Among patients with myeloid neoplasms including acute myeloid leukemia (AML), IDH2 R172 mutations (mR172) appear to be linked with improved overall survival, and moreover represent a distinct clinical disease subtype, according to research published in the American Journal of Clinical Pathology.
IDH1 and IDH2 mutations are relatively common mutations known in the AML space, as well as among patients with solid tumors including gliomas. For this retrospective study, researchers explored disease features among patients with AML with mR172 to determine whether this mutation is a hallmark of a distinct disease subtype.
The authors contrasted clinical samples and data from 39 patients with IDH2 R140 (mR140) or mR172. All patients had a myeloid neoplasm and increased blasts.
Analysis showed that mR172 was linked with lower leukocyte counts and bone marrow cellularity; moreover, blasts in samples with mR172 were more likely to be invaginated, have cleaved nuclei, and express CD34, HLA-DR, CD117, and CD13. Patients with mR172 were also more likely to have mutations in genes linked with myelodysplasia and/or an adverse karyotype.
Surprisingly, however, patients with mR172 had improved overall survival, compared with non-mR172 cases (P =.01); this finding was validated in an independent dataset.
“In an era of targeted therapy, with IDH1 and IDH2 small-molecule inhibitors receiving FDA approval and entering routine clinical use, resolution of the clinicopathologic features and survival expectations associated with distinct genetic subtypes of IDH-mutated myeloid neoplasia is imperative to aid in appropriate classification and prognostication, as well as guide appropriate therapy,” the authors wrote in their report.
Source: Davis AR, Canady BC, Aggarwal N, Bailey NG. Clinicopathologic features of IDH2 R172-mutated myeloid neoplasms. Am J Clin Pathol. Published online March 22, 2023.
IDH1 and IDH2 are among the most commonly mutated genes in myeloid neoplasms (MNs). It has been proposed that IDH2 R172 mutations (mR172) define a molecular subtype of acute myeloid leukemia (AML), but the clinicopathologic features of AML with mR172 have not been fully described.
Methods
We retrospectively identified and characterized all mR172 MNs with increased blasts in our archive for comparison to a similar number of MNs with IDH2 R140 (mR140) and IDH1 R132 mR132) mutations (n = 39).
Results
mR172 cases had lower leukocyte counts and bone marrow cellularity than did non-mR172 cases. mR172 MNs often displayed blasts with highly invaginated, cleaved nuclei and typically expressed CD34, HLA-DR, CD117, and CD13 but often with diminished CD33. mR172 cases often had co-occurring mutations in myelodysplasia-associated genes and/or an adverse karyotype. Despite frequent adverse-risk genetic changes, in our cohort mR172 cases had significantly improved overall survival vs non-mR172 cases (P = .01), and we validated that mR172 was associated with improved survival in an independent large data set.
Conclusions
We show that MNs with mR172 represent a morphologically and phenotypically distinct subtype, which in our cohort exhibited relatively favorable survival that is not captured in current AML risk assignment.
I didn't see anything that linked to MPNs, but there was this: see my reply...
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This is older, but involves the same or similar IDH mutations: Published: 13 September 2011
IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F
Abstract
Isocitrate dehydrogenase (IDH) mutations are frequent in blast-phase myeloproliferative neoplasms and might therefore contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). In all, 6 (50%) of the 12 IDH-mutated patients also expressed JAK2V617F. Overall, 18 (6%) patients displayed only MPL and 164 (54.3%) only JAK2 mutations. Multivariable analysis that accounted for conventional risk factors disclosed inferior overall survival (OS; P=0.03) and leukemia-free survival (LFS; P=0.003) in IDH-mutated patients: OS hazard ratio (HR) was 0.39 (95% confidence interval (95% CI) 0.2–0.75), 0.50 (95% CI 0.27–0.95) and 0.53 (95% CI 0.23–1.2) for patients with no, JAK2 or MPL mutations, respectively. Further analysis disclosed a more pronounced effect for the mutant IDH on OS and LFS in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64) of concomitant JAK2V617F. Analysis of paired samples obtained during chronic- and blast-phase disease revealed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F.
Introduction
Among the three BCR-ABL1-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia and primary myelofibrosis (PMF), the latter is by far the worst in terms of both survival and quality of life.1, 2 The more aggressive disease biology in PMF is also manifest by the higher prevalence of cytogenetic abnormalities3 and somatic mutations.4 The latter involve JAK2, MPL, TET2, ASXL1, CBL, isocitrate dehydrogenase (IDH)1, IDH2, IKZF1, LNK, EZH2 and DNMT3A.4, 5 Recent studies have reported higher frequencies of IDH1/IDH2 and LNK mutations in blast-phase MPN,6, 7 suggesting a pathogenetic contribution to disease progression.
