JAK2V617F-Positive Patients with Essential Thrombocythemia or Early Primary Myelofibrosis: The Impact of Histological Diagnosis on Outcome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1614-1614
Author(s):  
Nicola Polverelli ◽  
Roberto Latagliata ◽  
Giuseppe A. Palumbo ◽  
Alessia Tieghi ◽  
Margherita Perricone ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Primary Myelofibrosis ◽  
Jak2v617f Mutation ◽  
Event Free Survival ◽  
Disease Evolution ◽  
Free Survival ◽  
Mutational Status ◽  
Early Primary ◽  
The Impact

Abstract Introduction It is acknowledged that an accurate histological diagnosis may distinguish Essential Thrombocythemia (ET) from early Primary Myelofibrosis (early-PMF), which is projected to worse outcome in terms of survival and disease evolution into acute leukemia (AL) or overt myelofibrosis (MF). It is also accepted that the outcome of ET is related to the mutational status, with JAK2V617F mutation having a negative impact. In previous analyses, outcome data derived from the admixture of the two variables, histology and mutational status. Here, we present a large cohort of ET/early-PMF patients positive for the JAK2V617F mutation, with the aim to evaluate the impact on outcome of the sole histological definition. Methods A clinic-pathologic database of ET patients followed in four Italian Hematology Centers was created and a total of 475 WHO-diagnosed ET or early-PMF JAK2V617F-positive patients was collected. Bone marrow specimens were performed or reviewed at local institution. Baseline clinical/molecular characteristics and outcome measures (vascular complications, disease transformation/progression, overall and event-free survival) were evaluated. In all patients, JAK2V617F allele-burden was assessed in granulocyte DNA by using ipsogen JAK2 MutaQuant Kit (qPCR). The study was approved by the Ethic Committee of each participating Centers. Results Overall, 329 WHO-defined ET and 146 early-PMF patients positive for the JAK2V617F mutation were included in the study. Median follow-up was 6.6 years (range: 0.5-32.4). Compared to ET patients, early-PMF patients presented with older age (median, 57 versus 53.5yr, p=0.02), lower hemoglobin levels (median, 14.2 versus 14.5 g/dl, p=0.01), higher leukocyte count (median, 10.4 versus 9.5x109/l, p=0.01), and higher incidence of spleen enlargement (35.9% versus 13.9%, p<0.001). JAK2V617F mutation was heterozygous in 90% and 87% of ET and early-PMF patients, respectively (p=0.34). Use of antiplatelet and cytoreductive therapies was also comparable in the two groups. During follow-up, 32 (9.7%) ET and 18 (12.3%) early-PMF patients experienced a total of 59 thrombotic events (arterial: 49%), with an incidence rate of 1,3% patients/yr. The cumulative incidence of thrombosis was 8% and 14% at 5 and 10 years, respectively. Overall, 27 patients (5,6%) and 6 (1.2%) patients evolved to MF and AL, respectively. The cumulative incidence of disease progression into MF/AL was 2% and 5% at 5 and 10 years, respectively. At last contact, 28 (5.8%) patients had died, at a median age of 77.5 years (20-88), for an overall survival of 93.8% at 10 years. In early-PMF compared to ET, the 10-year survival rates (91.6% and 95%, respectively, p=0.75), leukemic transformation rates (6% and 1.2%, respectively, p=0.45) and rates of thrombosis (6.7% and 2.2%, p=0.12) were comparable. However, progression to overt MF at 5 years (4.4% and 0.9%, respectively) and 10 years (11.5% and 1.5%) was significantly worse (p=0.004). Multivariable analysis confirmed this finding and also identified homozygosity for the JAK2V617F mutation (p=0.008) as additional risk factor for disease evolution into secondary MF. The rate of composite outcomes (thrombosis, evolution into overt MF or AL and death) was significantly higher in early-PMF (3.1% vs 2,3% pts/yr) with a combined event-free survival of 69% versus 82% in ET patients at 10 yrs (figure 1). Conclusions. This study eliminates the confounding factor of different molecular status on outcome by focusing on a large cohort of WHO-defined ET/early-PMF patients, all carrying the JAK2V617F mutation. Overall, the study validates the clinical relevance of strict adherence to WHO criteria on prognosis, and particularly on disease progression into secondary MF. Figure 1. Combined event-free survival according to histology Figure 1. Combined event-free survival according to histology Disclosures Palumbo: Novartis: Honoraria, Other: Advisory Board. Martinelli:MSD: Consultancy; BMS: Speakers Bureau; Roche: Consultancy; ARIAD: Consultancy; Novartis: Speakers Bureau; Pfizer: Consultancy.

