A randomized clinical trial of the efficacy and safety of rivipansel for sickle cell vaso-occlusive crisis.

The efficacy and safety of rivipansel, a predominantly E-selectin antagonist, were studied in a phase 3, randomized, controlled trial for vaso-occlusive crisis (VOC) requiring hospitalization (RESET). A total of 345 subjects (204 adults and 141 children) were randomized and 320 were treated (162 with rivipansel, 158 with placebo) with an IV loading dose, followed by up to 14 additional 12-hourly maintenance doses of rivipansel or placebo, in addition to standard care. Rivipansel was similarly administered during subsequent VOCs in the Open-label Extension (OLE) study. In the full analysis population, the median time to readiness for discharge (TTRFD), the primary end point, was not different between rivipansel and placebo (-5.7 hours, P = .79; hazard ratio, 0.97), nor were differences seen in secondary end points of time to discharge (TTD), time to discontinuation of IV opioids (TTDIVO), and cumulative IV opioid use. Mean soluble E-selectin decreased 61% from baseline after the loading dose in the rivipansel group, while remaining unchanged in the placebo group. In a post hoc analysis, early rivipansel treatment within 26.4 hours of VOC pain onset (earliest quartile of time from VOC onset to treatment) reduced median TTRFD by 56.3 hours, reduced median TTD by 41.5 hours, and reduced median TTDIVO by 50.5 hours, compared with placebo (all P < .05). A similar subgroup analysis comparing OLE early-treatment with early-treatment RESET placebo showed a reduction in TTD of 23.1 hours (P = .062) and in TTDIVO of 30.1 hours (P = .087). Timing of rivipansel administration after pain onset may be critical to achieving accelerated resolution of acute VOC. Trial Registration: Clinicaltrials.gov, NCT02187003 (RESET), NCT02433158 (OLE).

Enhanced IgG immune response to COVID-19 vaccination in patients with sickle cell disease.

Patients with sickle cell disease (SCD) are considered to be immunocompromised, yet data on the antibody response to SARS-CoV-2 vaccination in SCD is limited. We investigated anti-SARS-CoV-2 IgG titres and overall neutralizing activity in 201 adults with SCD and demographically matched non-SCD controls. Unexpectedly, patients with SCD generate a more robust and durable COVID-19 vaccine IgG response compared to matched controls, though the neutralizing activity remained similar across both cohorts. These findings suggest that patients with SCD achieve a similar antibody response following COVID-19 vaccination compared to the general population, with implications for optimal vaccination strategies for patients with SCD.

Burden of disease, treatment utilization, and the impact on education and employment in patients with sickle cell disease: A comparative analysis of high- and low- to middle-income countries for the international Sickle Cell World Assessment Survey.

The international Sickle Cell World Assessment Survey (SWAY) reported a high impact of sickle cell disease (SCD) on patients' daily lives globally. In this study, we analyzed whether the reported burden differed between patients from the USA (n = 384) and other high-income (HI; n = 820) or low- to middle-income (LMI; n = 941) countries. We assessed symptoms and complications, incidence/management of vaso-occlusive crises (VOCs), treatment utilization/satisfaction, and the impact of SCD on education/employment. Certain symptoms (bone aches, insomnia, and joint stiffness) and complications (swollen/painful fingers/toes, gallstones, vision problems, blood clots, and asthma) were reported proportionally more by patients in the USA than in the HI/LMI countries. Self-reported VOCs were more common (mean [SD]: 7.1 [5.7] vs. 5.5 [8.9] and 4.4 [4.6] in the previous 12 months) and were managed more often by hospitalization (52% vs. 24% and 32%) in the USA than the HI and LMI countries. A higher proportion of patients from the USA than the HI/LMI countries reported a negative impact of SCD on their employment/schooling. Although high overall satisfaction with current treatments was reported globally, most patients indicated a strong desire for alternative pain medications. There are likely several reasons for the relatively high patient-reported burden in the USA group compared with the HI/LMI countries, including an older population and differences in newborn screening programs and pediatric/adult transition of care. It is clear that there is an urgent need for improved understanding and management of SCD globally, not just in the USA.