Isocitrate dehydrogenase-1 is located on chromosome 2q33.3 and IDH2 on chromosome 15q26.1. Both genes encode enzymes that catalyze oxidative decarboxylation of isocitrate to α-ketoglutarate. IDH mutations involve exon 4 and affect three specific arginine residues: R132 (IDH1), R172 (IDH2) and R140 (IDH2).8 The mutant IDH has decreased affinity for isocitrate but displays catalytic activity in converting α-ketoglutarate to 2-hydroxyglutarate.9, 10, 11, 12 Decreased supply of α-ketoglutarate or accumulation of 2-hydroxyglutarate is believed to underlie the oncogenic properties of the mutant IDH.9, 13
IDH mutations are prevalent in low-grade gliomas and secondary glioblastomas (mutational frequency ∼70%)14 and they have also been described, although at a much lower frequency, in myeloid malignancies including acute myeloid leukemia (AML; 10–20%),15, 16, 17, 18 myelodysplastic syndrome (MDS; 3–5%),19, 20 MPN (1–4%),8, 18 MDS/MPN including chronic myelomonocytic leukemia (∼9%),20 post-MDS AML (∼15%),19 post-MPN AML (∼22%),8 post-MDS/MPN AML (∼10%),20 del(5q)-associated high-risk MDS or AML (∼22%)21 and blast-phase chronic myelogenous leukemia (∼4%).22 Single case reports also included angioimmunoblastic lymphoma23 and acute lymphoblastic leukemia.18
Several studies have examined the phenotypic and prognostic effects of both IDH1 and IDH2 mutations in AML, and most have shown a consistent association with normal or intermediate-risk karyotype, sole trisomy 8 and NPM1 mutations.16, 17, 23, 24, 25, 26, 27 The mutant IDH1 was associated with worse prognosis in cytogenetically normal AML with NPM1+/FLT3− molecular profile17, 28, 29 and better prognosis in FLT3+ AML.27 In some17 but not other30 studies, the mutant IDH2 was associated with unfavorable prognosis in cytogenetically normal AML,17 whereas a more recent study suggested that the mutant IDH2R140 was prognostically more favorable than the mutant IDH2R172.31
Unlike the case with AML, there is limited information on the prognostic impact of IDH mutations in chronic myeloid neoplasms, including MDS19 and MPN.8 We recently reported on IDH1 and IDH2 mutational frequencies among 1473 patients with BCR-ABL1-negative MPN:8 0.8% in essential thrombocythemia, 1.9% in polycythemia vera, 4.1% in PMF, 1% in post-essential thrombocythemia/polycythemia vera MF, 0% in blast-phase essential thrombocythemia, 25% in blast-phase polycythemia vera and 25% in blast-phase PMF. The particular study included only 111 patients with chronic-phase PMF and complete clinical information; therefore, detailed prognostic analysis was limited, especially in terms of clinically relevant mutation interactions. In the current study, we examined the phenotypic and prognostic effects of IDH1 and IDH2 mutations among 301 patients with chronic-phase PMF, in the context of other MPN-associated mutations.
This study was approved by the Mayo Clinic Institutional Review Board. All patients provided informed written consent for study sample collection and permission for use in research. Study eligibility criteria included availability of bone marrow histology and cytogenetic information at the time of referral to the Mayo Clinic. The diagnoses of PMF and leukemic transformation were according to the World Health Organization criteria.32 Patients with blast-phase disease at the time of their referral to the Mayo Clinic were excluded from the study because one of the objectives of the study was to assess mutation impact on leukemic transformation. Unfavorable karyotype designation and DIPSS-plus (Dynamic International Prognostic Scoring System-plus) risk categorization were as described previously.33, 34 All study patients were fully characterized for karyotype, JAK2 and MPL mutational status and DIPSS-plus risk category.
DNA from bone marrow or peripheral blood was extracted using conventional methods. MPL and JAK2 mutation analyses were performed according to previously published methods.35, 36, 37, 38 IDH1 and IDH2 mutations were analyzed by direct sequencing and/or high-resolution melting assay. Direct sequencing for IDH1 exon 4 mutations was performed using the following primer sequences: sense, 5′-CGGTCTTCAGAGAAGCCATT-3′ and anti-sense, 5′-CACATTATTGCCAACATGAC-3′.18 IDH2 exon 4 was amplified using sense, 5′-CCACTATTATCTCTGTCCTC-3′ and anti-sense, 5′-GCTAGGCGAGGAGCTCCAGT-3′.19 Both reactions were performed in 25 μl volume containing 100 ng of DNA, 0.25 Units Taq polymerase, 0.3 mM each of dATP, dCTP, dGTP and dTTP, 5 μl of a 10 × PCR Buffer (Roche Diagnostics, Indianapolis, IN, USA) and 0.2 μM each of sense and anti-sense primers. The reaction was denatured at 94 °C for 3 min, followed by 35 cycles of denaturing at 94 °C for 30 s, annealing at 57 °C for 30 s and extension at 72 °C for 40 s. After a final extension at 72 °C for 2 min, the products were confirmed by 1.3% agarose gel and purified using Qiagen's PCR quick purification kit (Qiagen, Santa Clarita, CA, USA). The product was sequenced using the ABI PRISM 3730xl analyzer (Applied Biosystems Inc., Foster City, CA, USA) to screen for the presence of mutations.
