Pomalidomide augments fetal hemoglobin production without the myelosuppressive effects of hydroxyurea in transgenic sickle cell mice.

Pharmacologic induction of fetal hemoglobin (HbF) expression is an effective treatment strategy for sickle cell disease (SCD) and ß-thalassemia. Pomalidomide is a potent structural analog of thalidomide and member of a new class of immunomodulatory drugs. Recent reports demonstrated that pomalidomide reduced or eliminated transfusion requirements in certain hematologic malignancies and induced HbF ex vivo in CD34(+) progenitor cells from healthy and SCD donors. We investigated the effects of pomalidomide on erythropoiesis and hemoglobin synthesis in a transgenic mouse model of SCD. We found that 8 weeks of treatment with pomalidomide induced modest increases of HbF with similar efficacy as hydroxyurea. However, in stark contrast to hydroxyurea's myelosuppressive effects, pomalidomide augmented erythropoiesis and preserved bone marrow function. Surprisingly, combinatory therapy with both drugs failed to mitigate hydroxyurea's myelotoxic effects and caused loss of HbF induction. These findings support further evaluation of pomalidomide as a novel therapy for SCD.

The association between hydroxyurea treatment and pain intensity, analgesic use, and utilization in ambulatory sickle cell anemia patients.

BACKGROUND: We compared daily pain, home analgesic use, and utilization among ambulatory adults in the randomized multicenter study of hydroxyurea in sickle cell anemia (MSH). We related the fetal hemoglobin (HbF) hydroxyurea response to these response variables. METHODS: Patients rated their sickle cell pain intensity (0-9), use of analgesics, and visits for pain daily. Diaries were collected biweekly, and intensity was collapsed into single interval ratings. The interval proportions of days of analgesic use and medical visits for pain were also calculated. Group comparisons were made by intention to treat as well as by HbF change levels from baseline to 2 years of treatment (placebo and low, medium, high, or very high response). RESULTS: A total of 134 (44.8%) enrollees completed 2 years of follow-up. Pain intensity correlated with analgesic use (r = 0.83, P > 0.0001) and utilization (r = 0.50, P < 0.0001). Pain intensity was lower for patients on hydroxyurea (2.51 ± 0.062 vs 2.82 ± 0.063 placebo, F(1270) = 11.65, P = 0.0007). The difference, though small, appeared early and was sustained. Analgesic use and utilization were also slightly lower (analgesic use: F (1270) = 11.97, P = 0.0006; utilization: F(1270) = 32.0, P < 0.0001). Each was statistically significantly lower among hydroxyurea patients with higher HbF treatment responses to hydroxyurea. CONCLUSIONS: Hydroxyurea usage led to a small, statistically significant reduction in daily pain, analgesic use, and utilization in adults in MSH, corroborating previously shown larger reductions in crises and mortality. The degree of daily symptomatic reduction was related to the size of the HbF treatment response, further confirming HbF response as a useful laboratory correlate.

Transfusion and chelation practices in sickle cell disease: a regional perspective.

Although most common in tropical regions, population migration has meant that sickle cell disease is now one of the most prevalent genetic diseases worldwide. The issues and challenges faced by physicians and patients have been discussed by an international group of experts representing 4 key regions: the USA, Europe, Latin America, and the Middle East/Africa. Conclusive evidence to support the use of transfusion therapy for the prevention of stroke has resulted in key changes to patient management in all regions, and increasing numbers of patients are benefiting from this management approach. However, it is apparent that transfusion therapy is still under-utilized, largely due to concerns over iron overload, alloimmunization, limited blood supplies, and, sometimes, due to parental refusal. Once transfused, assessment and management of body iron levels can be poor, particularly in patients who are intermittently transfused. Compliance with chelation therapy regimens is a significant challenge, but new therapeutic options are likely to overcome some of the current barriers. Key requirements in all regions were considered to be the following: to provide greater physician, patient, and family education; to ensure effective transition from pediatric to adult care; and to establish national guidelines in order to ensure best practice is consistently applied.

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies.

Doppler-defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD-PH, two randomized, double-blind, placebo-controlled, 16-week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET-1 and -2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6-min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET-1 at baseline, 6MWD correlated with cardiac output (CO; P = 0.006) with non-significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0.07) and between 6MWD and right atrial pressure (P = 0.08). In ASSET-2 at baseline, there was a non-significant correlation between 6MWD and CO (P = 0.06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non-significant increases in CO were observed with bosentan compared to placebo. Similarly, non-significant decreases in PVR were observed with bosentan. Limited data in SCD-PH suggest that a low 6MWD predicts a low CO. Standard-dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.

Climatic and geographic temporal patterns of pain in the Multicenter Study of Hydroxyurea.

No multi-site comparisons have tested whether seasonally cold temperature or climate exacerbate pain intensity in sickle cell disease (SCD). We examined seasonal SCD pain intensity and frequency patterns and compared them with concurrent climate conditions (temperature and barometric pressure) and geography of patient residence in the Multicenter Study of Hydroxyurea (MSH). We conducted a time series analysis of the monthly average daily pain intensity (0-9 scale) and pain frequency of the 299 MSH patients from December 1991 to December 1994. We used both an unobserved component model (UCM) and a nonparametric local regression (LOESS) to probe for a cycle and/or trend associated with the time series. We also examined base mixed regression models of season, monthly average temperature and barometric pressure, and geographic region as stand-alone predictors of pain intensity and frequency. Expanded models included additional predictor variables. UCM and LOESS analyses showed a cyclic pattern of pain intensity and frequency with peaks in late Fall/early Winter and troughs in Spring. Base regression models showed colder seasons were significantly associated with greater pain intensity (p = .0035) but not frequency (p = .07); higher monthly temperatures were significantly associated with both lower pain intensity and pain frequency, but higher monthly barometric pressures were significantly associated with greater pain intensity and frequency (all p's < .0001); and northern sites had nonsignificantly higher pain intensity (p = .40) and frequency (p = .07) than southern sites. This pattern of results did not change in expanded models including other predictors. Our results suggest that seasonably colder temperatures exacerbate sickle cell-related pain, but low barometric pressure does not, and geographic region of residence is not significantly related to pain in this sample.

Red cell exchange in sickle cell disease.

Red cell exchange transfusions remain an effective but possibly underutilized therapy in the acute and chronic treatment of sickle cell disease. In sickle cell disease, increased blood viscosity can cause complications when the hemoglobin exceeds 10 g/dL even if this is due to simple transfusion. Red cell exchange can provide needed oxygen carrying capacity while reducing the overall viscosity of blood. Acute red cell exchange is useful in acute infarctive stroke, in acute chest and the multi-organ failure syndromes, the right upper quadrant syndrome, and possibly priapism. Neither simple or exchange transfusions are likely to hasten resolution of an acute pain episode.