Relationship of different platelet response criteria and patient outcomes in a romiplostim myelodysplastic syndromes trial

Abstract The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.

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Decitabine priming prior to low-dose chemotherapy improves patient outcomes in myelodysplastic syndromes-RAEB: a retrospective analysis vs. chemotherapy alone

Journal of Cancer Research and Clinical Oncology ◽

10.1007/s00432-016-2331-0 ◽

2017 ◽

Vol 143 (5) ◽

pp. 873-882 ◽

Cited By ~ 1

Author(s):

Li Ye ◽

Yanling Ren ◽

Xinping Zhou ◽

Chen Mei ◽

Liya Ma ◽

...

Keyword(s):

Retrospective Analysis ◽

Patient Outcomes ◽

Myelodysplastic Syndromes ◽

Low Dose ◽

Low Dose Chemotherapy

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TET2 mutations as a part of DNA dioxygenase deficiency in myelodysplastic syndromes

Blood Advances ◽

10.1182/bloodadvances.2021005418 ◽

2021 ◽

Author(s):

Carmelo Gurnari ◽

Simona Pagliuca ◽

Yihong Guan ◽

Vera Adema ◽

Courtney E Hershberger ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Prognostic Significance ◽

Age Groups ◽

Feedback Mechanism ◽

Dna Demethylation ◽

Compensatory Mechanisms ◽

Poor Outcomes ◽

Relationship Of ◽

The Impact

Decrease in DNA dioxygease activity generated by TET2 gene family is crucial in myelodysplastic syndromes (MDS). The general down-regulation of 5-hydroxymethylcytosine (5-hmC) argues for a role of DNA demethylation in MDS beyond TET2 mutations, which albeit frequent, do not convey any prognostic significance. We investigated TETs expression to identify factors which can modulate the impact of mutations and thus 5-hmC levels on clinical phenotypes and prognosis of MDS patients. DNA/RNA-sequencing and 5-hmC data were collected from 1,665 patients with MDS and 91 controls. Irrespective of mutations, a significant fraction of MDS patients exhibited lower TET2 expression, while 5-hmC levels were not uniformly decreased. In searching for factors explaining compensatory mechanisms, we discovered that TET3 was up-regulated in MDS and inversely correlated with TET2 expression in wild-type cases. While TET2 was reduced across all age-groups, TET3 levels were increased in a likely feedback mechanism induced by TET2 dysfunction. This inverse relationship of TET2 and TET3 expression also corresponded to the expression of L-2-hydroxyglutarate dehydrogenase, involved in agonist/antagonist substrate metabolism. Importantly, elevated TET3 levels influenced the clinical phenotype of TET2-deficiency whereby the lack of compensation by TET3 (low TET3 expression) was associated with poor outcomes of TET2 mutant carriers.

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Myelodysplasia

10.1093/med/9780199683307.003.0006_update_001 ◽

2018 ◽

Author(s):

Drew Provan ◽

Trevor Baglin ◽

Inderjeet Dokal ◽

Johannes de Vos ◽

Mammit Kaur

Keyword(s):

Prognostic Factors ◽

Clinical Features ◽

Myelodysplastic Syndromes ◽

Response Criteria ◽

Myeloproliferative Diseases ◽

Clinical Variants

Myelodysplastic syndromes (MDS) - Classification of MDS - Clinical features of MDS - Prognostic factors in MDS - Clinical variants of MDS - Management of MDS - Response criteria - Myelodysplastic/myeloproliferative diseases (MDS/MPD)

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Treatments targeting MDS genetics: a fool’s errand?

Hematology ◽

10.1182/asheducation-2018.1.277 ◽

2018 ◽

Vol 2018 (1) ◽

pp. 277-285 ◽

Cited By ~ 2

Author(s):

Amy E. DeZern

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Patient Outcomes ◽

Myelodysplastic Syndromes ◽

Bone Marrow Failure ◽

Targeted Agents ◽

Clonal Hematopoiesis ◽

Myeloid Neoplasms ◽

Improve Patient

Abstract The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure characteristically seen in patients. The heterogeneity of myelodysplastic syndrome pathobiology has historically posed a challenge to the development of newer therapies. Recent advances in molecular characterization of myelodysplastic syndromes are improving diagnostic accuracy, providing insights into pathogenesis, and refining therapeutic options for patients. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.