Impact of sickle cell disease on patients' daily lives, symptoms reported, and disease management strategies: Results from the international Sickle Cell World Assessment Survey (SWAY).

Sickle cell disease (SCD) is a genetic disorder, characterized by hemolytic anemia and vaso-occlusive crises (VOCs). Data on the global SCD impact on quality of life (QoL) from the patient viewpoint are limited. The international Sickle Cell World Assessment Survey (SWAY) aimed to provide insights into patient-reported impact of SCD on QoL. This cross-sectional survey of SCD patients enrolled by healthcare professionals and advocacy groups assessed disease impact on daily life, education and work, symptoms, treatment goals, and disease management. Opinions were captured using a Likert scale of 1-7 for some questions; 5-7 indicated "high severity/impact." Two thousand one hundred and forty five patients (mean age 24.7 years [standard deviation (SD) = 13.1], 39% ≤18 years, 52% female) were surveyed from 16 countries (six geographical regions). A substantial proportion of patients reported that SCD caused a high negative impact on emotions (60%) and school achievement (51%) and a reduction in work hours (53%). A mean of 5.3 VOCs (SD = 6.8) was reported over the 12 months prior to survey (median 3.0 [interquartile range 2.0-6.0]); 24% were managed at home and 76% required healthcare services. Other than VOCs, fatigue was the most commonly reported symptom in the month before survey (65%), graded "high severity" by 67% of patients. Depression and anxiety were reported by 39% and 38% of patients, respectively. The most common patient treatment goal was improving QoL (55%). Findings from SWAY reaffirm that SCD confers a significant burden on patients, epitomized by the high impact on patients' QoL and emotional wellbeing, and the high prevalence of self-reported VOCs and other symptoms.

Challenges in the treatment and prevention of delayed hemolytic transfusion reactions with hyperhemolysis in sickle cell disease patients.

BACKGROUND: Delayed hemolytic transfusion reactions (DHTRs) are serious complications of RBC transfusion that can occur in previously alloimmunized patients. Patients who require episodic transfusions during heightened inflammatory states, such as patients with sickle cell disease (SCD), are particularly prone to alloimmunization and developing DHTRs with hyperhemolysis. While efforts to mitigate these hemolytic episodes via immunosuppressive drugs can be employed, the relative efficacy of various treatment options remains incompletely understood. CASE REPORTS: In this study, we explored five patients with SCD and multiple RBC alloantibodies who received various forms of immunosuppressive therapy in an attempt to prevent or treat severe DHTRs. RESULTS: The clinical course for these five patients provides insight into the difficulty of effectively treating and preventing DHTRs in patients with SCD with currently available immunosuppressive therapies. CONCLUSION: Based on our experience, and the current literature, it is difficult to predict the potential impact of various immunosuppressive therapies when seeking to prevent or treat DHTRs. Future mechanistic studies are needed to identify the optimal treatment options for DHTRs in the presence or absence of distinct alloantibodies in patients with SCD.

Iron overload in patients with myelodysplastic syndromes: An updated overview.

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor-15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication.

Transfusion-transmitted malaria masquerading as sickle cell crisis with multisystem organ failure.