scholarly journals SF3B1 mutations in the Driver Clone Increase the Risk of Evolution to Myelofibrosis in Patients with Myeloproliferative Neoplasms (MPN)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-1
Author(s):  
Lin-Pierre Zhao ◽  
Rafael Daltro De Oliveira ◽  
Clemence Marcault ◽  
Juliette Soret ◽  
Nicolas Gauthier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Response To Therapy ◽  
Driver Mutation ◽  
Advisory Committees ◽  
Disease Evolution ◽  
Free Survival ◽  
Mutational Status ◽  
Significant Difference ◽  
The Impact

Introduction: Next generation sequencing (NGS) studies identified additional somatic mutations impacting disease evolution and prognosis in MPN. SF3B1, a component of the U2 small nuclear ribonucleoprotein splicing complex, is frequently mutated in myelodysplastic syndromes where it has been proposed to define a new entity (Malcovati et. al. Blood 2020). In MPN, SF3B1 is mutated in approximately 10% of patients with primary myelofibrosis (PMF) and 3-5% with polycytemia vera or essential thrombocytemia (ET). Recent reports suggested that spliceosome mutations may adversely affect myelofibrosis free survival (MFS) in ET (Tefferi et. al. Br J Haematol. 2020). The main objective of this study was to evaluate the impact of the concomitant presence of driver (JAK2, MPLor CALR) and SF3B1 clonal or sub-clonal mutations on MPN phenotype and evolution in a large single center cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria between January 2011 and May 2020 in our center, of whom 707 had molecular analysis by NGS targeting a panel of 36 myeloid genes performed at diagnosis and/or during follow-up. Significant variants were retained with a sensitivity of 0.5%. Patients were grouped according to variant allele frequencies (VAF) determined by NGS as "driver" SF3B1mutated patients when driver and SF3B1 mutations VAF were similar (double mutated clone), and as "non-driver" SF3B1 mutants when SF3B1VAF was lower than that of the driver mutation, suggestive of a sub-clone. 4 patients with SF3B1 mutations but no driver mutation were excluded. We then compared the characteristics and outcomes of 3 groups of patients according to their SF3B1 mutational status: wild type (WT), driver and non-driver SF3B1 mutations. Results: A total of 39/703 (5.6%) patients had SF3B1 mutations, of whom 11/39 (28.2%) and 28/39 (71.8%) harbored driver and non-driver SF3B1mutations, respectively. Driver SF3B1 mutations were associated with PMF (OR 6.1, 95%CI [1.1; 33.6], p= 0.039) and MPN unclassified (OR 15.6,95%CI [1.1; 116.5], p= 0.007) subtypes, presence of immature myeloid cells ≥ 2% (OR 9.3, CI [2.6; 32.8], p= 0.001) and peripheral blasts ≥ 1% (OR 5.0,95%CI [1.0; 24.7], p= 0.047) at diagnosis (Figure A). Other variables were not significantly different between patients with driver, non-driver and WT SF3B1, including age, driver mutation type, MPN-related symptoms, cytogenetics and high molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2or U2AF1). There was no significant difference in the response to therapy: complete hematological response was seen in 5/11 (45.5%), 10/28 (35.7%) and 327/664 (49.3%) of patients with driver, non-driver and WT SF3B1 respectively. After a median follow-up of 103.7 months IQR [47.2; 175.6], evolution to myelofibrosis occurred in 5/7 (71.4%), 6/20 (30.0%) and 99/564 (17.6%) of patients with driver, non-driver and WT SF3B1 respectively. Interestingly, driver SF3B1 but not non-driver SF3B1 mutational status adversely impacted MFS (OR 7.56,95%CI[2.95; 19.38], p&lt;0.001)(Figure B). Other variables independently associated with adverse MFS in multivariate COX regression analysis included age at MPN diagnosis (OR 1.02, 95%CI[1.00; 1.04], p=0.003), JAK2V617F allele burden (OR 1.03, 95%CI[1.02; 1.04], p&lt;0.001), MPL (OR 13.94, 95%CI[4.90; 39.70], p&lt;0.001) and CALR (OR 7.06, 95%CI[3.69; 13.51], p&lt;0.001) mutations. SF3B1 mutational status had no impact on overall survival, transformation to MDS/AML or thrombotic/hemorrhagic events free survival. Conclusion: This study in a large cohort of MPN patients highlights for the first time to our knowledge the adverse impact on MFS of SF3B1 and MPN-driver co-mutated clones. In contrast, presence of an SF3B1 mutation at sub-clonal level didn't increase the risk of MF development. In line with our findings, a recent study reported an association between rapid progression to myelofibrosis and SF3B1 mutations in patients with age-related clonal hematopoiesis (Bartels et al. Leukemia 2020). Further studies are warranted to confirm our results on independent cohorts and to investigate the mechanisms of bone marrow fibrosis development in patients with SF3B1 and MPN-drivermutations. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.

