We report the first successful treatment with the thrombopoietin receptor mimetic eltrombopag in a patient with severe aplastic anaemia (SAA) associated with HIV infection, thereby avoiding the use ...of standard immunosuppressive agents for treatment of SAA. Eltrombopag induced a trilineage haematological response. We also show that eltrombopag had an immunomodulatory role with a decrease in proinflammatory T helpers (Th1 and Th17 cells) with increased T-regulatory cell/T-helper ratio, thus contributing to recovery of haemopoiesis.
The COVID-19 pandemic has resulted in the rapid development of a range of vaccines against SARS-CoV-2. Vaccine-induced immune thrombocytopenia and thrombosis (VITT) is a rare but life-threatening ...complication of primarily adenoviral-based vaccines associated with the presence of antibodies to a PF4/polyanion neoepitope and measured by using enzyme-linked immunosorbent assays. Presented are serial anti–PF4/polyanion antibody, platelet, and D-dimer measurements in a large cohort of patients and their relation to relapse. Overall, 51% of patients using the Stago assay had persistently positive anti–PF4/polyanion levels 100 days' postdiagnosis, whereas 94% of patients monitored by using the Immucor assay remain positive. The median duration of positivity of the PF4 assay is 87 days, with 72% of patients remaining positive after a median follow-up of 105 days. The use of plasma exchange seemed to reduce anti–PF4/polyanion levels and increase platelet counts in the acute setting more rapidly than other therapies. The rate of relapse in this study was 12.6%, with all relapsed cases exhibiting persistently positive PF4 antibodies and falling platelet counts. Only one patient had extension of their thrombosis. Overall, despite the persistence of PF4 antibodies in 72% of patients, the rate of relapse was low and did not seem to result in recrudescence of the aggressive clinical picture seen at index presentation. Monitoring of these patients in the UK cohort is ongoing and will aid in definition of the natural history of this novel condition.
•72% of patients remain positive for PF4 antibodies at 100 days; differences exist in antibody persistence dependent on assay used.•Relapse rate is 12.6%, predominantly taking the form of recurrent thrombocytopenia, and all occurred within 90 days of presentation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PURPOSE OF REVIEWAllogeneic haematopoietic stem cell transplantation remains the only curative treatment for myelodysplastic syndrome. We highlight the various issues to consider in the ...pretransplant, transplant and posttransplant periods with emphasis on the management of relapse following transplant.
RECENT FINDINGSCytogenetic and molecular characteristics are becoming more important in predicting transplant outcome. Hypomethylating agents are effective in the pretransplant setting to reduce disease burden. Haploidentical and umbilical cord blood donations may be valid transplant options for patients without human leukocyte antigen-identical sibling or match unrelated donor options. A preemptive management approach to patients at high risk of relapse is more effective. Adjusting the timing and dose of donor lymphocyte infusion reduces the risk of graft-versus-host disease without jeopardizing the graft-versus-leukaemia effect of donor lymphocyte infusion.
SUMMARYAllogeneic haematopoietic stem cell transplantation is curative in up to 40% of myelodysplastic syndrome patients. Appropriate patient selection, modification of conditioning regimes and donor selection should be considered carefully. A preemptive approach for the management of patients at high risk of relapse should be employed following transplant, with the use of immune modulating therapies such as donor lymphocyte infusion and azacitidine.
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Kinase domain (KD) mutations in the BCR-ABL1 gene are associated with resistance to tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML). Next-generation Sequencing (NGS) allows ...detection of low-level KD mutations but its relevance in clinical practice remains debated, and the incidence and prognostic significance of finding of low-level KD mutation in chronic phase (CP) patients is unknown.
We analyzed the outcome for 121 newly diagnosed CP-CML patients treated with TKIs (imatinib 111, nilotinib 7 and dasatinib 3) who we routinely screened for KD mutations using ultra-deep NGS regardless of response to TKI. When a mutation was found by ultra-deep NGS (using Illumina NexteraXT and MiSeq platform) all available previous cDNA samples were analyzed to establish the date of its first occurrence and subsequent kinetics. ABL1 transcripts from 27 healthy donors were sequenced and used as a control. Sequencing for both single and nested PCR products were compared, and samples were re-sequenced in two independent runs in order to analyze reproducibility of variants detection.
Median age of patients was 56 years and the Sokal risk score was 'low' in 38% patients, 'intermediate' in 15.5% and 'high' in 46.5%.
