/L, or platelet transfusions) compared with placebo during weeks 5-12 in pts with advanced MDS or AML. Here we present data on the long-term durability of clinical benefit, overall survival (OS) and progression-free survival (PFS) for Part 2 pts within Part 2 and Part 3, and safety and tolerability of eltrombopag monotherapy in pts with advanced MDS or AML. Mean pt age was 72.2 years. Pts received a median eltrombopag daily dose of 298.8 mg with a median exposure of 11.1 weeks. At baseline, 40% of pts had an abnormal karyotype and 68% were platelet transfusion-dependent. OS (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.64-1.48) and PFS (HR 0.99, 95% CI 0.68-1.43) were not significantly different between long-term eltrombopag and placebo to eltrombopag switchers in Part 3 (median OS of 4.3 months vs 4.6 months, respectively). Median PFS was 0.94 months and 1.08 months for the placebo and eltrombopag group, respectively. CRTEs were summarized by week with the proportion of pts plotted by visit. Pts experienced large variability in CRTEs during weeks 1-40 with inconclusive results due to low number of pts at some time points (Fig. 1B). Hematological improvement (HI) was defined as improvement (platelets, neutrophils, hemoglobin) on treatment compared with placebo (Cheson et al. Blood 2006). Overall, 33% of pts showed HI with long-term eltrombopag use, compared with 10% during the double-blind phase. However, HI did not reach statistical significance compared with placebo in the double-blind phase. 46% of pts completed treatment. The main reasons for treatment discontinuation were physician decision (24%) and AEs (22%). Overall, 97% of pts experienced an AE during the extension phase plus 30 days. The most common AEs (≥20% of pts) were pyrexia, nausea, diarrhea, and epistaxis. Overall, 56% of pts died, with the disease under study being the most common cause (36%), and 37% of pts had treatment-related AEs. 31% of pts experienced Grade 3 or 4 AEs. The most commonly reported (>5%) were pneumonia, febrile neutropenia, anemia, hypokalemia, and urinary tract infection. Overall, 66% of pts experienced a serious AE (SAE). The most common (≥10%) were pneumonia, pyrexia, febrile neutropenia, and sepsis. The most common fatal SAEs (≥5%) were sepsis, pneumonia, and cardiac failure. ASPIRE Part 3 did not identify any new safety signals. The most common AEs were consistent with those expected for the disease under study and with eltrombopag treatment. There was no evidence of reduced OS or PFS. More pts met the criteria for HI with long-term eltrombopag use compared with those in the double-blind phase. The large CRTE variability observed with eltrombopag during Part 3 requires further assessment in adequately powered trials of high-risk MDS or AML pts and in a less seriously ill population. Figure 1 Disclosures Mittelman: Novartis: Honoraria, Research Funding, Speakers Bureau. Platzbecker:Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Portella:Novartis: Employment. Zhu:Novartis: Employment. Selleslag:Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau. OffLabel Disclosure: Eltrombopag is used for the treatment of thrombocytopenia in adult and pediatric patients 1 year and older with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Eltrombopag is not indicated for the treatment of patients with myelodysplastic syndrome (MDS).