High-resolution melting was performed using the LightCycler 480 Real-Time PCR system (Roche Diagnostics), using the above-mentioned primers for IDH1 mutations (R130) and the following primers for IDH2 mutations (R140 and R172): R140 sense, 5′-GCTGAAGAAGATGTGGAA-3′ and anti-sense, 5′-TGATGGGCTCCCGGAAGA-3′; R172 sense, 5′-CCAAGCCCATCACCATTG-3′ and anti-sense, 5′-CCCAGGTCAGTGGATCCC-3′.
All statistical analyses considered clinical and laboratory parameters obtained at the time of first referral to the Mayo Clinic, which in most instances coincided with the time of bone marrow biopsy at the Mayo Clinic and study sample collection. Differences in the distribution of continuous variables between categories were analyzed by either the Mann–Whitney (for comparison of two groups) or the Kruskal–Wallis (comparison of three or more groups) test. Patient groups with nominal variables were compared by the χ2-test. Overall survival (OS) was calculated from the date of first referral to the date of death (uncensored) or last contact (censored). Leukemia-free survival (LFS) was calculated from the date of first referral to the date of leukemic transformation (uncensored) or death/last contact (censored). OS and LFS curves were prepared by the Kaplan–Meier method and compared by the log-rank test. Cox's proportional hazard regression model was used for multivariable analysis. P-values <l0.05 were considered significant. The Stat View (SAS Institute, Cary, NC, USA) statistical package was used for all calculations.
Results
A total of 301 consecutive patients with PMF were included in this study. The median age at the time of study was 63 years (range, 14–82) and 65% were males. DIPSS-plus risk distribution was 11% low, 16% intermediate-1, 36% intermediate-2 and 37% high. Other clinical and laboratory characteristics at the time of Mayo Clinic referral are outlined in Table 1; 40 (13%) patients had received cytoreductive therapy at the time of their first referral at our institution. The study population included 178 patients who were evaluated at or near the time of their diagnosis and their presenting characteristics are separately outlined in Table 2.
The mutant IDH was detected in 12 patients (4%): 7 IDH2 (5 R140Q, 1 R140W and 1 R172G) and 5 IDH1 (3 R132S and 2 R132C). MPL exon 10 was mutated in 18 patients (6.3%) and constituted W515L in 14 patients, W515K in 3 and a novel frameshift mutation in 1 patient. JAK2V617F was detected in 169 (56%) patients. Six patients displayed both JAK2V617F and IDH mutations (IDH2R140Q in two patients, IDH2R140W in one and IDH1R132S in three); JAK2V617F allele burdens in these six patients with concomitant mutant IDH were 1, 7, 22, 27, 30 and 96%, respectively. One patient displayed both IDHR140Q and MPLW515R. In all, 107 (36%) patients were negative for all three mutations (that is, JAK2V617F, MPL exon 10 and IDH1/2).
The 12 IDH-mutated patients, with or without concomitant JAK2V617F, were clinically compared with patients belonging to the 3 other molecular subgroups: mutated for JAK2 only (n=164), mutated for MPL only (n=18) and unmutated for all three (n=107). As can be seen in Tables 1 and 2, the four molecular subgroups were remarkably similar in their phenotype with few exceptions; IDH-mutated patients were significantly older than those with no mutations (P=0.04), whereas age distribution was similar between patients with mutant IDH, MPL or JAK2. At the time of this writing, 192 (64%) deaths and 36 (12%) leukemic transformations were documented. The median follow-up time for living patients was 68 months (range 12–296). Treatment over the course of the disease was primarily with conventional drugs, and a total of 53 therapeutic splenectomies and 24 transplants were documented.
In univariate analysis, IDH-mutated patients lived shorter than did those with JAK2 (P=0.03), MPL (P=0.047) or no mutations (P=0.0009). The OS data for the four molecular subgroups are shown in Figure 1. IDH-mutated patients also showed significantly shorter LFS, compared with those with JAK2 (P=0.0008), MPL (P=0.02) or no mutations (P=0.001), as shown in Figure 2. LFS was similar between patients with no mutations and those with either MPL (P=0.47) or JAK2 (P=0.99). The OS of patients with no mutations was significantly longer than those with JAK2V617F (P=0.01), but not than those with MPL mutations (P=0.41). After accounting for age, the OS difference between patients with JAK2V617F and no mutations became insignificant (P=0.40), whereas the presence of the mutant IDH remained a significant disadvantage for both OS (P=0.04) and LFS (P=0.005).
