CLINICAL NEWS
AEs identified by the researchers as “ significant ” occurred in the 100 mg group : one case each of grade 3 fatigue and grade 3 headache .
Following six cycles of idasanutlin monotherapy in part A , four patients had non-responsive disease and were treated with concurrent pegylated interferon in part B . Of this group , three patients had PRs , and four had complete responses ( CRs ). Three of the patients in part B were evaluable . One patient had no response , one had PR , and one had CR , for a combined response rate of 75 percent in both study parts .
“ Some patients didn ’ t even need to be treated every month ; they got ‘ treatment holidays ,’” Dr . Mascarenhas said during his presentation , noting that one patient required no treatment for nine months following completion of the third cycle .
The median reduction in JAK2 V617F VAF was 43 percent ( range not provided ), with one patient achieving a 92 percent reduction , the authors observed . Seven of 10 patients achieved a ≥50 percent improvement in total symptom score from baseline .
Based on these results , an international , multicenter , single-arm , phase II trial evaluating idasanutlin 150 mg in patients with hydroxyurea-resistant or -intolerant PV is enrolling participants .
The study was limited by its small patient population , single-center design , and short duration of follow-up .
The authors report no conflicts of interest .
REFERENCE
Mascarenhas J , Lu M , Virtgaym E , et al . Open label phase I study of single agent oral RG7388 ( idasanutlin ) in patients with polycythemia vera and essential thrombocythemia . Abstract 254 . Presented at the 2017 American Society of Hematology Annual Meeting , December 9 , 2017 ; Atlanta , GA .
Treating MRD With Azacitidine in Patients With High-Risk AML and MDS
For 58 percent of patients with acute myeloid leukemia ( AML ) or myelodysplastic syndromes ( MDS ) at high risk for relapse , treatment of minimal residual disease ( MRD ) with azacitidine was feasible , according to results from the prospective RELAZA2 trial .
“ Monitoring of MRD in morphologic complete remission has been shown to allow for predicting subsequent hematologic relapse , thus opening a window for preemptive therapeutic interventions ,” said lead author Uwe Platzbecker , MD , from University Hospital Carl Gustav Carus in Dresden , Germany , during his presentation of the results at the 2017 ASH Annual Meeting . “[ Findings from this trial ] support the prognostic importance of MRD in AML and may serve as a platform for future studies combining hypomethylating agents with novel targeted therapies .”
Researchers enrolled 205 patients from 2011 to 2015 at 11 centers in Germany : 27 people had advanced MDS and 178 had AML . All experienced complete remission ( CR ) following either conventional chemotherapy only ( n = 58 ) or allogeneic hematopoietic cell transplantation ( alloHCT ; n = 147 ).
Investigators monitored MRD ( measured by level of NPM1 mutation or leukemia-specific fusion genes in bone marrow or peripheral blood , or CD34-positive donor chimerism in alloHCT-treated patients ) starting at day 56 after completion of last therapy , followed by monthly intervals for two years .
Fifty-three of the 205 patients with CR had measurable MRD above the predefined threshold for “ imminent relapse ” and went on to receive preemptive azacitidine ( 75 mg / m 2 subcutaneously on days 1-7 , followed by an additional 6-12 cycles , for up to 18 additional months ).
Median age of the 53 treated patients was 59 years ( range = 52-69 years ); 48 ( 91 %) had AML and five ( 9 %) had MDS . After completion of the initial six cycles of azacitidine ,
31 patients ( 58 %) were still in hematologic CR ( primary endpoint ). This included 19 participants ( 36 %) with “ major response ,” defined as a decline of MRD below a predefined threshold ( NPM1 mutation level ≤1 % or CD34-positive donor chimerism ≥80 %). Another 12 patients ( 23 %) had “ minor response ,” defined as MRD of CD34-positive donor chimerism < 80 percent or mutation level ≤1 percent but no relapse .
The overall response rate varied between patients with and without antecedent alloHCT ( 71 % and 48 %, respectively ; p = 0.007 ).
Twenty-two participants ( 42 %) relapsed after a median of three cycles of azacitidine ( range not provided ). After six months , 24 patients continued to receive azacitidine , for a median of nine subsequent cycles ( range not provided ). In eight of those patients , hematologic relapse occurred at a median of 397 days following initial MRD detection ( range not provided ).
At a median follow-up of 13 months ( range not provided ), secondary endpoints of overall and progression-free survival rates were 76 percent and 42 percent , respectively .
Preemptive treatment with azacitidine also appeared to be well tolerated . Infections and pneumonia were the most commonly reported severe adverse events during the initial six cycles ( n = 4 and n = 3 , respectively ).
“ We still saw some late relapses in these patients , even after continuation of azacitidine ,” Dr . Platzbecker added , “ but the data look promising – especially in patients with relapse after transplantation .”
The open-label design and relatively small number of patients are limitations of the study .
The authors report financial relationships with Celgene , the manufacturer of azacitidine .