A mutation was detected in 25 of the 121 patients (20.6%) at a median time of 14 months from starting TKI. 19 different mutations were identified, the most frequents being F317L (n=17), Y253H (n=15), M244V (n=14) and T315I (n=10).
All mutations previously detected by Sanger sequencing were also found using ultra-deep NGS. In addition low-level mutations (<20%) were found using ultra-deep NGS in 23 samples (16 patients), while not being detected using Sanger sequencing. Multiple mutations were found in 14 samples (10 patients).
Eighteen patients discontinued imatinib while still in CP and received dasatinib, nilotinib or an allogeneic stem cell transplantation. The overall progression-free survival (absence of advanced phase) at 5 years was 85%. Complete cytogenetic responses (CCyR) and major molecular responses (MMR) with front-line TKI therapy were achieved in 74 (61%) and 52 (43%) patients respectively.
We stratified patients according to response to TKI therapy as per 2009 ELN guidelines (Baccarani et al., 2009): patients with optimal response ('responders', R), failure at any time ('non-responders', NR) and sub-optimal response (SR). Patients with known TKI dose-interruption were analyzed separately. Mutations were classified and analyzed according to clinical relevance (clinically relevant versus clinically non relevant mutations, Branford et al., 2009).
Among non-responders (NR), 37% of patients developed a mutation (29% among patients who lost CCyR), compared to only 5% among responders (2 patients, both with KD mutations sensitive to imatinib). Among patients with suboptimal response (SR), 19% developed a mutation while being in CCyR but not in MMR with all clinically relevant mutated clone percentages increasing in patients being treated with a TKI to which the KD mutation was conferring resistance. Similarly in all NR patients the mutated clone percentage rose in sequential samples if a clinically relevant mutation was detected.
Patients harboring a mutant clone had a poorer PFS at 5 years compared to patients without mutation (67% versus 92%, p<.001). By multivariate analysis, factors associated with worse EFS (progression to AP/BP, death or loss of CCyR) were the presence of a KD mutation and failure to achieve CCyR at 12 months (relative risks 5.4 and 3.6, p=.003 and p=.015, respectively).
We next evaluated the incidence and impact of finding of KD mutations at the early molecular response time point (3-months BCR-ABL1 transcript level). Samples from 41 patients were analyzed at 3 months of which 20 with a BCR-ABL1 transcript level > 10%. A KD mutation was found at 3 months in 4/41 patients (9.7%) all of whom progressed subsequently to advanced phase compared to only 3/37 in patients without mutation (p<0.001). Of note 3/4 patients with a KD mutation had a 3-months BCR-ABL1 transcript level >10%, while only one patient had a 3-months BCR-ABL transcript level <10%.
In conclusion, ultra-deep NGS can reliably and consistently detect early appearance of KD mutation in patients who fail to achieve early molecular response at 3 months as well as in non responder patients or patients who are in CCyR but not in MMR, thus allowing potential early clinical intervention.
Best:Onconova Therapeutics Inc: Research Funding. Pocock:Janssen: Honoraria. McLornan:Novartis: Research Funding, Speakers Bureau. Mufti:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Lavallade:Ariad: Research Funding; Novartis: Consultancy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
To the Editor:
In their study involving 439 patients with aplastic anemia, Yoshizato and colleagues (July 2 issue)
1
bring us closer to understanding clonal hematopoiesis in patients with this ...disease. However, a key conceptual aspect of the study is that the investigators prescreened patients for somatic mutations in genes that are mutated in myeloid cancers using targeted sequencing, followed by whole-exome sequencing, mainly in patients with mutations in the targeted genes. Furthermore, the study population included those with the post–aplastic anemia myelodysplastic syndrome (MDS), which further biased the identified pattern of clonal hematopoiesis toward MDS-associated mutations. Using an unbiased approach . . .
Immune derangements and altered T cell hemostasis play an important role in the pathogenesis of Myelodysplastic syndromes (MDS) contributing to the increased clone susceptibility to accelerated ...apoptosis. In addition, escape of immune surveillance may be a mechanism of MDS disease progression. The association between MDS and autoimmune diseases (AID) is well described. Small case series reported distinct clinical features and outcome for MDS patients with AID. We report here the largest cohort examining the prevalence of AID among MDS patients, compare characteristics and outcome of MDS patients with and without AID.