Multivariable analysis of OS that included risk categorization per DIPSS-plus33 confirmed the independent prognostic relevance of the mutant IDH (P=0.03): hazard ratio (HR) for patients with no mutations=0.39, 95% confidence interval (95% CI) 0.2–0.75; HR for JAK2-mutated patients=0.50, 95% CI, 0.27–0.95; HR for MPL-mutated patients=0.53, 95% CI, 0.23–1.2. A similar analysis for LFS that included risk factors for leukemic transformation (that is, unfavorable karyotype and platelet count <100 × 109/l) as covariates also confirmed the prognostic relevance of the mutant IDH (P=0.003): HR for patients with no mutations=0.16; 95% CI, 0.06–0.46; HR for JAK2-mutated patients=0.18; 95% CI, 0.06–0.48; HR for MPL-mutated patients=0.09; 95% CI, 0.01–0.76).33 Further analysis disclosed that the negative OS (Figure 3) and LFS (Figure 4) effect of the mutant IDH was most pronounced in the presence (P=0.0002 and P<0.0001, respectively) as opposed to the absence (P=0.34 and P=0.64, respectively) of concomitant JAK2V617F expression. Analysis of paired samples obtained during the chronic and blast phases of the disease was possible in two IDH-mutated patients and showed the presence of both IDH and JAK2 mutations at both time points.
The most feared disease complication in MPN is leukemic transformation.39 In PMF, risk factors for leukemic progression include unfavorable karyotype,3 thrombocytopenia (platelet count <100 × 109/l) and ⩾3% circulating blasts;33, 40 the 10-year incidence of AML was estimated at 12% in the absence of unfavorable karyotype and thrombocytopenia and 31% in the presence of either one of the two risk factors.33 Prognosis in post-PMF AML is dismal with a median survival of <3 months and is not favorably affected by conventional chemotherapy.39 The discovery of JAK2V617F in the majority of patients with PMF raised hopes of better outcome with effective molecularly targeted therapy.41 However, it has since been realized that the presence or absence of JAK2V617F in PMF did not affect leukemic transformation35 and that leukemic blasts in JAK2-mutated patients who develop AML did not necessarily express the mutation.42 These observations suggest that JAK2V617F is neither necessary nor sufficient for leukemic progression in PMF.
This study suggests that the presence of the mutant IDH signifies an increased risk of leukemic transformation in PMF and also raises the intriguing possibility of leukemogenic collaboration between the mutant IDH and JAK2V617F; 4 (67%) of 6 patients with concomitant IDH and JAK2 mutations developed AML as opposed to only 1 (17%) of 6 IDH-mutated patients without concomitant JAK2V617F, 1 (6%) of 18 with MPL mutations, 17 (10%) of 164 with only JAK2 mutation and 13 (12%) of 107 patients with no mutations (P<0.0001; Figure 4). A similar clinical observation was made in a recent report that showed an inferior LFS in IDH-mutated myeloid malignancies with isolated del(5q);43 in the particular study, two of six patients with IDH mutations also carried JAK2V617F and both had transformed into AML, whereas only two of the remaining four IDH-mutated patients without concomitant JAK2V617F had transformed into AML.43 The possibility that the mutant IDH collaborates with other oncogenes is further supported by a recent report in which the mutant IDH enhanced growth and mitogen-activated protein kinase and signal transducer and activator of transcription-3 signaling in BRAF-mutated melanoma cells.44
Currently known mutations in PMF are believed to represent late genetic events derived from an ancestral abnormal clone the genetic make up of which remains elusive. The fact that many of these mutations are infrequent and lack disease specificity further undermines their pathogenetic contribution to disease initiation.4 On the other hand, the absence of mutual exclusivity and the higher prevalence of some MPN-associated mutations (for example, IDH,6 LNK,7 IKZF145 and TP5346 mutations) in blast-phase, as opposed to chronic-phase, disease suggests possible pathogenetic contribution to leukemic transformation. The observations from this study suggest one possibility in which mutations with non-redundant functional consequences collaborate to amplify the development of AML. Alternatively, the presence of mutations of interest (such as the mutant IDH) in at-risk patients might simply constitute a marker of genomic instability associated with impending leukemic transformation. A third possibility considers the distribution of specific mutations in independent clones that arise from a common ancestral clone that is susceptible to both emergence of mutations of interest and leukemic transformation.47
The prognostic impact of IDH mutations in AML has been studied extensively.16, 17, 23, 24, 25, 26, 27, 28, 29, 30 In contrast, very few studies have looked into this matter in chronic myeloid malignancies. Both IDH1 and IDH2 mutations occur in MDS, although some studies19 have reported a preponderance of IDH1 mutations, whereas others have shown the opposite.20 In the current PMF study, 7 of the 12 IDH mutations involved IDH2. In MDS and other myeloid neoplasms associated with sole del(5q), the presence of mutant IDH has been associated with inferior OS and LFS.19, 21, 43 It is noteworthy that the MDS study showing a detrimental prognostic effect of the mutant IDH involved only IDH1 mutations.19 In this study, there was no evidence to suggest that IDH1 and IDH2 mutations were prognostically different (data not shown). Regardless, the number of cases with IDH mutations in this study (n=12) was too small to accurately determine the individual prognostic contribution of IDH1 vs IDH2 mutations in PMF.