Arterial Versus Venous Events in Essential Thrombocythemia and Their Impact on Overall and Thrombosis Free Survival

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1611-1611
Author(s):  
A Kamel Abou Hussein ◽  
Naseema Gangat ◽  
Yoseph Elala ◽  
Curtis A. Hanson ◽  
Animesh Pardanani ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Arterial Thrombosis ◽  
Leukocyte Count ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Jak2v617f Mutation ◽  
Prognostic Impact ◽  
Free Survival ◽  
Male Sex

Abstract Background : Current risk stratification for thrombosis in essential thrombocythemia (ET) utilizes age >60 years, history of thrombosis, JAK2V617F mutation and cardiovascular risk factors (Barbui, Blood 2012;26:5128). Thrombosis history is also predictive of inferior overall survival (OS) in ET (Passamonti, Blood 2012;6:1197). However, whether or not the prognostic impact of thrombosis in ET is contributed by arterial versus venous thrombosis is unclear. Methods: More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Details of type of thrombotic events were obtained by careful review of the medical record. A subset of patients was molecularly annotated for the JAK2, CALR and MPL mutations. OS was calculated from time of initial diagnosis to the time of last follow-up or death. Thrombosis-free survival (TFS) was calculated from the time of diagnosis of ET to the time of development of thrombosis or last follow up or death, in patients censored for thrombosis. Conventional statistics was utilized for all analyses. Results :Patient characteristics: A total of 610 patients met the above-stipulated criteria (median age 57 years; 61% females). 76 patients (12%) had thrombosis documented either prior to or at diagnosis of which 50 patients (66%) experienced arterial events. 302 patients were screened for JAK2/CALR/MPL mutations with a frequency of 53.5%, 31%, and 3% respectively, while12.5% were "triple-negative".Impact of thrombosis history on OS: At a median follow-up of 8.9 years (range: 0-43.6 years), 185 (30%) deaths were documented. Themedian OS for the entire cohort was 20 years. On univariate survival analysis, the predictors of inferior OS included: age ≥60 years (p<0.001), leukocyte count ≥11 x 10(9) (p<0.001), male sex (p=0.0002), thrombosis before or at diagnosis (p=0.01), and presence of the JAK2V617F mutation (p=0.03). All but JAK2 V617F (p=0.64) remained significant on multivariable analysis. When arterial and venous events were considered separately, in univariate analysis, only arterial (p<0.001) but not venous (p=0.387) thrombotic events retained significance. The significant prognostic contribution, to survival, of arterial thrombosis history was sustained (p=0.02) during multivariable analysis, that included age ≥ 60 years (p=<0.001), leukocyte count ≥11 x 10(9) (p=0.001), and male sex (p=0.001) on OS.Impact of thrombosis history on TFS: A total of 84 (14%) patients experienced thrombotic events during follow-up amongst which 60 (71%) experienced arterial thrombosis. On univariate analysis the predictors of inferior TFS included: age ≥ 60 years (p=0.016), leukocyte count ≥11 x 10(9) (p=0.001), thrombosis before or at diagnosis (p<0.001), and presence of the JAK2V617F mutation (p=0.002). On multivariable analysis, thrombosis before or at diagnosis (p<0.001), along with leukocyte count ≥11 x 10(9) (p=0.03), and presence of the JAK2V617F mutation (p=0.01) remained significant; the significance of age ≥60 years became borderline (p=0.07). When arterial and venous thrombosis were analyzed separately, only arterial (p<0.001), but not venous (p=0.48), thrombosis history was significantly associated with inferior TFS. The factors that predicted worse outcome with TFS included arterial thrombosis at or before diagnosis (p<0.001), leukocyte count ≥11 x 10(9) (p=0.03) and presence of the JAK2V617F mutation (p=0.01); the significance of age ≥60 years became borderline (p=0.13). Conclusions : The prognostic impact of thrombosis in ET, in terms of both overall and thrombosis-free survival, might be attributed to only arterial but not venous thrombotic events. The current study also confirms the independent prothrombotic role of JAK2V617F mutation in ET and suggests an additional role for leukocytosis. Disclosures Barbui: Novartis: Speakers Bureau.

