Margaret T. Lee

Kasabach-Merritt phenomenon : a retrospective study of treatment with vincristine

Purpose Kasabach-Merritt phenomenon (KMP) is characterized by profound thrombocytopenia, microangiopathic hemolytic anemia, a consumptive coagulopathy, and an enlarging vascular lesion. The syndrome develops in infancy and is associated with a high morbidity and mortality rate. The purpose of this study was to assess the effectiveness of vincristine in the treatment of KMP. Methods We retrospectively reviewed the clinical and laboratory data of 15 patients with KMP treated with vincristine at 9 institutions across the United States, South America, and Europe. Results All 15 patients had profound thrombocytopenia and consumption of fibrinogen at presentation. Ten patients had biopsies of their lesions, and results included five (33.3%) kaposiform hemangioendotheliomas, three (20%) tufted angiomas, one lesion (6.7%) with features of both kaposiform hemangioendothelioma and tufted angioma, and one (6.7%) unclassified vascular tumor. All 15 patients had an increase in platelet count of at least 20,000 with an average response time of 4.0 weeks after initiation of vincristine therapy. Thirteen patients had an increase in fibrinogen level of 50 mg/dL with an average response time of 3.4 weeks. In 13 patients there was a significant decrease in the size of the vascular lesion. The average duration of treatment was 21.5 (±12.6) weeks. Four patients (26%) relapsed. All four were successfully treated with a second course of vincristine. Complications included one patient with abdominal pain, one patient with transient loss of deep tendon reflexes, and one patient with irritability. Conclusion Vincristine presents a safe and sometimes effective treatment option in the management of KMP.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia - TCD with Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial

Background For children with sickle cell anaemia and elevated transcranial Doppler (TCD) flow velocities, regular blood transfusions effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxyurea in this setting is unknown. Methods TWiTCH was a multicentre Phase III randomised open label, non-inferiority trial comparing standard treatment (transfusions) to alternative treatment (hydroxyurea) in children with abnormal TCD velocities but no severe vasculopathy. Iron overload was managed with chelation (Standard Arm) and serial phlebotomy (Alternative Arm). The primary study endpoint was the 24-month TCD velocity calculated from a general linear mixed model, with non-inferiority margin = 15 cm/sec. Findings Among 121 randomised participants (61 transfusions, 60 hydroxyurea), children on transfusions maintained <30% sickle haemoglobin, while those taking hydroxyurea (mean 27 mg/kg/day) averaged 25% fetal haemoglobin. The first scheduled interim analysis demonstrated non-inferiority, and the sponsor terminated the study. Final model-based TCD velocities (mean ± standard error) on Standard versus Alternative Arm were 143 ± 1.6 and 138 ± 1.6 cm/sec, respectively, with difference (95% CI) = 4.54 (0.10, 8.98), non-inferiority p=8.82 × 10−16 and post-hoc superiority p=0.023. Among 29 new neurological events adjudicated centrally by masked reviewers, no strokes occurred but there were 3 transient ischaemic attacks per arm. Exit brain MRI/MRA revealed no new cerebral infarcts in either arm, but worse vasculopathy in one participant (Standard Arm). Iron burden decreased more in the Alternative Arm, with ferritin difference −1047 ng/mL (−1524, −570), p<0.001 and liver iron difference −4.3 mg Fe/gm dry weight (−6.1, −2.5), p=0.001. Interpretation For high-risk children with sickle cell anaemia and abnormal TCD velocities, after four years of transfusions and without severe MRA vasculopathy, hydroxyurea therapy can substitute for chronic transfusions to maintain TCD velocities and help prevent primary stroke.BACKGROUND For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participants maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING National Heart, Lung, and Blood Institute, National Institutes of Health.

Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury

Chronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% +/- 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% +/- 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% +/- 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% +/- 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

Cobalamin C disease presenting as hemolytic-uremic syndrome in the neonatal period.

Anew case of cobalamin C disease associated with hemolytic-uremic syndrome (HUS) in the neonatal period is described. A 28-day-old boy presented with failure to thrive, hypotonia, pancytopenia, and features of HUS (microangiopathic hemolytic anemia, thrombocytopenia, and renal failure). The possibility of the diagnosis of an underlying vitamin B12 disorder was prompted by evidence of megaloblastic changes on the peripheral smear and by finding in the literature a suggested association of neonatal HUS with this cobalamin-related metabolic disorder. Amino acid analysis showed elevated homocysteine levels in the plasma and increased levels of both homocysteine and methyl malonic acid in the urine. Diagnosis of cobalamin C disease was confirmed by complementation studies using skin fibroblasts. Therapy included parenteral hydroxocobalamin, carnitine, and leucovorin calcium (folinic acid). Cobalamin C disease should be considered in the diagnosis of patients presenting with HUS in infancy who have unexplained megaloblastosis, pancytopenia, neurologic impairment, and failure to thrive. Early diagnosis and institution of therapy may be effective in improving survival and quality of life.