JAK2V617F in PMF and other MPN is associated with advanced age.48 This study suggests that IDH mutations in PMF also cluster with older age. A similar observation has been made in AML as well28 and underscores the importance of accounting for age in evaluating the prognostic significance of IDH mutations. Another characteristic feature of IDH-mutated PMF in this study was the relative paucity of abnormal or unfavorable karyotype. This particular observation has also been noted in the context of AML, MDS, MDS/MPN and post-MDS/MPN AML8, 18, 20 and suggests that IDH mutations are not simply markers of genomic instability.
Our clinical observations underscore the potential relevance of looking for other mutations or epigenetic abnormalities that functionally mimic the mutant IDH, in JAK2-mutated PMF.13 It would also be interesting to examine the mutant IDH-induced phenotypic modifications of JAK2V617F mouse models. Whether therapeutic targeting of the mutant IDH or interfering with the production/function of its ‘oncogenic’ metabolite (that is, 2-hydroxyglutarate) would favorably affect leukemic progression in PMF remains to be seen.
ONE COMMENT: This is a study with a very small "N" or number of participants, so even if it was really well done, generalizing to other patients is done at your own risk.
wow! That’s a lot of information but as I’m stuck in hospital right now I will have time to go through it. I have post ET MF possibly now progressing to AML so this is all very interesting to me. Thank you for posting
I'm sorry to hear that you're in hospital, and I hope that you kick butt and get out soonest!
I'm also sorry to hear about your disease progression, but hope [and will pray] for you to have as positive an experience with it as is possible and especially a positive outcome.
This may also be of some interest to you, even though it's a relatively old article [circa 2019, that is]:
The Evolving Understanding of Prognosis in Post–Essential Thrombocythemia Myelofibrosis and Post–Polycythemia Vera Myelofibrosis vs Primary Myelofibrosis
Patients with post-essential thrombocythemia and post-polycythemia vera differ from patients with primary myelofibrosis
Abstract
Prognostic scoring systems for primary myelofibrosis (PMF) are not accurate in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis (PET-MF; PPV-MF). Given the paucity of data describing the clinical characteristics, disease course and outcomes of these patients, we sought to describe and compare the clinical characteristics and outcomes of 755 patients with PMF, 181 with PPV-MF, and 163 with PET-MF referred to our institution between 1984 and 2013. The median follow-up was 31 months, and 56% (n=616) patients had died. Over an observation period of 3,502 person-years, 11% of patients had progression to AML, with similar rates among groups. The proportion of patients with transfusion dependency (higher in PMF), leukocytosis and systemic symptoms (higher in PPV-MF), and thrombocytopenia (higher in PMF, PPV-MF) differed among groups. Median overall survival (OS) was longest in PET-MF patients (73 mo vs 45 mo (PMF) vs 48 mo (PPV-MF), p<0.001). Stratification of OS by DIPSS was only discriminatory in patients with PMF, and it failed to distinguish higher risk patients with PPV/PET-MF. In multivariate analysis, predictors of inferior OS were higher age, anemia, systemic symptoms, thrombocytopenia, and high peripheral blasts in PMF; age, anemia, and systemic symptoms for PPV-MF; and anemia, peripheral blasts and thrombocytopenia in PET-MF. Although the clinical characteristics of PPV/PET-MF patients are not substantially different from those with PMF, their outcomes differ and prognostic scoring systems for PET/PPV-MF should be improved.
1.0 INTRODUCTION
The classical Ph negative chronic myeloproliferative neoplasms (MPN) polycythemia vera (PV) and essential thrombocythemia (ET), though considered relatively benign, share a propensity to progress toward a fibrotic stage (so-called post polycythemia vera myelofibrosis, [PPV-MF] and post essential thrombocythemia myelofibrosis [PET-MF]). PPV- and PET-MF, like primary MF (PMF), are characterized by typical MF features: decreased peripheral blood counts owing to accumulation of reticulin/collagen fibrosis and subsequent bone marrow failure; extramedullary hematopoiesis often accompanied by significant splenomegaly; and debilitating systemic symptoms [1]. PPV-MF and PET-MF are therefore considered as a natural evolution of these neoplasms, with median time to transformation of 7–20 years from PV/ET diagnosis [2–6]. The cumulative incidence of PPV-MF and PET-MF at 15 years has been reported to be between 5–14% for PV and 1.6–9% for ET [2, 7–9]. Although multiple factors have been reported to influence the rate of transformation, leukocytosis >15 × 109 is the most consistently reported factor [10]. Histopathologic findings in the bone marrow of PET/PPV-MF and PMF patients share overlapping features, and clinical characteristics are also very similar, with a typical picture of bone marrow failure, splenomegaly and chronic inflammatory status, leading to worsening quality of life and cachexia.