Sequential Analysis By Next Generation Sequencing of 18 Genes in Polycythemia Vera and Essential Thrombocythemia Reveals a Association Between Mutational Status and Clinical Outcome after 3-Year Follow-up

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2808-2808
Author(s):  
Damien Luque Paz ◽  
Aurelie Chauveau ◽  
Caroline Buors ◽  
Jean-Christophe Ianotto ◽  
Francoise Boyer ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Jak2 V617f Mutation ◽  
Poor Prognostic Factor ◽  
Disease Evolution ◽  
Allele Burden ◽  
V617f Mutation

Abstract Introduction Myeloproliferative neoplasms (MPN) are molecularly characterized by driver mutations of JAK2, MPL or CALR. Other somatic mutations may occur in epigenetic modifiers or oncogenes. Some of them have been shown to confer a poor prognosis in primary myelofibrosis, but their impact is less known in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). In this study, we investigated the mutational profile using NGS technology in 50 JAK2 V617F positive cases of MPN (27 PV and 23 ET) collected at the time of diagnosis and after a 3 year follow-up (3y). Patients and Methods All patients were JAK2 V617F positive and already included in the prospective cohort JAKSUIVI. All exons of JAK2, MPL, LNK, CBL, NRAS, NF1, TET2, ASXL1, IDH1 and 2, DNMT3A, SUZ12, EZH2, SF3B1, SRSF2, TP53, IKZF1 and SETBP1 were covered by an AmpliseqTM custom design and sequenced on a PGM instrument (Life Technologies). CALR exon 9 mutations were screened using fragment analysis. Hotspots that mutated recurrently in MPN with no sequencing NGS coverage were screened by Sanger sequencing and HRM. A somatic validation was performed for some mutations using DNA derived from the nails. The increase of a mutation between diagnosis and follow-up has been defined as a relative increase of twenty percent of the allele burden. An aggravation of the disease at 3y was defined by the presence of at least one of the following criteria: leukocytosis &gt;12G/L or immature granulocytes &gt;2% or erythroblasts &gt;1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; inadequate control of the patient's condition using the treatment (defined by at least one treatment change for reasons other than an adverse event). Results As expected, the JAK2 V617F mutation was found in all patients with the use of NGS. In addition, we found 27 other mutations in 10 genes out of the 18 genes studied by NGS (mean 0.54 mutations per patient). Overall, 29 of 50 patients had only the JAK2 V617F mutation and no other mutation in any of the genes analysed. No CALR mutation was detected. Nine mutations that were not previously described in myeloid malignancies were found. The genes involved in the epigenetic regulation were those most frequently mutated: TET2, ASXL1, IDH1, IDH2 and DNMT3A. In particular, TET2 mutations were the most frequent and occurred in 20% of cases. There was no difference in the number or in the presence of mutations between PV and ET. At 3y, 4 mutations appeared in 4 patients and 15 out of 50 patients (9 PV and 6 ET) were affected by an allele burden increase of at least one mutation. At 3y, 24/50 patients suffered an aggravation of the disease as defined by the primary outcome criterion (16 PV and 8 ET). The presence of a mutation (JAK2 V617Fomitted) at the time of the diagnosis was significantly associated with the aggravation of the disease (p=0.025). Retaining only mutations with an allele burden greater than 20%, the association with disease aggravation is more significant (p=0.011). Moreover, a mutation of ASXL1, IDH1/2 or SRSF2, which is a poor prognostic factor in primary myelofibrosis, was found in 8 patients, all having presented an aggravation of their disease (p=0.001). Only 4 patients had more than one somatic mutation other than JAK2 V617F and all of them also had an aggravation at 3y (p=0.046). In this cohort, appearance of a mutation at 3y was not associated with the course of the disease. Conversely, the increase of allele burden of at least one mutation was associated with an aggravation (p=0.019). Discussion and conclusion Despite the short follow-up and the limited number of patients, this study suggests that the presence of additional mutations at the time of the diagnosis in PV and TE is correlated to a poorer disease evolution. The increase of mutation allele burden, which reflects clonal evolution, also seems to be associated with the course of the disease. These results argue for a clinical interest in large mutation screening by NGS at the time of the diagnosis and during follow-up in ET and PV. Disclosures Ugo: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: ASH travel.