IDH Mutations and Trisomy 8 In Myelodysplastic Syndromes and Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4009-4009
Author(s):  
Domenica Caramazza ◽  
Terra Lasho ◽  
Christy Finke ◽  
Naseema Gangat ◽  
David Dingli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Trisomy 8 ◽  
Idh Mutations ◽  
De Novo Aml ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 4009 Trisomy 8 is the most common among sole cytogenetic abnormalities in both acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In the very first paper published on isocitrate dehydrogenase (IDH) mutations in AML, 13 of the 16 IDH1 mutations detected were associated with normal karyotype, 2 with trisomy 8 and one with trisomy 13. Trisomy 8 was also recurrent in patients with IDH1/IDH2-mutated post-MDS AML. In the current study we examined the prevalence and disease distribution of IDH1 and IDH2 mutations in a large (n=157) group of patients with hematologic malignancies and isolated trisomy 8. The Mayo Clinic cytogenetic database allowed identification of 157 patients with isolated trisomy 8. Archived bone marrow cell pellets were used to extract DNA for IDH1 and IDH2 mutation analysis. Eighteen IDH mutations were identified: 15 IDH2 (14 R140Q and one R140W) and 3 IDH1 (2 R132C and one R132G). Seventeen of the 18 IDH mutations occurred in myeloid malignancies whereas one (IDH2R140W) occurred in a patient with angioimmunoblastic lymphoma who was not previously exposed to chemotherapy or radiotherapy, and in whom the IDH2 mutation disappeared after effective lymphoma chemotherapy. Among the 17 IDH-mutated myeloid malignancies, disease-specific IDH1/IDH2 mutational frequencies were as follows: 27% (3/11) for post-MDS AML, 25% (3/12) for therapy-related MDS/AML, 15% (8/54) for de novo MDS, 13% (2/15) for de novo AML and 3% (1/32) for myeloproliferative neoplasm (MPN). In contrast, IDH mutational frequencies were significantly lower among 64 additional patients with AML or MDS without isolated trisomy 8: 7% in de novo AML (n=28), 0% in de novo MDS (n=21), 0% in post-MDS AML (n=11) and 0% in therapy-related MDS/AML (n=4). In the 54 patients with trisomy 8-associated de novo MDS, prognosis was similar between IDH mutated (n=8; median survival 14 months) and unmutated (n=46; median survival 16 months) cases (p=0.7). The majority of IDH-mutated cases with de novo MDS belonged to high risk MDS disease category. However, 3 of the 8 IDH-mutated patients with de novo MDS and 2 of the 3 with therapy-related MDS did not display excess bone marrow blasts. The current study suggests a possible association between IDH mutations and trisomy 8 in AML and MDS but not in MPN or MDS/MPN. The fact that the mere presence of trisomy 8 did not result in a more than expected incidence of IDH mutations in MPN or MDS/MPN makes it unlikely that such an association would be secondary to trisomy 8-associated genetic or biologic changes. Instead, it is possible that IDH mutations, which have been shown to cluster with high-risk disease in both MPN and MDS associated with 5q-, promote a selective advantage for the survival of the clone that harbors trisomy 8. Consistent with this contention, we were able to demonstrate in one of our patients with relapsed AML, the presence of IDHR132C both at initial AML diagnosis and time of relapse, whereas the trisomy 8 abnormality was seen only at the time of relapse. Regardless, the presence of molecular heterogeneity among patients with trisomy 8-associated AML or MDS might explain the controversial prognostic influence of the specific cytogenetic abnormality. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Relative survival following response to 7 + 3 versus azacytidine is similar in acute myeloid leukemia and high-risk myelodysplastic syndromes: an analysis of four SWOG studies

Leukemia ◽  
2018 ◽  
Vol 33 (2) ◽  
pp. 371-378 ◽  
Author(s):  
Megan Othus ◽  
Mikkael A. Sekeres ◽  
Sucha Nand ◽  
Guillermo Garcia-Manero ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Relative Survival ◽  
Acute Myeloid

Flt3 Receptor Inhibition Abolishes Constitutive NFκB Activation in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2434-2434
Author(s):  
Jennifer Grosjean ◽  
Lionel Ades ◽  
Simone Bohrer ◽  
Pierre Fenaux ◽  
Guido Kroemer
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Plasma Membrane ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Constitutive Activation ◽  
Nf Kappab ◽  
Acute Myeloid

Abstract High-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are characterized by the constitutive activation of the anti-apoptotic transcription factor NF-kappaB, via the activation of the IKK complex. We show that constitutive activation of the receptor tyrosine kinase Flt3 is responsible for IKK activation and this activation of the NF-kappaB pathway was found to involve a not yet described phosphorylation of the IKK and IkBa complex involving tyrosine residues compared to serine residues in the classical NF-kappaB pathway. Chemical inhibition or knockdown of Flt3 with small interfering RNAs abolished NF-kappaB activation in MDS and AML cell lines, as well as in primary CD34+ bone marrow cells from patients, causing mitochondrial apoptosis. Epistatic analysis involving the simultaneous inhibition of Flt3 and IKK indicated that both kinases act via the same anti-apoptotic pathway. An IKK2 mutant with a constitutive kinase activity and a plasma membrane-tethered mutant of NEMO that activates IKK1/2 prevented the cytocidal action of Flt3 inhibition. IKK2 and Flt3 physically associated in MDS and AML cells and Flt3 inhibition caused the release of IKK2 from a preferential association with the plasma membrane. Flt3 inhibition only killed CD34+ bone marrow cells from high-risk MDS and AML patients, in correlation with the blast numbers and the NF-kappaB activity, yet had no lethal effect on healthy CD34+ cells or cells from low-risk MDS. These results suggest that Flt3 inhibitors might exert an anti-neoplastic effect in high-risk MDS and AML through inhibition of constitutive NF kappaB activation.