Few studies have specifically focused on comparing biologic, clinical and prognostic features of PET/PPV-MF patients [11–13] with those of patients with PMF and findings have been conflicting [13–18]. Prognostication in PPV-MF and PET-MF is evolving, and evidence suggests that the International Prognostic Score System (IPSS), an established prognostication tool in PMF, can’t accurately discriminate different risk categories in PET/PPV-MF patients. However, there is a paucity of data describing clinical characteristics, disease course and outcomes of patients with PET/PPV-MF. In clinical practice, PET/PPV-MF patients are managed similarly to those with PMF; however, whether this practice should change is not known. Here, we describe the clinicopathologic characteristics of patients with PET/PPV-MF and compare their clinical, biologic, and prognostic features with those of PMF patients seen at our center.
2.0 PATIENTS AND METHODS
We retrospectively reviewed the medical records of 1099 patients with MF who were referred to our institution between 1984 and 2013. PMF was diagnosed according to 2008 World Health Organization (WHO) criteria. PET/PPV-MF was diagnosed according to The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria, which requires a previously documented World Health Organization (WHO)-defined diagnosis of PV or ET and the presence of bone marrow fibrosis grade ≥ 2 (3-point scale) or ≥3 (4-point scale) and two or more additional features: anemia (≥ 2 mg/l decrease from baseline), a leukoerythroblastic peripheral blood smear, splenomegaly, or ≥1 constitutional symptoms, sustained loss of need for phlebotomy and/or cytoreductive therapy for PV or elevated lactate dehydrogenase for ET.[19] Diagnoses of PV or ET were established based on WHO criteria in use at the time of diagnosis. Bone marrow fibrosis grading was assessed according to European Consensus criteria [20]. Molecular testing was performed by real time PCR-based sequencing, using a next generation sequencing platform in our CLIA-certified molecular diagnostic laboratory, as previously reported [21]. All clinical data were collected at the time of referral. Overall survival (OS) was calculated from the date of referral to the date of last follow-up or death, whichever came first. Clinicopathological parameters (categorical and continuous variables) were analyzed by the Fisher’s exact, Kruskal–Wallis or Mann–Whitney U tests, as appropriate. Survival analyses were carried out with the Kaplan–Meier method and compared with the log-rank test. Patients were not censored at the time of SCT (n=99) for the purpose of OS analysis, due to the retrospective study design and because we were not evaluating the impact of therapy. Associations between the clinicopathological factors and survival were assessed by univariate and multivariate analysis. Variables with statistical significance on univariate tests were subsequently analyzed in a multivariate model by using Cox proportional hazard regression with stepwise forward selection. All p-values are two-sided and p < 0.05 was considered to be statistically significant. All statistical computations were performed using SPSS, version 23.0 (Chicago, IL).
Sixty-one percent of patients were men (n=668), with a significantly higher proportion (65%) among patients with PMF (p25) and systemic symptoms with significant splenomegaly; and those with PET-MF were less likely to be thrombocytopenic (platelets < 100) (Table 1). Other clinical features did not differ among subtypes.
Cytogenetic data with ≥ 10 analyzable metaphases were obtained in 981 (89%) patients, 660 with PMF and 321 with PET/PPV-MF. Overall, 360 (37%) patients had an abnormal karyotype (Abn), and 17% of them had 3 or more abnormalities (complex karyotype, CK, n=62). Abnormal karyotypes present in >10% of patients were single 20q- (n=75, 21%), single 13q- (n=38, 11%), and CK (n=62, 17%). Other abnormalities, such as single +8, +9, single -7/7q-, -5/5q-, or various combinations of two Abn occurred less frequently. Importantly, chromosome (chr) 17 Abn were found only in patients with PMF, while all other Abn were similarly distributed among PMF and PET/PPV-MF (Table 2).
In total, 698 patients (69%) were tested for all 3 known driver mutations (JAK2 V617F, MPL and CALR). An additional 170 patients (39 PET-MF, 131 PMF) who tested negative for JAK2 and MPL, were not tested for CALR mutations. The distribution of driver mutations was similar among disease subtypes (Table 2). As expected, the majority of patients were JAK2 positive (n=592; 68%) and all PPV-MF patients carried a JAK2 mutation (JAK2V617F mutation in all except 2 who had a JAK2 exon 12 mutation). The JAK2 allele burden was significantly higher in PPV-MF patients than in others (median allele burden 86% for PPV-MF, 47% for PMF, and 58% for PET-MF; p<0.001). High molecular risk mutations (ASXL1, EZH2, IDH1 and IHD2) were tested in 383 (35%) patients (23% of PMF, 26% of PET-MF, 81% of PPV-MF) and were present in total of 67 patients (17%). The frequency of high molecular risk mutations were similar among diagnoses.