Doppler-defined pulmonary hypertension and the risk of death in children with sickle cell disease followed for a mean of three years

Pulmonary hypertension (PH) is associated with increased mortality in adults with sickle cell disease (SCD), but its prognostic significance in children is unknown. Eighty‐eight children with SCD were followed after echocardiographic screening for PH. After a mean follow‐up of 3 years, all 18 subjects with PH were alive. In our children, as in adults with SCD, PH was associated with increased haemolysis. In contrast, our subjects with PH did not have overt systemic disease observed in adults. PH may be a manifestation of progressive organ damage from chronic haemolysis and systemic vasculopathy that ultimately leads to early death in adulthood.

Chronic transfusion practice for children with sickle cell anaemia and stroke

Chronic transfusions to maintain haemoglobin S (HbS) ≤30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre‐transfusion %HbS was 35 ± 11% (institutional range 22–51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the ≤30% goal.

Medical management of tumors associated with Kasabach-Merritt phenomenon: an expert survey.

Kasabach-Merritt phenomenon (KMP) is a rare consumptive coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia occurring in association with the vascular tumors kaposiform hemangioendothelioma (KHE) and tufted angioma (TA). Treatment remains challenging without consensus on the optimal medical management. The authors compiled expert opinions regarding management to establish treatment recommendations. Twenty-seven vascular anomalies centers in the United States and Canada were surveyed using 2 representative cases of KHE/TA with and without KMP. Overall response rate was 92% (25/27) with 88% completion (24/27). Most sites (23/25; 92%) do not have a standard of practice for management. The most frequent initial therapy for KHE+KMP was a combination of systemic corticosteroids and vincristine (VCR) (12/24 centers; 50%) followed by corticosteroids alone (29%). Second-line treatments were VCR (38%), rapamycin (21%), and propranolol (21%). Management of KHE/TA without KMP was variable; initial treatments included systemic corticosteroids (8/24; 33%) alone or with VCR (9/24; 38%), monitoring without medication (33%), VCR (8%), propranolol (8%), aspirin (4%), and rapamycin (4%). This survey highlights certain trends in the management of KMP-associated tumors, without standard protocols and consensus.

Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities

Chronic transfusions are recommended for children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities ( 200 cm/sec) to help prevent the occurrence of a primary stroke [1]. The goal is usually to maintain the sickle hemoglobin concentration (HbS) <30%; however, this goal is often difficult to achieve in clinical practice. The NHLBI-sponsored trial ‘‘TCD With Transfusions Changing to Hydroxyurea (TWiTCH)’’ will compare standard therapy (transfusions) to alternative therapy (hydroxyurea) for the reduction of primary stroke risk in this patient population. Transfusions will be given according to current transfusion practices at participating sites. To determine current academic community standards for primary stroke prophylaxis in children with SCA, 32 clinical sites collected data on 340 children with abnormal TCD velocities receiving chronic transfusions to help prevent primary stroke. The average (mean ± 1 SD) pretransfusion HbS was 34 ± 11% (institutional average 23–48%); the 75th and 90th percentiles were 41 and 50%, respectively. Lower %HbS was associated with higher pretransfusion Hb values and receiving transfusions on time. These data indicate variable current transfusion practices among academic pediatric institutions and in practice, 30% HbS may not be an easily attainable goal in this cohort of children with SCA and abnormal TCD. Children with sickle cell anemia (SCA) compose a high risk group for the development of stroke. If untreated, 11% will experience a clinical stroke by 20 years of age [2]. Adams et al. have shown that children with SCA who are at risk for primary stroke can be identified by measuring time-averaged mean blood flow velocities in the internal carotid or middle cerebral arteries by TCD [3]. Abnormal TCD velocities ( 200 cm/sec) are associated with high risk for stroke and warrant transfusion therapy to reduce the risk of primary stroke. First stroke can be successfully prevented in 90% of children with SCA and abnormal TCD velocities by the use of chronic transfusion therapy, with a goal of keeping HbS concentrations less than 30% [1]. TCD with Transfusions Changing to Hydroxyurea (TWiTCH) is an NHLBIsponsored, Phase III, multicenter trial comparing standard therapy (monthly transfusions) to alternative therapy (daily hydroxyurea) to reduce the risk of primary stroke in children with SCA and documented abnormal TCD velocities. Since transfusions compose the standard treatment arm, accurate %HbS values achieved in actual clinical practice were needed for protocol development. The majority of our information about transfusing patients with SCA to prevent stroke comes from secondary stroke prevention, i.e., the use of chronic red blood cell transfusions to prevent a second stroke after a first clinical stroke has occurred. Classically, transfusions are administered at 4-week intervals to maintain HbS at less than 30%. After several years of transfusion therapy, a few centers increase transfusion interval to 5–6 weeks and allow HbS to increase toward 50% in selected patients [4,5]. Our previous study in 295 children with SCA who received transfusions for secondary stroke prevention revealed an average pretransfusion HbS of 35 ± 11% with highly variable institutional %HbS levels ranging from 22 to 51% [6] In order to determine the current clinical standard of transfusion therapy for primary stroke prevention for elevated TCD velocities, we performed a larger survey of potential TWiTCH sites. We hypothesized that average pretransfusion HbS values achieved at pediatric academic centers would be higher than 30%. This study defines the current practice at academic medical centers in provision of chronic transfusion therapy to help reduce the risk of primary stroke in children with SCA. A total of 340 children with SCA and history of abnormal TCD velocities receiving chronic PRBC transfusions for primary stroke prophylaxis were identified at 32 institutions (Table I). The number of patients per site ranged from 3 to 33 (median 9 per site). A total of 3,970 transfusions were administered over the 12-month period, with a mean of 11.7 ± 2.8 transfusions per patient. Results were similar when analyzed by each patient contributing equally or each transfusion contributing equally (Table II). The predominant transfusion type by patient was defined as the technique used 6 times over the 12-month period. Most children (79%) received primarily simple transfusions, while 19% had primarily exchange transfusions (11% partial / manual exchange, 8% erythrocytapheresis), and 2% multiple transfusion types. The transfusion goal was <30% at almost all sites (84%), while at five sites, the %HbS was allowed in selected patients to increase to 50% after a period of clinical stability. The majority (95%) of the transfusions were administered within the defined 7-day window. On average, late transfusions were given 1.3 ± 5.5 days after the defined 7-day window. Thirty percent of the patients had at least one late transfusion and 14% had 2 or more late transfusions in the 1-year period. For the 3,653 transfusions with reported %HbS values (representing 92% of the 3,970 transfusions), the mean pretransfusion HbS percentage was 33.2 ± 14.0% (median 32%). The 75th percentile for HbS values was 41%, while the 90th percentile was 51%. There were substantial differences among institutional pretransfusion %HbS values, ranging from 23 ± 14% HbS at one institution where HbS was reported for 103 transfusions given to nine patients during the 12-month period, to 48 ± 15% at another institution where HbS was reported for 95 transfusions administered to nine patients during the same time frame (Table III). The five sites with increased HbS goals to 50% in selected patients did not have higher values than others. For each transfusion, subjects were less likely to have pretransfusion HbS <30% if they were older [OR 0.92 for each year increase in age, 95% CI (0.89, 0.96)] and on transfusions for a longer period of time [OR 0.90 for each year increase in duration, 95% CI (0.86, 0.94)]. Patients with higher pretransfusion Hb levels were more likely to have pretransfusion HbS <30% [OR 1.63 for each g/dL increase in Hb, 95% CI (1.46, 1.83)] and late transfusions were less likely to be associated with a pretransfusion HbS <30% [OR 0.27, 95% CI (0.18, 0.41)]. The Hb result does not appear to be a function of late transfusions since both covariates remained significant when modeled jointly. History of alloor autoantibodies, TCD velocity, and erythrocytapheresis use were not significant predictors of a pretransfusion HbS <30%. During the initial STOP study, transfusions were given to maintain pretransfusion HbS values at less than 30% [3]. However, there were frequent transient rises of HbS above this level [7]. Furthermore, extended follow-up results from the STOP study showed that pretransfusion %HbS values during the post-trial follow-up were higher than those during the STOP study [8]. The average %HbS per patient was 27.5 ± 12.4, still within the desired goal of 30%. However, pretransfusion HbS levels were 30–34.9% in 12%, 35–39.9% in 7%, and greater than 40% in 12% of the transfusions. In the STOP2 study, where children with abnormal TCD velocities whose Doppler readings became normal were randomly assigned to continue or stop transfusions, 24% of the patients had pretransfusion HbS levels greater than 30% [9]. These findings indicate that even in the context of a prospective clinical trial, maintaining HbS <30% was difficult to achieve. With the subsequent recommendation to treat all children with SCA who are at risk for primary stroke with transfusions to maintain HbS <30%, the feasibility of this approach in actual clinical practice is not known. Possible Letters

Organ iron accumulation in chronically transfused children with sickle cell anaemia: baseline results from the TWiTCH trial

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open‐label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r2 = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin‐creatinine ratios. Extra‐hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Effects of hydroxyurea treatment for patients with hemoglobin SC disease

Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/β0‐thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso‐occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence‐based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States. To date, only 5 publications have reported short‐term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso‐occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo‐controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease. Am. J. Hematol. 91:238–242, 2016.