Prevalence, severity and correlates of fatigue in newly diagnosed patients with myelodysplastic syndromes

The primary objective of this study was to investigate factors associated with fatigue severity in newly diagnosed patients with higher-risk myelodysplastic syndromes (MDS). The secondary objectives were to assess symptom prevalence and to examine the relationships between fatigue, quality of life (QoL) and overall symptom burden in these patients. The analyses were conducted in 280 higher-risk MDS patients. Pre-treatment patient-reported fatigue was evaluated with the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). Female gender (P = 0·018), poor performance status (i.e., ECOG of 2-4) (P < 0·001) and lower levels of haemoglobin (Hb) (P = 0·026) were independently associated with higher fatigue severity. The three most prevalent symptoms were as follows: fatigue (92%), dyspnoea (63%) and pain (55%). Patients with higher levels of fatigue also had greater overall symptom burdens. The mean global QoL scores of patients with the highest versus those with the lowest levels of fatigue were 29·2 [standard deviation (SD), 18·3] and 69·0 (SD, 18·8), respectively and this difference was four times the magnitude of a clinically meaningful difference. Patient-reported fatigue severity revealed the effects of disease burden on overall QoL more accurately than did degree of anaemia. Special attention should be given to the female patients in the management of fatigue

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies

Implications of TP53 allelic state for genome stability, clinical presentation and outcomes in myelodysplastic syndromes

Tumor protein p53 (TP53) is the most frequently mutated gene in cancer1,2. In patients with myelodysplastic syndromes (MDS), TP53 mutations are associated with high-risk disease3,4, rapid transformation to acute myeloid leukemia (AML)5, resistance to conventional therapies6–8 and dismal outcomes9. Consistent with the tumor-suppressive role of TP53, patients harbor both mono- and biallelic mutations10. However, the biological and clinical implications of TP53 allelic state have not been fully investigated in MDS or any other cancer type. We analyzed 3,324 patients with MDS for TP53 mutations and allelic imbalances and delineated two subsets of patients with distinct phenotypes and outcomes. One-third of TP53-mutated patients had monoallelic mutations whereas two-thirds had multiple hits (multi-hit) consistent with biallelic targeting. Established associations with complex karyotype, few co-occurring mutations, high-risk presentation and poor outcomes were specific to multi-hit patients only. TP53 multi-hit state predicted risk of death and leukemic transformation independently of the Revised International Prognostic Scoring System (IPSS-R)11. Surprisingly, monoallelic patients did not differ from TP53 wild-type patients in outcomes and response to therapy. This study shows that consideration of TP53 allelic state is critical for diagnostic and prognostic precision in MDS as well as in future correlative studies of treatment response

Tracheal intubation in traumatic brain injury

Background: We aimed to study the associations between pre- and in-hospital tracheal intubation and outcomes in traumatic brain injury (TBI), and whether the association varied according to injury severity. Methods: Data from the international prospective pan-European cohort study, Collaborative European NeuroTrauma Effectiveness Research for TBI (CENTER-TBI), were used (n=4509). For prehospital intubation, we excluded self-presenters. For in-hospital intubation, patients whose tracheas were intubated on-scene were excluded. The association between intubation and outcome was analysed with ordinal regression with adjustment for the International Mission for Prognosis and Analysis of Clinical Trials in TBI variables and extracranial injury. We assessed whether the effect of intubation varied by injury severity by testing the added value of an interaction term with likelihood ratio tests. Results: In the prehospital analysis, 890/3736 (24%) patients had their tracheas intubated at scene. In the in-hospital analysis, 460/2930 (16%) patients had their tracheas intubated in the emergency department. There was no adjusted overall effect on functional outcome of prehospital intubation (odds ratio=1.01; 95% confidence interval, 0.79–1.28; P=0.96), and the adjusted overall effect of in-hospital intubation was not significant (odds ratio=0.86; 95% confidence interval, 0.65–1.13; P=0.28). However, prehospital intubation was associated with better functional outcome in patients with higher thorax and abdominal Abbreviated Injury Scale scores (P=0.009 and P=0.02, respectively), whereas in-hospital intubation was associated with better outcome in patients with lower Glasgow Coma Scale scores (P=0.01): in-hospital intubation was associated with better functional outcome in patients with Glasgow Coma Scale scores of 10 or lower. Conclusion: The benefits and harms of tracheal intubation should be carefully evaluated in patients with TBI to optimise benefit. This study suggests that extracranial injury should influence the decision in the prehospital setting, and level of consciousness in the in-hospital setting. Clinical trial registration: NCT02210221

A novel method for the laboratory workup of anaphylactic transfusion reactions in haptoglobin-deficient patients

Patients with congenital haptoglobin deficiency can develop anti-haptoglobin antibodies after exposure to blood products, and they can suffer from life-threatening anaphylactic transfusion reactions. Here, we present a case of a 57-year-old Chinese male with myelodysplastic syndrome who manifested an anaphylactic transfusion reaction during the transfusion of platelets. The only abnormality detected during his reaction laboratory workup was an undetectable haptoglobin level in the absence of evidence of hemolysis. Surface plasmon resonance (SPR) was explored as a method to be able to detect the presence of anti-haptoglobin antibodies in serum. First, haptoglobin was immobilized to the surface of an SPR sensor chip. The patient's serum sample was injected, and the binding response was monitored in real time. Serum samples from five healthy volunteers were used as negative controls. Binding specificity was assessed in competition experiments using soluble haptoglobin. Anti-IgG, -IgA, -IgM, -IgD and -IgE antibodies were used to identify the antibody isotype. An IgG anti-haptoglobin antibody was detected in the patient's serum with SPR. SPR provided a rapid, readily available method for the detection of an IgG anti-haptoglobin antibody in an anhaptoglobinemic individual. This confirmed the underlying etiology of the anaphylactic nonhemolytic transfusion reaction and justified the necessity of stringently washed cellular products for all future transfusions and strong caution for future use of plasma-containing products