3.2 Treatment
During the entire follow-up at our institution, 195 (18%) patients never received any therapy, and of those 130 (67%) were followed > 12 months. The remaining 904 (82%) patients were treated with a median of 2 therapies (range, 1–11), hydroxyurea being the most common (56% of patients, n=506), followed by the JAK2 inhibitor ruxolitinib (32%, n=288), IMIDs (23%, n=206) and other, mostly investigational agents (46%, n=413) (Supplemental Table 1). A total of 145 patients (16%) received more than 3 therapies. Splenectomy was performed after an MF diagnosis in 120 patients (12%) (PMF n=89, 12%; PET-MF n=12, 7%; and PPV-MF n=19). An additional 21 patients had splenectomy at outside institutions prior to progression to PET/PPV- MF (6 ET and 15 PV). Ninety-nine patients (10%) underwent allogeneic stem cell transplantation after a median of 20 months (range, 2–265) from MF diagnosis (PMF n=75, 10%; PPV-MF n=10, 6%, PET-MF n=14, 9%).
3.3 Survival outcomes
3.3.1 Overall survival The overall median follow-up time from presentation to our institution was 31 months (range, 0.2–251) and was similar among all groups. Median overall survival (OS) was significantly longer among patients with PET-MF than that of those with PMF and PPV-MF (median 73 vs 45 vs 48 months; p<0.001, Figure 1A). Three year OS rates were 69% vs 63% vs 55% for PET-MF, PPV-MF and PMF, respectively. To eliminate referral bias, we also conducted a sub-analysis including only those patients who were referred to MDACC < 3 months from diagnosis and were previously untreated (considered newly diagnosed; n=595, 375 PMF, 122 PPV-MF and 98 PET-MF). Among this subgroup, OS trends were similar to those of the whole group, with PET-MF patients having the longest OS (PET-MF, 92 mo vs PPV-MF, 57 mo vs PMF 52 months; p=0.003, Figure 1B).
3.3.2 Driver mutations and overall survival Overall survival was the longest in patients with a CALR mutation, with OS of 171 months for PET-MF and not reached for PMF. Patients with PMF who were triple negative had the shortest OS (median 15 months), and PET-MF/PPV-MF patients with a JAK2 mutation had OS of 65 and 48 months, respectively. We did not have enough PET-MF triple negative patients (n=4) to evaluate for representative OS (Figure 2A & B). Similar results were observed in a sub-analysis including only newly diagnosed patients (time to referral < 3 months, Supplemental Table 2). Patients harboring the same driver mutations (CALR, JAK2) had similar OS regardless of diagnosis (CALR mutated PET/MF vs PMF - 171 months vs NR, p=0.919; and JAK2 mutated PET/MF vs PPV/MF vs PMF, 65 vs 48 vs 50 months, p=0.37). Due to the small number of patients with MPL mutation or those who were triple negative (TN) within each diagnosis, comparison of OS in these patients was not performed.
3.3.3 DIPSS/IPSS score and overall survival When patients were stratified according to their DIPSS score, only those with PMF had distinct survival curves for each risk group (Table 3, Figure 3A). Among PPV-MF patients, those classified as int-2 or high-risk had similar OS (Figure 3B). Among those with PET-MF, the low and int-1 risk as well as the int-2 and high risk survival curves overlapped (Figure 3C). An OS analysis stratified by IPSS for patients with newly diagnosed MF confirmed these results (Supplemental Figure 1A–C).
3.3.4 Progression to AML During an observation period of 3,502 person-years, 108 (11%) patients had progression to AML after a median time from presentation of 25 months (range, 0.2–175), with an incidence rate of 3.05 cases per 100 person-years. The incidence of AML was similar among PMF (n=78, 10% of all), PET-MF (n=16, 8%) and PPV-MF (n=14, 10%) patients. Among 99 patients with progression to AML who had corresponding cytogenetic data, 44% had an Abn karyotype, and the proportions were similar among patients with PMF and PET/PPV-MF.
3.3.5 Cause of death During the entire observation period, 56% (n=616) of patients died. Fewer patients with PET-MF died than those with PMF and PPV-MF (59% PMF, n=445, 55% PPV-MF, n=99; and 45% PET-MF, n=72; p<0.05). Causes of death were known in 53% of patients (n=327), and included progression of MF/AML in 45% (n=147), infection in 14% (n=47), multi-organ failure in 18% (n=58), and complications after SCT, secondary malignancy, or other medical conditions (<10% each) (Supplemental Table 3).
3.4 Prognostic factors
To identify prognostic factors for each disease subtype, we performed univariate analysis. Hemoglobin 65 years was a prognostic factor for PMF and PPV-MF patients, while transfusion dependency was prognostic for PMF and PET-MF patients only. Abnormal unfavorable karyotype vs others (diploid, single deletion 13q, 20q and abnormalities of chromosome 9) was a significant prognostic factor for PMF and PET-MF patients, but not for PPV-MF. In multivariate logistic regression analysis, age > 65 years, hemoglobin 65 years, hemoglobin <10 g/dl, and symptoms remained significant. For PET-MF, hemoglobin < 10 g/dl, platelets < 100 × 109/L, peripheral blasts ≥ 1% l retained significance.