REFERENCE
Platzbecker U , Middeke JM , Sockel K , et al . Minimal-residual disease guided treatment with azacitidine in MDS / AML patients at imminent risk of relapse : results of the prospective RELAZA2 trial . Abstract # 565 . Presented at the 2017 American Society of Hematology Annual Meeting , December 11 , 2017 ; Atlanta , GA .
Feeding the Fire : CHIP and Inflammation
Clonal hematopoiesis of indeterminate potential ( CHIP ), known as a “ premalignant ” state in the blood critical to the development of blood cancer , increases in frequency with age and also has been associated with a higher risk for developing coronary heart disease . In an analyis presented at the 2017 ASH Annual Meeting , Elina K . Cook , MD , PhD-c , from Queen ’ s University in Kingston , Ontario , reported that CHIP is associated with increased risk for other cardiometabolic diseases exacerbated by inflammation , including cardiopulmonary disease .
Based on previous research about comorbidities associated with CHIP in inflammatory disease , researchers hypothesized that CHIP clones , stratified by mutation type , may be linked to unique , inflammatory diseases of aging . “ Specifically , mutated TET2 clones may be more likely to emerge in , or to condition , a pro-inflammatory disease environment ( e . g ., one containing increased interleukin [ IL ] -6 ),” they explained .
The researchers analyzed leukocyte genomic DNA from 348 healthy adults older than 65 years ( mean age = 80.4 years ) at two centers in Toronto . Samples were sequenced for 48 commonly mutated myeloid genes and correlated with blood lab results and data on 28 comorbidities .
CHIP was detected in 28 percent of participants . This proportion increased with age , from less than 13 percent among those less than 70 years to 29 percent among those greater than 85 years .
Patients with CHIP were more than four times as likely as those without CHIP to have higher monocyte counts ( odds ratio [ OR ] = 4.1 ; 95 % CI 1.2-13.9 ; p = 0.021 ) and three times more likely to have valvular heart disease ( OR = 2.9 ; 95 % CI 1.4-6.6 ; p = 0.007 ), compared with patients without CHIP . People with CHIP also had higher odds of The odds of having chronic asymptomatic / symptomatic cardiopulmonary disease ( OR = 2.8 ; 95 % CI 1.4-5.5 ; p = 0.003 ), a higher Eastern Cooperative Oncology Group performance status score ( OR = 1.6 ; 95 % CI 1.1-2.3 ; p = 0.013 ), and a higher Charlson Comorbidity Index ( OR = 1.2 ; 95 % CI 1.0-1.4 ; p = 0.031 ).
Together , these translated to lower predicted rates of 10-year survival and “ support previous associations between cardiovascular disease , CHIP , and mutant monocytes / macrophages ,” the researchers noted .
TET2 and DNMT3A were the most commonly mutated genes among this patient group . Those with CHIP and DNMT3A mutations ( D-CHIP ) were more likely to have comorbid diseases such as gastroesophageal reflux diseases ( OR = 3.1 ; 95 % CI 1.4-6.8 ; p = 0.005 ) than those with TET2 mutations ( T-CHIP ; OR = 1.5 ; 95 % CI 0.6-3.7 ; p = 0.36 ), while T-CHIP patients were more likely to have valvular heart disease ( ORs = 3.6 [ 95 % CI 1.3-10.0 ; p = 0.015 ] vs . 1.7 [ 95 % CI 0.5-6.1 ; p = 0.44 ]).
“ We reported novel connections of comorbidities with CHIP and found specific comorbidities associated with either or both T-CHIP and D-CHIP subtypes ,” the researchers wrote . “ Moreover , for the first time in humans , we find higher serum levels of certain pro-inflammatory drivers in each CHIP subtype .”
In those with T-CHIP , serum levels of the pro-inflammatory IL-6 were elevated , compared with D-CHIP ( p = 0.013 ), while those with D-CHIP had elevated serum Eotaxin-1 / CCL11 , an eosinophil chemo-attractor ( p = 0.028 ). These markers remained elevated in their respective subgroups , even after adjusting for potential comorbidity confounders .
“ In the clinical realm , knowing one ’ s CHIP subtype ( e . g ., T-CHIP ) may enable personalized monitoring for specific diseases and preventative , proactive approaches ,” the authors concluded . “ Ultimately , this may lead to therapeutic avenues that target mutant clones and their specific inflammatory environments to reduce the burden of CHIP and associated comorbidities .”
“ CHIP is more prevalent than previously reported , possibly due to our aged cohort ,” the authors observed , noting a possible limitation of the study . ●
The authors report no financial conflicts .
REFERENCE
Cook EK , Izukawa TR , Young S , et al . Feeding the fire : the comorbid and inflammatory backdrop of clonal hematopoiesis of indeterminate potential ( CHIP ) by mutation subtype . Abstract # 426 . Presented at the 2017 American Society of Hematology Annual Meeting , December 10 , 2017 ; Atlanta , GA .
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