Clinical Activity of DNA Methyltransferase Inhibitors In Therapy-Related Myelodysplastic Syndromes: A Retrospective Study

Abstract Abstract 1891 Therapy-related myelodysplastic syndrome (tMDS) is a poor-risk subtype of MDS with no standard treatment options, and yet patients (pts) with tMDS are often excluded from trials where they would have the opportunity to benefit from novel treatment approaches. DNA methyltransferase inhibitors are a treatment option for tMDS, and are being evaluated as a bridge to stem cell transplant in these often heavily pre-treated patients to avoid the organ toxicity of intensive chemotherapy. However, the response rate of tMDS to DNA methyltransferase inhibitor (DNMTI) therapy is unknown. In this retrospective study, adult patients tMDS were culled from a fully annotated, IRB-approved database of all MDS patients who received either decitabine (DAC) on both the 3-day and 5-day schedules or 5-azacytidine (5-aza) at our institution from 4/8/2002 to 6/18/2010. Patients who received interrupted therapy were only analyzed for response to their initial course of therapy. Patients who received sequential DNMTI therapy (i.e., DAC followed by 5-aza or 5-aza followed by DAC) were included, but response to only their initial therapy was assessed. Responses were determined using the modified International Working Group criteria (Cheson BD, et al, 2006). Of the 35 patients initially identified with tMDS who received DNMTI therapy, 4 were deemed inevaluable for response due to marrow involvement with the primary malignancy (n= 1), missing records (n=2), or delivery of < 1 full cycle of therapy (n=1). The 31 evaluable pts included 14 males and 17 females with a median age of 65 years (range 25–85). Therapy for the primary malignancy included chemotherapy alone (n=13), chemotherapy plus radiotherapy (n=14), radioactive iodine and radiotherapy (n=2), radioactive iodine and chemotherapy (n=2), and autologous stem cell transplant (n=3). Prior to DNMTI therapy, the MDS FAB subtypes were as follows: RA, n= 6; RARS, n= 3; RAEB, n= 19; RAEBt, n=2; CMMoL, n=1. Pre-DNMTI therapy included lenalidomide (n=4) and alloSCT (n=1). Of the 31 evaluable patients, 20 received DAC, including 7 pts who received tretinoin with DAC in a clinical trial, and 11 received 5-aza. DAC recipients received a median of 2 cycles of therapy (range, 1–12) and 5-aza recipients received a median of 5 cycles (range, 1–9). Best responses were as follows: CR, n=1; Marrow CR plus HI, n=6 (3 trilineage HI, 1 HI-P+ HI-N, 2 HI-P); Stable Disease, n=6; Progressive Disease, n=6; Failures (death during 1st cycle or before response evaluation), n=3. Rate of CR + mCR was 22% (n=7). Additional patients had inevaluable (aparticulate) marrows, or refused follow-up marrow studies, but showed signs of stable (n= 3), improved, (n=2; HI-P, HI-P+HI-N), or progressive cytopenias (n= 3). Median time to best response was 1.5 cycles (range 1–6). Fifty-eight percent (n=18) of 31 pts achieved stable disease or better responses (including 4 pts with stable cytopenias or HI with inevaluable marrow response). Four patients proceeded directly to transplant after DNMTI therapy. Two subsequently died from relapsed disease after transplant, while 1 pt is lost to follow-up and 1 pt is without evidence of MDS 2.5 years after transplant. Nine pts had persistence of their primary malignancy during DNMTI therapy, and 5/9 pts required interruption or cessation of their DNMTI therapy because of progressive primary malignancy. 24/31 pts died from complications of MDS (n=5) or subsequent AML (11), complications of MDS/AML with likely contribution from their primary malignancy (n=4), infection during DNMTI nadir (n=2), GVHD post AlloSCT (n=1), or unknown reasons (n=1). Living pts (n=7; median follow-up from start of DNMTI therapy = 12.5 months, range 4.1 – 35.1 months) include 5 who are not transplant candidates. In conclusion, DNMTI therapy produced modest clinical benefit in our tMDS cohort. In some patients, persistence of the primary malignancy interfered with our ability to deliver optimal DNMTI therapy and to assess response. Although DNMTIs represent a potential therapeutic option for tMDS, treatment of a larger cohort is required to clarify the response rate of these agents in tMDS. Disclosures: Klimek: Celgene: Consultancy

Phase I trial of sodium salicylate in patients with myelodysplastic syndromes and acute myelogenous leukemia

Sodium salicylate is an inexpensive, readily available anti-inflammatory agent which inhibits NF-κB in in vitro models. We examined whether it was possible to safely achieve and maintain salicylate levels known to inhibit NF-κB in vitro in 11 patients with MDS or AML taking sodium salicylate. Most patients achieved the target blood salicylate level (20–30mg/dL) with acceptable toxicity, including reversible grade 1/2 elevations of hepatic transaminases (n=4) and ototoxicity (n=4). One patient had grade 3/4 elevations in AST/ALT. This study suggests that sodium salicylate may be safely combined with conventional chemotherapy regimens which are not associated with significant ototoxicity or hepatotoxicity