BACKGROUND: Fever accompanying vaso-occlusive crisis is a common presentation in patients with sickle cell disease (SCD) and carries a broad differential diagnosis. Here, we report a case of transfusion-transmitted malaria in a patient with SCD presenting with acute vaso-occlusive crisis and rapidly decompensating to multisystem organ failure (MSOF). CASE REPORT: An 18-year-old African American male with SCD was admitted after multiple days of fever and severe generalized body pain. He received monthly blood transfusions as stroke prophylaxis. A source of infection was not readily identified, but treatment was initiated with continuous intravenous fluids and empiric antibiotics. The patient developed acute renal failure, acute hypoxic respiratory failure, and shock. He underwent red blood cell (RBC) exchange transfusion followed by therapeutic plasma exchange and continuous veno-venous hemodialysis. A manual peripheral blood smear revealed intraerythrocytic inclusions suggestive of Plasmodium, and molecular studies confirmed Plasmodium falciparum infection. Intravenous artesunate was given daily for 1 week. A look-back investigation involving two hospitals, multiple blood suppliers, and state and federal public health departments identified the source of malaria as a unit of RBCs transfused 2 weeks prior to admission. CONCLUSIONS: Clinical suspicion for transfusion-related adverse events, including hemolytic transfusion reactions and transfusion-transmitted infections, should be high in typically and atypically immunocompromised patient populations (like SCD), especially those on chronic transfusion protocols. Manual blood smear review aids in the evaluation of patients with SCD presenting with severe vaso-occlusive crisis and MSOF and can alert clinicians to the need for initiating aggressive therapy like RBC exchange and artesunate therapy.

Does the frequency of molecular monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of patients with chronic myeloid leukemia?

BACKGROUND: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with "reduced frequency" molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482-88. © 2017 American Cancer Society.

Predicting early blast transformation in chronic-phase chronic myeloid leukemia: is immunophenotyping the missing link?

BACKGROUND: Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic-phase chronic myeloid leukemia (CP-CML) is unknown. We hypothesized that finding aberrant cells with FC in CP-CML may predict early blast-phase (BP) transformation. METHODS: Results for FC performed at the time of diagnosis for adult and pediatric patients with CP-CML who were referred to our institution were reviewed, and they were correlated with outcomes. RESULTS: FC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP-CML. Aberrant populations, representing a median of 2% (range, 0.3%-15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first-line treatment. With a median follow-up of 43 months (range, 2-113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4-72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31). CONCLUSIONS: In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP-CML appears to be associated with early progression to lymphoid BP.

Incidence and geographic distribution of adult acute leukemia in the state of Georgia.

OBJECTIVE: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta. METHODS: Cases reported to the Georgia Comprehensive Cancer Registry and the national Surveillance Epidemiology and End Results cancer registry between 1999 and 2008 were analyzed. Age-adjusted incidence rates were calculated for all of the counties and public health regions and were compared with national rates calculated using Surveillance Epidemiology and End Results 17 data. Cases of adult acute myeloid leukemia served as controls. RESULTS: Age-adjusted incidence rates of adult ALL (0.8/100,000) and acute myeloid leukemia (4.6/100,000) were comparable to the national rates (0.9 and 5.2, respectively). The age-adjusted incidence rate of ALL in northern Georgia was 1.1 (95% confidence interval 0.8-1.5) and was not affected by race. CONCLUSIONS: The observed increase in cases of ALL at our tertiary center results from a referral pattern rather than heterogeneous distribution of adult ALL across Georgia.

Riociguat in patients with sickle cell disease and hypertension or proteinuria (STERIO-SCD): a randomised, double-blind, placebo controlled, phase 1-2 trial.