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Diagnosis, management and response criteria of iron overload in myelodysplastic syndromes (MDS): updated recommendations of the Austrian MDS platform

Expert Review of Hematology ◽

10.1080/17474086.2018.1420473 ◽

2018 ◽

Vol 11 (2) ◽

pp. 109-116 ◽

Cited By ~ 2

Author(s):

Peter Valent ◽

Reinhard Stauder ◽

Igor Theurl ◽

Klaus Geissler ◽

Thamer Sliwa ◽

...

Keyword(s):

Iron Overload ◽

Myelodysplastic Syndromes ◽

Response Criteria

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The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes

Blood Cancer Journal ◽

10.1038/bcj.2015.11 ◽

2015 ◽

Vol 5 (3) ◽

pp. e291-e291 ◽

Cited By ~ 11

Author(s):

K L McGraw ◽

L M Zhang ◽

D E Rollison ◽

A A Basiorka ◽

W Fulp ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Tp53 Mutation ◽

Disease Outcome ◽

Relationship Of ◽

The Relationship

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5-Azacytidine in the Treatment of High Risk Myelodysplastic Syndromes: Clinical Response Can Occur without Demethylation of the CDKN2B, CDKN1A or TP73 Gene Promoters.

Blood ◽

10.1182/blood.v104.11.2369.2369 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2369-2369 ◽

Cited By ~ 1

Author(s):

Kavita Raj ◽

Alison John ◽

Aloysius Ho ◽

Nicholas Shaun B. Thomas ◽

Ghulam J. Mufti

Keyword(s):

High Risk ◽

Clinical Response ◽

Myelodysplastic Syndromes ◽

Post Treatment ◽

Acute Pulmonary Oedema ◽

Gene Promoters ◽

Platelet Response ◽

College Hospital ◽

Blast Count

Abstract Inhibition of DNA methylation by 5-azacytidine (azacitidine) has been shown to alter the natural course of myelodysplastic syndromes (MDS). Treatment with azacitidine is superior to supportive care, with an improved quality of life. Whether this is accomplished by re-expression of silenced genes in vivo has not yet been shown. The promoter of the CDKN2B gene, encoding p15INK4b, is commonly hypermethylated in MDS and this is linked to disease progression and poor prognosis. Patients with transfusion dependent MDS were treated under the NIH compassionate use protocol at King’s College Hospital with ethical approval and informed consent. Patients were studied for clinical response to azacitidine and associated changes in promoter methylation of the CDKN2B, CDKN1A and TP73 genes associated with cell cycle progression was investigated by methylation-specific polymerase chain reaction (MS-PCR). 17 patients (Male n=13 and Female n=4), with a mean age of 64 years (median 67 years, range 51–81 years), predominantly high risk MDS (FAB: RA, 5q-(n=2), RAEB1 (n=7), RAEB-2 (n=7), AML (n=1)) underwent treatment with at least one cycle of azacitidine (range 1–8 cycles of treatment). Patients previously treated with cytokines (n=2), Farnesyl transferase Inhibitor (Zarnestra n=2) and standard chemotherapy for AML or MDS (n=4) were included in the study. 1 patient (RA 5q-) withdrew after 1 cycle of treatment without adverse event and was not included in the evaluation of efficacy. Azacitidine was administered subcutaneously at 75mg/m2 daily for 7 days every 28 days. Dose reduction by 50% was made for prolonged neutropenia. Bone marrow aspirates and trephines were evaluated after at least one cycle of treatment to assess reponse and for methylation studies. Response was assessed using the International standard working group criteria for MDS (Cheson et al) and six of sixteen patients had a response (37.5%). Complete remission (cytogenetic with loss of 47XX, +8) was seen in one patient and haematological improvement (HI) in five patients. HI-Platelets occurred in 5 patients (major n=3, minor n=2). Median time to a platelet response was 46.5 days (28–84 days) with a mean increase in platelet count of 78.6X109. This was maintained for a mean of 64.75 days (28–115 days). HI-Haemoglobin occured in 1 patient (accompanied by HI-P major), duration 9.5 months. HI -neutrophils occurred in 1 patient. Blast count was 11% mean (0–30%) pre treatment and reduced to 4%(0–14%) post treatment. In 5 patients this was preceded by HI-P, in one patient blast count decreased with worsening cytopenias. Four patients had stable disease and 6 patients failed treatment with either transformation to AML or death (acute pulmonary oedema n=1, GI bleed n=1). Methylation of the CDKN2B, CDKN1A, and TP73 promoters in CD34+, CD33+ and CD34-/CD33- cells were analysed by MS-PCR in 14 patients pre and 7 patients post treatment. At best clinical response, CDKN2B was demethylated in at least one cell fraction in 3/7 and TP73 in 1/7. Conterintuitively, CDKN1A became methylated whilst on treatment in 3/7 cases. Azacitidine is clinically effective in high risk MDS, however the HI- in platelets, reduction in blast counts and demethylation of the promoters investigated occur independently of each other.