Impact of c-kit mutations, including codons 557 and/or 558, on the recurrence-free survival after curative surgery in patients with GIST.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 12-12
Author(s):  
T. Watanabe ◽  
H. Cho ◽  
T. Yoshikawa ◽  
A. Tsuburaya ◽  
O. Kobayashi
Keyword(s):  
Significant Prognostic Factor ◽  
Recurrence Free Survival ◽  
Adjuvant Imatinib ◽  
Curative Surgery ◽  
Free Survival ◽  
Primary Gist ◽  
Mutational Status ◽  
Exon 11 ◽  
The Impact

12 Background: Recently, c-kit exon 11 deletions, including codons 557 and/or 558, have been reported to predict a worse prognosis in GIST patients. However, it is difficult to prove the correlation between genotype and tumor aggressiveness in the imatinib- adjuvant era because exon 11 mutations respond well to imatinib. In this study, we evaluated the impact of c-kit mutational status on recurrence-free survival (RFS) after resection of primary GIST. Methods: Clinical and pathological characteristics of 89 GIST patients in our single institution study were retrospectively analyzed. Tumors were categorized into 4 subgroups based on their mutational locations; A1: mutated codons including neither 557 nor 558, A2: either 557 or 558, B1: only 557 and 558, B2: both 557 and 558. All of the patients underwent curative surgery, and none received adjuvant imatinib. The median duration of follow-up was 49 months. Results: Tumors originated from the stomach (n=75/89, 84%), small intestine (n=10), and colorectum (n=4). Mutation subgroup B was associated with both Fletcher and Miettinen high-risk categories. The 2-year recurrence free survival rate for A1, A2, B1, B2, was 84.9%, 85.7%, 50%, 57%, respectively. Group B2 had a significantly worse RFS than groups A1 (p=0.0004) and A2 (p=0.0014). Multivariate analysis for RFS indicated that only the mutational subgroup was a significant prognostic factor (p=0.03, HR=2.42). Conclusions: C-kit mutations, including both 557 and 558, affected the RFS of GIST patients after curative surgery, but those including either 557 or 558 did not. Our results indicate that the locations of c-kit mutations are associated with PFS, and they may therefore affect the selection of candidates with GIST for adjuvant imatinib. No significant financial relationships to disclose.

Results of the ECOG E1900 Trial in Younger Adults with AML Using an Event Free Survival Endpoint Are Concordant with Results Based on Overall Survival: Potential for a Surrogate Endpoint to Facilitate Rapid Approval of Therapies in AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2599-2599 ◽  
Author(s):  
Marlise R. Luskin ◽  
Ju-Whei Lee ◽  
Hugo F. Fernandez ◽  
Hillard M. Lazarus ◽  
Jacob M. Rowe ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Treatment Failure ◽  
Induction Treatment ◽  
High Dose ◽  
Event Free Survival ◽  
Npm1 Mutation ◽  
Free Survival ◽  
The Impact