BACKGROUND: Although nitric oxide based therapeutics have been shown in preclinical models to reduce vaso-occlusive events and improve cardiovascular function, a clinical trial of a phosphodiesterase 5 inhibitor increased rates of admission to hospital for pain. We aimed to examine if riociguat, a direct stimulator of the nitric oxide receptor soluble guanylate cyclase, causes similar increases in vaso-occlusive events. METHODS: This was a phase 1-2, randomised, double blind, placebo-controlled trial. Eligible patients were 18 years or older, had confirmed sickle cell disease documented by haemoglobin electrophoresis or HPLC fractionation (haemoglobin SS, SC, Sß-thalassemia, SD, or SO-Arab), and stage 1 hypertension or proteinuria. Participants were randomly assigned 1:1 to receive either riociguat or matching placebo via a web-based system to maintain allocation concealment. Both treatments were administered orally starting at 1·0 mg three times a day up to 2·5 mg three times a day (highest tolerated dose) for 12 weeks. Dose escalation by 0·5 mg was considered every 2 weeks if systolic blood pressure was greater than 95 mm Hg and the participant had no signs of hypotension; otherwise, the last dose was maintained. The primary outcome was the proportion of participants who had at least one adjudicated treatment-emergent serious adverse event. The analysis was performed by the intention-to-treat. This trial is registered with ClinicalTrials.gov (NCT02633397) and was completed. FINDINGS: Between April 11, 2017, and Dec 31, 2021, 165 participants were screened and consented to be enrolled into the study. Of these, 130 participants were randomly assigned to either riociguat (n=66) or placebo (n=64). The proportion of participants with at least one treatment-emergent serious adverse event was 22·7% (n=15) in the riociguat group and 31·3% (n=20) in the placebo group (difference -8·5% [90% CI -21·4 to 4·5]; p=0·19). A similar pattern emerged in other key safety outcomes, sickle cell related vaso-occlusive events (16·7 [n=11] vs 21·9% [n=14]; difference -5·2% [-17·2 to 6·5]; p=0·42), mean pain severity (3·18 vs 3·32; adjusted mean difference -0·14 [-0·70 to 0·42]; p=0·69), and pain interference (3·15 vs 3·12; 0·04 [-0·62 to 0·69]; p=0·93) at 12 weeks were similar between groups. Regarding the key clinical efficacy endpoints, participants taking riociguat had a blood pressure of -8·20 mm Hg (-10·48 to -5·91) compared with -1·24 (-3·58 to 1·10) in those taking placebo (-6·96 mm Hg (90% CI -10·22 to -3·69; p<0·001). INTERPRETATION: Riociguat was safe and had a significant haemodynamic effect on systemic blood pressure. The results of this study provide measures of effect and variability that will inform power calculations for future trials. FUNDING: Bayer Pharmaceuticals.

Epsilon aminocaproic acid prevents bleeding in severely thrombocytopenic patients with hematological malignancies.

BACKGROUND: Despite prophylactic platelet transfusions, bleeding remains a significant problem in thrombocytopenic patients. METHODS: The antifibrinolytic agent epsilon aminocaproic acid (EACA) was administered to 44 chronically (median duration, 273 days) and severely (platelet count, 8 × 10(9)/L; range, 1 × 10(9)/L-19 × 10(9)/L) thrombocytopenic patients with hematological malignancies. Prophylactic EACA at a dose of 1 g twice daily was orally administered for a median duration of 47 days (range, 7 days-209 days) until the platelet count recovered to > 30; × 10(9) /L. Platelets were only transfused if bleeding occurred. RESULTS: While receiving EACA, 59% of the patients did not bleed, 25% had 19 episodes of spontaneously resolving minor bleeding that did not require platelet transfusion, and 16% received a median of 4 platelet transfusions (range, 1 transfusion-8 transfusions) for 1 major traumatic and 9 spontaneous grade 2 to grade 3 bleeding (based on the World Health Organization classification of idiopathic thrombocytopenic purpura). No EACA toxicities were noted, and venous thromboses were not observed. CONCLUSIONS: EACA is well tolerated and is associated with a low risk of major bleeding in patients with hematological malignancies who are experiencing chronic severe thrombocytopenia.

Presentations and outcomes among sickle cell disease patients with COVID-19 at a large southern healthcare system.

OBJECTIVES: Compared with the general population, patients with sickle cell disease (SCD) typically have substantially reduced life expectancies. It is unclear whether SCD patients who acquire COVID-19 have higher rates of complications and mortality than the general population. We sought to elucidate COVID-19 presentation and outcomes in patients with SCD. METHODS: Using retrospective chart review, we evaluated demographic characteristics, presenting symptoms, chest imaging findings, blood transfusion requirements, need for mechanical ventilation or pressor support, medication administration (including remdesivir and dexamethasone), and survival among individuals with SCD hospitalized with COVID-19 from March 2020 to December 2021. RESULTS: Among 72 SCD patients, increased pain was the most common presenting symptom followed by cough, fever, and dyspnea. Thirty-seven (44%) received simple transfusion and 14 (17%) underwent exchange transfusion. Lung imaging findings suggestive of COVID-19 were observed in 27 (37%) patients; 21 (29%) patients were treated with remdesivir and 26 (35%) received dexamethasone. Three patients (4%) required mechanical ventilation and pressor support; all three died from COVID complications. CONCLUSIONS: Pain is the most common presenting symptom in SCD patients with COVID-19. We observed a mortality rate higher than that among the general population among patients who required mechanical ventilation and pressor support.