Clinical Activity, Pharmacokinetics, and Pharmacodynamics of Sorafenib In Pediatric Acute Myeloid Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1073-1073
Author(s):  
Hiroto Inaba ◽  
Jeffrey E Rubnitz ◽  
Elaine Coustan-Smith ◽  
Lie Li ◽  
Brian D Furmanski ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Leukemic Cells ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Pediatric Acute Myeloid Leukemia ◽  
Rtk Signaling ◽  
Acute Myeloid

Abstract Abstract 1073 Background: Aberrant receptor tyrosine kinase (RTK) signaling arising from genetic abnormalities, such as FLT3-internal tandem duplications (FLT3-ITD), is an important mechanism in the development and growth of acute myeloid leukemia (AML) and is often associated with a poor outcome. Hence, inhibition of RTK signaling is an attractive novel treatment option, particularly for disease that is resistant to conventional chemotherapy. We evaluated the clinical activity of the multikinase inhibitor sorafenib in children with de novo FLT3-ITD–positive AML or relapsed/refractory AML. Methods: Fourteen patients were treated. Six patients with newly diagnosed FLT3- ITD–positive AML (aged 9–16 years; median, 12 years) received 2 cycles of remission induction therapy and then started sorafenib (200 mg/m2 twice daily for 20 days) the day after completing induction II (low-dose cytarabine, daunorubicin, and etoposide). Nine patients (aged 6–17 years; median, 9 years) with relapsed AML (including one treated on the above regimen) received sorafenib alone (2 dose levels; 200 and 150 mg/m2) twice daily for the first week of therapy, concurrently with clofarabine and cytarabine on days 8–12, and then alone from days 13 to 28. Sorafenib pharmacokinetics were analyzed at steady-state on day 8 of sorafenib in patients with newly diagnosed AML and on day 7 in patients with relapsed AML. In patients with relapsed AML, the effect of sorafenib on signaling pathways in AML cells was assessed by flow cytometry. Results: All 6 newly diagnosed patients, including 2 whose AML was refractory to induction I, achieved a complete remission (CR) after induction II; 5 had negative minimal residual disease (MRD; <0.1% AML cells in bone marrow) after induction II. Both patients in this group who relapsed achieved second remissions, one with sorafenib alone and one on the relapse regimen described above. Of the 9 patients with relapsed AML, 6 (4 with FLT3-ITD) were treated with sorafenib 200 mg/m2. All 6 had a >50% decrease in blast percentage and/or bone marrow cellularity after 1 week of sorafenib. After concurrent sorafenib and chemotherapy, 5 of the 9 patients with relapsed AML achieved CR (2 had negative MRD) and 2 achieved a partial remission (PR; 5%-25% AML cells in bone marrow); all 4 patients with FLT3-ITD had a CR or PR. After sorafenib treatment, 6 patients underwent HSCT while 2 with FLT3-ITD who could not receive HSCT were treated with single-agent sorafenib and have maintained CR for up to 8 months. Hand-foot skin reaction (HFSR) or rash occurred in all patients and improved with cessation of sorafenib. Dose-limiting toxicity (DLT, grade 3 HFSR and/or rash) was observed in 3 of the 6 patients with relapsed AML treated with 200 mg/m2 of sorafenib; no DLT was observed at 150 mg/m2. The effect of sorafenib on downstream RTK signaling was tested in the leukemic cells of 4 patients: in most samples, phosphorylation of S6 ribosomal protein and 4E-BP1 was inhibited. The mean (± SD) steady-state concentration (Css) of sorafenib was 3.3 ± 1.2 mg/L in the newly diagnosed group and 6.5 ± 3.6 mg/L (200 mg/m2) and 7.3 ± 3.6 mg/L (150 mg/m2) in those with relapsed AML. In both groups, the mean conversion of sorafenib to sorafenib N-oxide was 27%-35% (approximately 3 times greater than previously reported), and mean sorafenib N-oxide Css was 1.0–3.2 mg/L (2.1-6.7 μM). In a 442-kinase screen, the inhibitory profiles of sorafenib N-oxide and sorafenib were similar, and FLT3-ITD phosphorylation was potently inhibited by both forms (sorafenib N-oxide Kd = 0.070 μM; sorafenib Kd = 0.094 μM). Sorafenib N-oxide inhibited the growth of an AML cell line with FLT3-ITD (IC50 = 0.026 μM) and 4 AML cell lines with wild-type FLT3 (IC50 = 3.9–13.3 μM) at approximately half the potency of sorafenib. Conclusion: In children with de novo FLT3-ITD and relapsed/refractory AML, sorafenib given alone or with chemotherapy induced dramatic responses and inhibited aberrant RTK signaling in leukemic cells. Sorafenib and its active metabolite (sorafenib N-oxide) likely contribute to both efficacy and toxicity. These results warrant the incorporation of sorafenib into future pediatric AML trials. Disclosures: Inaba: Bayer/Onyx: Research Funding. Off Label Use: Sorafenib and clofarabine: both used for treatment of pediatric acute myeloid leukemia.