Abstract Background: Novel therapies are required to improve the outcome of patients with AML. New agents are asked to demonstrate an overall survival (OS) benefit before qualifying for FDA approval. The long duration of clinical trials required in order to achieve this endpoint hampers quick evaluation of candidate therapies, including novel agents. Identification of reliable surrogate endpoints for OS in AML is needed. Here we compare the results of therapy for patients with untreated AML ages 16-60 years on the Eastern Cooperative Oncology Group 1900 trial (E1900) of induction chemotherapy followed by consolidation and autologous transplant in order to evaluate the validity of an event free survival (EFS) endpoint as a surrogate for OS. Methods:OS was measured from randomization for induction therapy to death from any cause (censored at last contact). EFS was measured from randomization to induction treatment failure, relapse after compete response (CR), or death in remission (censored at last contact). Hazard ratios (HR) were computed using Cox proportional hazards models. The association between EFS and OS was evaluated using the Kendall tau-a rank correlation for censored data. Results:There were657 patients enrolled of which 426 patients relapsed or had induction treatment failure before death or date of last contact. Median EFS and OS were 8.0 months (95% CI, 6.3 to 9.7 months) and 23.6 months (95% CI, 16.9 to 23.6 months), respectively. With a median follow-up of 80.1 months, there is a statistically significant correlation between EFS and OS (Kendall tau-a = 0.467, 95% confidence interval (CI) = (0.425, 0.510), p<0.001). This correlation was similarly significant at a median follow-up of 25.2 months (Kendall tau-a = 0.361, 95% CI (0.323, 0.400), p <0.001) when the E1900 trial was originally reported (Fernandez et al. NEJM 2009). Key findings reported based on the original OS endpoint are similar when analyzed with an EFS endpoint (Table 1). High-dose daunorubicin (90 mg/m2) (DNR 90) confers both an EFS and OS benefit in patients aged < 50 years and patients with intermediate cytogenetic risk, and does not confer an EFS or OS benefit in older patients and patients with unfavorable cytogenetic risk, on univariate analysis. Divergent results are only seen in the small subset of favorable cytogenetic risk patients, where DNR 90 conferred an OS benefit (p=0.027) without an EFS benefit (p=0.32). Both EFS and OS endpoints consistently reflect the impact of mutation status on survival. The presence of a FLT3-ITD or DNMT3A mutation has a negative impact on both EFS and OS while an IDH2 mutation has a favorable impact on EFS and OS. The presence of a NPM1 mutation confers a favorable impact on EFS and OS in patients who received DNR 90 and did not impact EFS or OS in patients receiving standard-dose daunorubicin (45 mg/m2) (DNR 45). The presence of an IDH1 mutation does not impact EFS or OS. Conclusions:The results of E1900 demonstrating superiority of DNR 90 in AML induction in patients up to age 60 are concordant when using an EFS or OS endpoint. This is true for the group as a whole as well as for subgroups for which targeted agents are in development (FLT3/IDH2 inhibitors). Further investigation of whether EFS is a reliable surrogate for OS is warranted in AML. If confirmed, its use as a primary endpoint could be adopted by regulatory agencies in order to allow more rapid completion of clinical trials in AML and bring new therapies to AML patients in a timely fashion. Table 1. Results of E1900 based on an EFS endpoint versus an OS endpoint. Subgroup N OS HR (DNR 90/DNR 45) & 95% CI Wald P EFS HR (DNR 90/DNR 45) & 95% CI Wald P DNR 45 DNR 90 Age < 50 yrs ³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.118 0.64 (0.50, 0.82) 0.86 (0.67, 1.10) 0.0004 0.23 Cytogenetic Favorable Intermediate Unfavorable 38 141 59 51 127 63 0.51 (0.28, 0.93) 0.68 (0.50, 0.92) 0.79 (0.54, 1.16) 0.027 0.012 0.225 0.76 (0.44, 1.31) 0.63 (0.47, 0.83) 0.72 (0.49, 1.05) 0.32 0.001 0.09 Subgroup N OS HR (MUT/WT) & 95% CI Wald P EFS HR (MUT/WT) & 95% CI Wald P FLT3-ITD WT MUT 456 147 1.62 (1.31, 2.01) <.0001 1.48 (1.21, 1.82) 0.0002 DNMT3A WT MUT 371 119 1.30 (1.03, 1.65) 0.03 1.23 (0.98, 1.54) 0.07 IDH1 WT MUT 465 36 0.88 (0.59, 1.33) 0.55 0.91 (0.62, 1.34) 0.64 IDH2 WT MUT 451 50 0.63 (0.43, 0.93) 0.02 0.68 (0.48, 0.97) 0.03 NPM1 DNR 45 DNR 90 245 257 0.84 (0.61, 1.16) 0.60 (0.41, 0.89) 0.30 0.01 0.90 (0.66, 1.22) 0.59 (0.41, 0.84) 0.49 0.004 Disclosures No relevant conflicts of interest to declare.

Survival Trends in Essential Thrombocythemia in the Face of Changing Treatment Practices

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2805-2805
Author(s):  
A Kamel Abou Hussein ◽  
Naseema Gangat ◽  
Yoseph Elala ◽  
Alexandra Wolanskyj ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Leukocyte Count ◽  
Multivariable Analysis ◽  
Controlled Study ◽  
Free Survival ◽  
Treatment Practices ◽  
Group 3 ◽  
The Impact