In this study, we compared clinical characteristics and outcomes of 1,099 patients with PPV-MF, PET-MF, and PMF from a single institution. Some important differences in overall survival and prognostic factors were identified. We found that age > 65 years, hemoglobin 65, hemoglobin 30 × 109/l are independent risk factors for shorter survival of PPV-MF patients, with a 4.2-fold increased risk of death when any of these risk factors are present.
Similar to what was reported by Rotunno et al [23] we found leukocytosis and systemic symptoms with organomegaly more frequently in patients with PPV-MF and thrombocytopenia less frequently in patients with PET-MF, both likely explainable by the phenotype of the antecedent MPN disorder. In contrast, we did not observe more anemia in patients with PET-MF.
The frequencies of cytogenetic abnormalities were similar among disease subtypes, with the exception that only patients with PMF had chr 17 Abn. This is in contrast to results published by Boiocchi et al[15] who reported that patients with PPV-MF tend to have a higher frequency of cytogenetic abnormalities, with a larger number of abnormalities and often complex karyotype. The authors postulated that this was a consequence of slowly progressive clonal disease. Our findings that chr 17 Abn, which confer an unfavorable prognosis across most of hematologic malignancies, were only present in PMF, and the similar frequencies of other abnormalities among disease types suggest the opposite.
Regarding the frequency of driver mutations among disease groups, we found the distribution of CALR, JAK2V617F, MPLW515 mutations to be similar among PMF and PET-MF patients[17]. Median JAK2 allele burden was highest in patients with PPV-MF (p<0.001), but it did not have any impact on OS, in line with a previous report[13]. Similar to previous reports in PMF patients, patients with the CALR mutation constitute a group with a more favorable prognosis than those with JAK2 or MPL mutations, and patients who are negative for the 3 driver mutations (so called “triple negative”) have the worst prognosis among PMF patients. For reasons that are unclear, we observed a higher percentage of JAK2 (PMF 83%, PET-MF 65%) and lower percentage of CALR mutated patients (PMF 7%, PET-MF 23%) across all diagnoses compared with those previously published by Rumi et al for patients with PMF[17] (JAK2 65%, CALR 23%) or Rotunno et al for PET-MF[23] (JAK2 49% and CALR 34%). We also observed shorter OS than what has been published by the previous authors in all patients across all diagnostic entities. This observation was more prominent among JAK2-positive patients, even after adjustment for only newly diagnosed patients. This observation may be due in part to the fact that our institution is a referral center, where we see a higher proportion of advanced cases (48–56% present with int-2 or high-risk DIPSS score and 65–80% present with int-2 or high-risk IPSS score).
Because analyses of mutations beyond the 3 driver mutations were not available in all patients and because the proportions of patients tested within each diagnosis were not equal, we can’t make any conclusions regarding the type, frequency and prognostic impact of so called “high molecular risk” (ASXL1, EZH2, SRSF2, IDH1, and IDH2) mutations in our population. A recently published study [23], suggests that the mutational profile of patients with PPV/PET-MF is different from those with PMF, and their prognostic relevance is not known. Therefore, improved molecular profiling of these patients to better understand the relevance of their genetic background to disease behavior is needed, and studies are currently underway at our institution.
Eleven percent of all patients progression to blast phase (AML), and the incidence of transformation did not differ by disease entity, which is in contrast to the study from Rotunno et al., showing that patients with PPV-MF had a higher rate of progression to AML that those with PMF.
In our study, we show that patients with PET-MF have better OS than those with PMF and PPV-MF. As reported previously,[10] we found that PPV-MF and PMF patients have similar OS. We also confirmed previous reports [22, 24] that the current prognostic scoring systems, such as IPSS and DIPSS, which were developed for PMF, are not effective for prognostic stratification of patients with PET/PPV-MF, and thus, should not be used for medical decision-making in these patients. Better identification of prognostic factors for patients with secondary MF is strongly needed to guide appropriate treatment. Results from our multivariate analysis suggest that anemia with hemoglobin < 10 g/dL and poor performance status with significant symptoms were independent risk factors in patients with PPV-MF, and platelets < 100 × 109/L and blasts ≥ 1% were independent risk factors in patients with PET-MF. These risk factors should be tested in a larger cohort of patients for validation.
A major limitation of our study is that it is based on retrospective data from a single center. Therefore, the data should be interpreted with caution. A prospective multicenter, observational study should be performed in the future to provide a better understanding of the biology and clinical behavior of these diseases. Future studies specifically focused on PET/PPV-MF patients are crucial for developing more accurate predictors of survival with potential clinical implications.
Highlights
Retrospective comparison of 1099 patients with primary and PET/PPV-MF myelofibrosis.
Patients with PET-MF have longer overall survival than those with PPV-MF and PMF.
Current prognostic scoring systems are not valid for prognostication of PET/PPV-MF.
More accurate prognostic factors for PET/PPV-MF are needed.
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