Sickle Cell Disease and Kidney.

Sickle cell disease causes several kidney manifestations. They include defects in urine concentration, impaired handling of potassium and hydrogen ion, albuminuria, acute kidney injury, and chronic kidney disease to name a few. Glomerular hyperfiltration, tubular hyperfunctioning, endothelial damage from repeated sickling and vaso-occlusive episodes, and iron-induced proinflammatory changes in the glomerular mesangium and tubulointerstitium are some of the mechanisms of kidney damage. Albuminuria is one of the most and common clinical features of kidney disease and progresses with age. Kidney disease in patients with sickle cell is associated with increased mortality. Annual screening for proteinuria starting at age 10 years and limiting the use of nonsteroidal anti-inflammatory agents and the use of angiotensin-converting enzyme inhibitors may help in early detection and delaying the progression of kidney disease. Adequate hydration, angiotensin-converting enzyme inhibitors, and adequate control of sickle cell are the main stay of treatment for albuminuria. The hemoglobin goal for patients with sickle cell nephropathy is lesser (10 g/dL) than that for patients with chronic kidney disease due to other causes given that a higher hemoglobin level increases viscosity and the risk of precipitating vaso-occlusive episodes. A multidisciplinary approach is recommended for managing patients with sickle cell and kidney diseases.

Catastrophic Neurological Complications in 2 Patients With Sickle Cell Disease and COVID-19.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is commonly associated with neurological complications. Patients with sickle cell disease are at increased risk of developing neurologic complications throughout their lifetimes and often have underlying cardiopulmonary comorbidities that may predispose them to poor outcomes during serious infections. In this case series, we describe 2 patients with sickle cell disease who developed devastating neurologic complications following SARS-CoV-2 infection, which ultimately led to brain edema and death. We highlight the unusual manifestations of coronavirus disease 2019 in patients with sickle cell disease and address the risk of these patients to develop catastrophic neurologic injury due to COVID-19, if not recognized promptly.

Sickle Cell Transplantation Evaluation of Long-term and Late Effects Registry (STELLAR) to Compare Long-term Outcomes After Hematopoietic Cell Transplantation to Those in Siblings Without Sickle Cell Disease and in Nontransplanted Individuals With Sickle Cell Disease: Design and Feasibility Study.

BACKGROUND: There are sparse data on the long-term and late effects of hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). OBJECTIVE: This study aims to establish an international registry of long-term outcomes post-HCT for SCD and demonstrate the feasibility of recruitment at a single site in the United States. METHODS: The Sickle Cell Transplantation Evaluation of Long-Term and Late Effects Registry (STELLAR) was designed to enroll patients with SCD ≥1 year post-HCT, their siblings without SCD, and nontransplanted controls with SCD to collect web-based participant self-reports of health status and practices by using the Bone Marrow Transplant Survivor Study (BMTSS) surveys, health-related quality of life (HRQOL) using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Profile-25 or Pediatric Profile-29 survey, chronic graft-versus-host disease (cGVHD) using the symptom scale survey, daily pain using an electronic pain diary, the economic impact of HCT using the financial hardship survey, sexual function using the PROMIS Sexual Function SexFSv2.0 survey, and economic productivity using the American Time Use Survey (ATUS). We also piloted retrieval of clinical data previously submitted to the Center for International Blood and Marrow Transplant Research (CIBMTR); recorded demographics, height, weight, blood pressure, waist and hip circumferences, timed up and go (TUG) test, and handgrip test; and obtained blood for metabolic screening, gonadal function, fertility potential, and biorepository of plasma, serum, RNA, and DNA. RESULTS: Of 100 eligible post-HCT patients, we enrolled 72 (72%) participants aged 9-38 (median 17) years. We also enrolled 19 siblings aged 5-32 (median 10) years and 28 nontransplanted controls with SCD aged 4-46 (median 22) years. Of the total 119 participants, 73 (61%) completed 85 sets of surveys and 41 (35%) contributed samples to the biorepository. We completed ATUS interviews of 28 (24%) participants. We successfully piloted retrieval of data submitted to the CIBMTR and expanded recruitment to multiple sites in the United States, Canada, the United Kingdom, and Nigeria. CONCLUSIONS: It is feasible to recruit subjects and conduct study procedures for STELLAR in order to determine the long-term and late effects of HCT for SCD. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/36780.

Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors.

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4-190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1-53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

Myocardial infarction in a 28-year-old thalassemia intermedia patient.

A 28-year-old Lebanese thalassemia intermedia (TI) patient with homozygous IVS1-110 mutation sustained atypical chest pain of 1 day's duration. The EKG reading revealed ST segment elevation in the chest leads V(1) to V(5). Coronary angiography showed 2 plaques in the left anterior descending coronary artery. He underwent subsequent angioplasty with stenting of the left anterior descending coronary artery. An extensive thrombophilia profile was negative. He was started on medication, and his medical condition improved and chest pain ceased. This is the first case report of myocardial infarction in a TI patient among thalassemics. We propose that such cases will emerge more frequently as our population ages, keeping in mind a possible thrombotic mechanism.

Relation between iron-overload indices, cardiac echo-Doppler, and biochemical markers in thalassemia intermedia.

Cardiovascular impairment is a major cause of morbidity and mortality in patients with thalassemia intermedia. In this study, echocardiographic assessment of left heart condition was performed in patients with thalassemia intermedia, and its relation to hematologic variables--amino terminal pro-brain natriuretic peptide (NT-proBNP), ferritin, hemoglobin--and liver iron concentration (LIC) was investigated. Echocardiographic assessment was performed using pulse-wave Doppler and tissue Doppler imaging. Data from 74 patients with thalassemia intermedia--35 men, 39 women, mean age 26.5 years (8 to 63)--were randomly selected and evaluated. Blood samples were collected for NT-proBNP levels in a random subgroup of 19 patients. Mean baseline values were hemoglobin 8.4 g/dl (4.9 to 13.1), serum ferritin 902.6 ng/ml (15 to 4,140), LIC 9.0 mg Fe/g (0.5 to 32.1), and NT-proBNP 113.5 pg/ml (16.4 to 371). Correlation between LIC and pulmonary artery systolic pressure was significant, suggesting that iron loading in the liver is indicative of cardiovascular sequelae. NT-proBNP was significantly correlated with the ratio of the left ventricular early rapid filling wave to early diastolic velocity at the mitral annulus (r = 0.50, p = 0.04) and hemoglobin (r = -0.49, p = 0.03), but not with other characteristics assessed. In conclusion, this study has highlighted the importance of using tissue Doppler imaging rather than pulse-wave Doppler to characterize left ventricular diastolic dysfunction in patients with thalassemia intermedia. Demonstration of the correlation of LIC and pulmonary artery systolic pressure independent of left ventricular filling pressures supports our hypothesis that left ventricular diastolic dysfunction does not contribute to the increased pulmonary artery systolic pressure in patients with thalassemia intermedia.

Thrombosis of the corpora cavernosa complicating lenalidomide therapy of myelofibrosis.

Venous thrombosis is a well-recognized complication of lenalidomide therapy in patients with multiple myeloma, but its occurrence during the treatment of other hematologic malignancies is less well described. In this report, we detail the occurrence of corpora cavernosa thrombosis in a patient receiving lenalidomide for the therapy of myelofibrosis. This case highlights the need for clinical vigilance in patients who present with unusual symptoms during investigational therapy, and indicates that the occurrence of venous thrombosis complicating therapy with lenalidomide or related compounds is not isolated to patients with multiple myeloma.