Abstract Background : Hydroxyurea has been the mainstay of cytoreductive therapy in essential thrombocythemia (ET) for over four decades. In 1988, anagrelide was first reported as an effective drug in ET (Silverstein et al. NEJM 1988;318:1292) and hundreds of patients were enrolled in clinical trials, which subsequently led to FDA approval in 1997. As a result, an increasing number of patients with ET were being treated with anagrelide until a subsequent controlled study suggested an inferior treatment outcome with anagrelide compared to hydroxyurea (Harrison et al. NEJM 2005;353:33). In the current study, we examined the impact of the corresponding practice changes on overall, myelofibrosis-free and leukemia-free survival, by comparing patients with ET diagnosed before 1988, between 1988 and 1997, and between 1998 and 2005 Methods: More than 45,000 patient charts with "thrombocytosis" were reviewed to identify those who met either PVSG (older patient cohort) or WHO criteria for diagnosis of ET. Survival was calculated from time of initial diagnosis to the time of last follow-up or death. For leukemia- or fibrosis-free survival, the time of the transformation events was considered as the uncensored variable. Conventional statistics was utilized for all analyses. Patients were divided into three groups commensurate with changes in treatment practices, corresponding to the aforementioned publications; Group 1 patients were diagnosed prior to 1988 (n =222), Group 2 1988 to 1997 (n =253), and Group 3 1998 to 2005 (n =264). Results : A total of 739 patients met the above-stipulated criteria (median age 57 years; 65% females). At a median follow-up of 12.2 years (range: 0.01-43.6 years), 368 (50%) deaths, 48 (6.5%) fibrotic transformations and 23 (3%) leukemic transformations were documented. Median overall survival (OS) was 18.6 years. On multivariable analysis, older age (P <0.001), increased leukocyte count (P <0.001), thrombosis history (P =0.04), and male sex (P<0.0001) were identified as predictors of inferior OS. Myelofibrosis-free survival (MFS) was predicted by platelet count <100 x 10(9)/L and lower hemoglobin level (multivariate P values 0.03 and <0.001, respectively). Leukemia-free survival (LFS) was predicted by increased leukocyte count, on multivariable analysis (P =0.002). Comparison of presenting features and outcome by period of diagnosis: Significant differences, in presenting features, between groups 1, 2, and 3 included age (median 55, 56, and 59 years, respectively; P =0.003), female preponderance (68, 69, and 58%, respectively; P =0.02), platelet count (1080, 995, and 890 x 10(9)/L, respectively; P <0.001), and leukocyte count (10, 9.6, and 8.4 x 10(9)/L, respectively; P <0.001). Median survival was 20.7 years, 19 years and 14.3 years, in groups 1, 2 and 3, respectively (P =0.02) (Figure 1). However, the difference in survival was no longer apparent during multivariable analysis that included age as a covariate (P=0.88). In univariate analysis, MFS was significantly shorter in group 3 patients (P=0.02; Figure 2); borderline significance was retained during multivariable analysis (p=0.13). LFS was similar among the three groups (P = 0.27). Conclusions : The results from the current retrospective study suggest increased rate of progression to myelofibrosis in ET patients diagnosed in the anagrelide era, an observation that is consistent with the results from a previous controlled study (Harrison et al. NEJM 2005;353:33). Regardless, survival in ET in the last four decades remains unchanged. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Pardanani: Stemline: Research Funding.

Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification

Blood ◽  
2011 ◽  
Vol 117 (21) ◽  
pp. 5710-5718 ◽  
Author(s):  
Jürgen Thiele ◽  
Hans Michael Kvasnicka ◽  
Leonhard Müllauer ◽  
Veronika Buxhofer-Ausch ◽  
Bettina Gisslinger ◽  
...  
Keyword(s):  
Clinical Diagnosis ◽  
Essential Thrombocythemia ◽  
Survival Data ◽  
Primary Myelofibrosis ◽  
Clinical Findings ◽  
World Health ◽  
And Gender ◽  
Early Primary ◽  
Health Organization ◽  
The Impact

AbstractControversy persists regarding the role of histopathology in the distinction between essential thrombocythemia (ET) and early-prefibrotic primary myelofi-brosis (PMF) presenting with thrombocythemia. To investigate the impact and reproducibility of bone marrow (BM) morphology according to the World Health Organization classification, 295 patients with the presumptive clinical diagnosis of either ET or early PMF were studied. Data of this cohort (Vienna group) were compared with 732 corresponding patients (Cologne group). Evaluating blindly (only age and gender known) BM specimens, the 2 groups of pathologists achieved an overall consensus of 78% regarding the total series and 88% concerning the discrimination between ET versus PMF. In 126 ET and 81 early PMF patients without pretreatment and complete documentation, a 90% concordance with the independently established clinical diagnosis was found. In 12 patients, overlapping of histopathology and some clinical findings between ET and polycythemia vera occurred. Contrasting ET, early PMF showed significant differences of presenting hematologic data and an unfavorable prognosis (estimated mean survival, 14 vs 21 years). Comparison of clinical and survival data of the Vienna cohort with the historical Cologne series revealed an overall congruence. This study highlights the impact of BM morphology for the differentiation between true vs false ET.

scholarly journals L-Asparaginase Toxicity in the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (19) ◽  
pp. 4419
Author(s):  
Madalina-Petronela Schmidt ◽  
Anca-Viorica Ivanov ◽  
Daniel Coriu ◽  
Ingrith-Crenguta Miron
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Children And Adolescents ◽  
Lymphoblastic Leukemia ◽  
Event Free Survival ◽  
Long Term Outcomes ◽  
Term Survival ◽  
Free Survival ◽  
The Impact

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children’s Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1–11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis (p = 0.015) and hypertriglyceridemia (p = 0.043) and a lower risk of clinical hypersensitivity (p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