The Prognostic Impact and Stability of IDH2 Mutation and the Insufficiency of the Mutation Alone for Leukemogenesis In Adult Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2697-2697
Author(s):  
Weng-Chi Lei ◽  
Wen-Chien Chou ◽  
Bor-Shen Ko ◽  
Hsin-An Hou ◽  
Hwei-Fang Tien
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Normal Karyotype ◽  
Idh1 Mutation ◽  
Group 12 ◽  
Worse Prognosis ◽  
Idh2 Mutation ◽  
Acute Myeloid

Abstract Abstract 2697 Purpose: Although the clinical and biological features of Isocitrate dehydrogenase (IDH) mutations in acute myeloid leukemia (AML) have been characterized, its stability and in vivo sufficiency of the mutation alone for leukemogenesis remain uninvestigated. Patients and Methods: Mutations of IDH and other clinically relevant genes were analyzed in the bone marrow from 446 adult patients with de novo non-M3 AML. IDH2 mutations were examined serially in 140 patients at diagnosis and after chemotherapy. Results: Among the 446 adults with de novo non-M3 AML, IDH2 R172, R140, and IDH1 R132 mutations occurred at a frequency of 2.9%, 9.2%, and 6.1%, respectively. IDH2 mutation was associated with higher platelet counts (p=0.046), intermediate-risk (p=0.002) or normal karyotype (p=0.023), and isolated +8 (p=0.014), but was inversely correlated with expression of HLA-DR (p=0.002), CD34 (p=0.039), CD15 (p=0.003), CD7 (p=0.010), and CD56 (p=0.048), and was mutually exclusive with WT1 mutation (p=0.037) and core-binding factor translocations (p=0.001). All these correlations became stronger when IDH1 and IDH2 mutations were considered together, suggesting similarity of biological roles between these 2 mutations. However, IDH2 but not IDH1 mutation conferred a better prognosis (Fig 1), especially in those with normal karyotype or intermediate cytogenetics (median overall survival: not reached vs. 58 months, p=0.044 and not reached vs. 19 months, p=0.027 for normal and intermediate karyotype group, respectively). Importantly, IDH2 but not IDH1 mutation was an independent favorable prognostic factor (HR: 0.332, 95% CI: 0.159–0.694; p=0.003). Patients with IDH2−/FLT3-ITD+ genotype had especially worse prognosis (median OS of IDH2−/FLT3-ITD+ vs. IDH2+/FLT3-ITD− group: 12 months vs. not reached; p=0.003; median OS of IDH2−/FLT3-ITD+ vs. IDH2+/FLT3-ITD+ or IDH2−/FLT3-ITD− group : 12 months vs. 35 months; p<.0001) (Fig 2A). The worse prognosis was also seen in patients with IDH−/FLT3-ITD+ genotype (Fig 2B). Serial analyses of IDH2 mutations during the clinical course of 140 patients confirmed the stability of this mutation; all the patients with IDH2 mutations at diagnosis harbored the same mutation at relapse with the exception of one patient who had extramedullary but not bone marrow relapse, while none of the IDH2-wild patients acquired this mutation at relapse. Importantly, sequential samples from two patients in long-term remission retained the original R140Q mutation while other accompanied mutations, FLT3-ITD in the first patient and NPM1 in the second, respectively, disappeared. In the first patient, the skin tissue was absent of the mutation and in the second, the mutation was restricted in myeloid cells but spared in lymphocytes indicating the mutation was acquired in these two patients. Conclusion: IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis. FLT3-ITD combined with wild type IDH2 exerted synergistic negative impact on survival. IDH2 mutation alone is insufficient for leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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