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Azacitidine and Lenalidomide Combination In Higher-Risk Myelodysplastic Syndromes-Preliminary Results Of The Vilen-01 Protocol

Blood ◽

10.1182/blood.v122.21.1576.1576 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1576-1576 ◽

Cited By ~ 1

Author(s):

Moshe Mittelman ◽

Kalman Filanovsky ◽

Hanna Rosenbaum ◽

Pia Raanani ◽

Andrei Braester ◽

...

Keyword(s):

Myelodysplastic Syndromes ◽

Conflicts Of Interest ◽

Single Agent ◽

Normal Karyotype ◽

Response Duration ◽

Cytogenetic Response ◽

High Response Rate ◽

Induction Phase ◽

Platelet Response ◽

Erythroid Response

Abstract Background Hypomethylating agents are the standard therapy for higher-risk (HR, Int-2 and high-risk) myelodysplastic syndromes (MDS). Lenalidomide is effective in lower-risk (LR) MDS, with or without 5q-, in HR-MDS and in acute leukemia. Many patients remain resistant to a single agent. A potential synergistic effect of both agents has been shown [Sekeres M et al, Am J Hemat 2010; Blood 2012]. Thus, the MDS Israel group has designed a phase II clinical trial (NIH trial #: TASMC-10-MM-0437-09-CTIL). Protocol The ViLen-01 protocol consists of 3 phases. The induction phase includes 6 monthly cycles of SC azacitidine (Aza), 75 mg/m daily, days 1-5, and PO lenalidomide (Len) 10 mg daily, days 6-21, followed by a 7-day (days 22-28) respite. The consolidation consists of 6 monthly cycles of Aza only for 5 days each, followed by 12 months of maintenance with Len only. Response is evaluated by the IWG criteria [Cheson B et al, Blood 2006]. Results As of July 2013, 7 medical centers have enrolled 18 patients. Patients had been diagnosed with either HR-MDS, or LR-MDS with transfusion-dependence, erythropoietin resistance and poor cytogenetics. Adverse events (AE) were as expected in these elderly HR-MDS patients. The common AEs were grade IV transient cytopenias, requiring dose modification in 15 patients. Only 2 patients stopped the protocol due to AE. Thirteen patients completed the induction, 8 continued to consolidation, and 5 patients continued to maintenance. Eight of the 18 enrolled patients (44%, 8 of the 13, 61.5%) who had completed the induction, achieved CR. Three of the 8 patients in CR also attained cytogenetic response. The other 5 had normal karyotype on study initiation. Five other patients obtained erythroid response and became transfusion-free, and another patient achieved platelet response, for a total of 14 (78%) responders. It is still too early to evaluate response duration and survival. One patient is in early induction, and 4 are still being treated. The others have either died or have discontinued for various reasons (patient refusal, progressive disease, transplant). Conclusions These preliminary data in a small group of patients with HR-MDS and expected poor prognosis, demonstrate a high response rate and a reasonable safety profile. The study is ongoing. If these results are confirmed in randomized trials, it may set new standards for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.

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