Mutations and Long-Term Outcome of 217 Young Patients with Essential Thrombocythemia or Early Primary Myelofibrosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3190-3190
Author(s):  
Francesca Palandri ◽  
Nicola Polverelli ◽  
Roberto Latagliata ◽  
Alessia Tieghi ◽  
Emanuela Ottaviani ◽  
...  
Keyword(s):  
Young Adults ◽  
Triple Negative ◽  
Univariate Analysis ◽  
Primary Myelofibrosis ◽  
Event Free Survival ◽  
Abnormal Karyotype ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Mutational Status

Abstract Introduction Young adults with Essential Thrombocythemia (ET) or early Primary Myelofibrosis (early-PMF) are a category of patients projected to a prolonged survival but also to an extended utilization of medical resources. Mutations, including those in the calreticulin (CALR) gene, have been reported to affect main clinical features and outcome in large cohorts of patients with Ph-negative MPNs. However, no data are available on mutational status and long-term outcome in young MPN patients. Methods A clinic-pathologic database of ET patients followed in 5 Italian Hematology Centers was created. A total of 217 WHO-diagnosed ET or early-PMF patients ≤ 40 years at diagnosis was retrieved from the general database of 2635 patients. All bone marrow biopsies were reviewed at local institution. Baseline clinical/molecular characteristics and outcome measures (thrombosis, hemorrhages, secondary MF and AL, second neoplasia, death, overall and event-free survival) were evaluated. JAK2V617F allele-burden was assessed in granulocyte DNA by using ipsogen JAK2 MutaQuant Kit (qPCR). CALR mutations were identified by next generation sequencing (NGS) approach on GS Junior (Roche-454 platform); MPL mutations were evaluated by using ipsogen MPLW515L/K MutaScreen Kit. Results Overall, 197 WHO-defined ET and 20 early-PMF (age range: 16-40, median 34) were included in the study. Mutational frequencies were 61% for JAK2, 25% for CALR, 1% for MPL and 13% for triple negative. Baseline clinical characteristics and use of antiplatelet/cytoreductive therapies were comparable in ET and early-PMF, although frequency of triple negative was higher in the early-PMF cohort. Compared to the JAK2 positive population, both CALR and triple-negative patients showed higher platelet count and lower hemoglobin and hematocrit levels (Table 1). Median follow-up was 10.2 years (range: 0.5-37.5). During follow-up, 19 (9,6%) ET and 3 (15%) early-PMF patients experienced a total of 31 thrombotic (arterial: 38%) and 12 hemorrhagic events, with an incidence rate of 0.91% and 0.39% patients/yr, respectively. The cumulative incidence of thrombosis was 0,14% and 0,24% at 15 and at 20 years, respectively. Overall, 10 patients (4,6%) and 1 (0,4%) patients evolved to MF and AL, respectively; 10 developed a second neoplasia. The cumulative incidence of disease progression into MF/AL was 0,03% and 0,13% at 15 and at 20 years, respectively. At last contact, 6 (2,7%) patients had died, at a median age of 61 years (20-71), for an overall survival of 98% at 15 years. Causes of death were related to the myeloproliferative neoplasm (disease evolution or thrombotic complications) in all patients but one. Event-free survival was similar in the ET/early-PMF cohorts considering both every event separately and all together. In univariate analysis, male sex (p=0.003), previous thrombosis (p=0.001), splenomegaly (p=0.037), JAK2V617F (p=0.019) were associated with increased thrombotic risk; in multivariate Cox analysis, only previous thrombosis and male sex remained significant (p=0.012). Baseline splenomegaly was the only predictive factor for subsequent hemorrhages (p=0.017). Abnormal karyotype was associated with secondary MF (p=0.013) and also with second neoplasia (p<0.001). Together with JAK2V617F positivity and leukocytosis >11x109/L, abnormal karyotype was also associated with worse survival in univariate analysis. However, in multivariate analysis only JAK2V617F mutation remained as negative predictor of survival (p=0.019). Also, multivariable analysis confirmed JAK2 mutation and splenomegaly as independent risk factors for cumulative events. Conclusions With the limitations due to the low number of early-PMF, the outcome of young adults with early-PMF and true ET seemed to be comparable. The correlation of abnormal karyotype with MF transformation and second neoplasia suggests the need for an accurate cytogenetic analysis at diagnosis. Mutational status did influence disease phenotype, in terms of baseline characteristics and prognosis. Indeed, JAK2 mutational status confirmed a negative prognostic role for thrombosis and survival, while event-free survival was significantly better in triple-negative patients. Notably, causes of death were mostly related to the hematological malignancy, pointing out the substantial impact that this generally indolent disease may acquire in young adults. Disclosures Latagliata: Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Cavo:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Honoraria.

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