We identified all confirmed MDS cases through the Moffitt Cancer Center (MCC) MDS database and King's College Hospital (KCH). Therapy related MDS (t-MDS) cases were excluded. All charts were reviewed for documented past or active AID and its treatment. Patients were divided into 2 groups, those with de novo MDS associated with AID (AIDA-MDS) and those with no documented AID (non AIDA-MDS). Baseline characteristics were compared between the two groups. Chi square test was used for comparison of categorical variables and t-test for continuous variables. Kaplan-Meier estimates were used for overall survival (OS).
At time of this analysis 1408 pts were included, 1044 cases from MCC and 364 at KCH. We identified 391 MDS patients with AID (28%). The median duration of follow up was 74 months (mo) (95% CI 69-78)
Hypothyroidism was the most common AID identified, accounting for 44% (n=171) of cases with AID (12% among all MDS cases in this analysis). Other AID with ≥5% prevalence included ITP 12% (n=46), rheumatoid arthritis 10% (n= 41), gout 9% (n=36), and psoriasis 7% (n=28). To confirm the observed rate of hypothyroidism among our cohort, we explored the rate among MDS pts in the SEER registry where 45% of those registered as MDS had one or more hypothyroid claims (ICD code 244.9) among Medicare beneficiaries (2000-2005). (The prevalence of subclinical hypothyroidism is about 5% of women and in 3% of men with higher prevalence in elderly general population)
Baseline characteristics comparing AIDA-MDS (n=391) and non-AIDA-MDS (n=1017) (summarized in Table-1) were similar except AID were more common in females, RA or RCMDWHO subtype and pts were less RBC transfusion dependent.
Table 1Baseline characteristicsAIDA-MDS n=391Non AIDA MDS n= 1017P valueAge> 60293 (75%)739 (73%)0.4GenderFemale172 (44%)305 (30%)<0.005WHORA53 (14%)95 (9%)0.02RCMD131 (34%)299 (29%)RARS32 (8%)90 (9%)Del 5q12 (3%)45 (4%)RAEB I60(15%)193 (19%)RAEB II56 (14%)169 (17%)AML8 (2%)36 (4%)CMML8 (2%)24 (2%)MDS U13 (3%)10 (1%)MDS/MPN -U18 (5%)50 (5%)unknown06 (1%)IPSSLow85 (23%)183 (20%)0.25Int-1186 (50%)464 (50%)Int-283 (22%)204(22%)High22 (5%)82 (8%)R-IPSSVery low68 (19%)128 (14%)0.1Low127 (35%)306(34%)Intermediate77 (21%)188 (21%)High51 (14%)142 (16%)Very High41 (11%)135 (15%)Hypocellular marrowMCC only/Yes31 (10%)70 (10%)0.5Marrow FibrosisMCC only/Grade 2-340 (13%)95 (13%)0.7PNH clonedetected6 (2%)14 (1%)0.8LGL cloneMCC only / >50024 (8%)41 (6%)0.053T cell clonalityMCC only / + Beta or gamma28/71 (39%)55/112 (40%)0.5KarytotypeFavorable260 (66%)640 (65%)0.4Intermediate67 (17%)152 (15%)Poor59 (15%)183 (19%)missing5 (1%)15 (2%)Trisomy 8Yes44 (12%)89 (9%)0.3RBC transfusionDependence256 (66%)729 (72%)0.016HMA (MCC)Azacitidine168 (54%)344 (47%)0.8Decitabine38 (12%)119 (16%)0.1
Median OS was 60 mo (95% CI 50-70) for AIDA-MDS compared to 45 mo (95% 40-49) for those with no AIDA-MDS (log rank test, p = 0.006). By multivariate analysis adjusting for revised IPSS and age >60, AID was a statistically significant independent factor for OS (HR 0.78 (95% CI 0.66-0.92) (p=0.004). The rate of AML transformation was 23% (n=89) among AIDA-MDS compared to 30% (n=301) in non AIDA-MDS (p=0.006). There were no observed differences in response to treatment including azacitidine or Lenalidomide among evaluable patients for response.
AID are commonly associated with MDS, accounting for 28% of patients in our large cohort. Hypothyroidism was the most prevalent AID (12%) with similar high observation among Medicare MDS beneficiaries. AID was significantly more common in women, and associated with more RA/RCMD WHO subtypes with significantly reduced risk of AML transformation and death.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
9.
Managing heparin infusions Brown, Nicholas F; Bart-Smith, Emily; Gillett, Donald
British journal of hospital medicine (London, England : 2005),
06/2012, Volume:
73, Issue:
6
Journal Article
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