Hematopoietic stem cell transplantation after reduced-intensity conditioning as treatment of sickle cell disease

OBJECTIVE: Sickle cell disease generates considerable morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (SCT) has the potential of curing the disease and halting end-organ damage. However, in older patients this treatment is associated with a significant risk of toxicity and death. SCT after reduced-intensity conditioning (RIC) might be a safer approach for the treatment of sickle cell disease. MATERIALS AND METHODS: A 22-year-old male had experienced multiple, life-threatening hemolytic crises. We treated him with G-CSF-mobilized stem cells from his heterozygote, human leukocyte antigen-matched brother after RIC with fludarabine and cyclophosphamide. GVHD prophylaxis consisted of cyclosporine (CyA) and mycophenolate mofetil (MMF). Chimerism of peripheral blood mononuclear cells was evaluated using short tandem repeat analysis and hemoglobin analysis was performed by high-performance liquid chromatography. RESULTS: There were no major treatment-related toxicities. At day +30 after transplantation the patient had mixed hematopoietic chimerism, which later converted to full chimerism. Hemoglobin analysis revealed 3.4% HbA(2), 1.0% HbF, and 41.2% HbS, which essentially is the same hemoglobin partition as in his brother's blood. MMF was discontinued on day +35 and CyA on day +120. After discontinuation of CyA the patient developed mild chronic GVHD, which resolved with continued CyA, low-dose steroids, and the retinoid isotretinoin. He is doing well on day +315 without evidence of GVHD. CONCLUSIONS: Allogeneic SCT after RIC is feasible in adult patients with sickle cell disease. Mixed chimerism is sufficient to relieve disease-related symptoms and is possibly correlated with less acute GVHD.     

Fludarabine-based conditioning for allogeneic transplantation in adults with sickle cell disease

Although allogeneic transplantation can be curative for patients with sickle cell disease, the toxicity of conditioning regimens has precluded its use in adults with significant end-organ damage. Newer conditioning regimens have been developed that are less toxic and that may broaden the applicability of allogeneic transplantation in this disorder. We report two adults with end-stage sickle cell disease, who underwent allogeneic transplantation from an HLA-identical sibling donor after conditioning with fludarabine/melphalan and ATG. Both patients had been extensively transfused and one had multiple RBC antibodies. One of the patients also had end-stage renal disease, and was dialysis dependent. Engraftment occurred promptly in both patients. Both achieved 100% donor chimerism and both were free of pain crises after transplant. The first patient died of a respiratory failure related to chronic graft-versus-host disease (GVHD) on day 335 after transplantation. The second patient developed severe gastro-intestinal GVHD and TTP and died on day 147 after transplantation. Conditioning with fludarabine/melphalan and ATG followed by allogeneic stem cell transplantation resulted in prompt and reliable engraftment in adults with end-stage sickle cell disease. The incidence of severe GVHD was unacceptably high and may be related to the ethnicity of the patients or to the inflammatory state associated with pre-existing sickle cell disease.     

Stem-cell transplantation in children and adults with sickle cell disease: an update

Sickle cell disease (SCD) is associated with significant morbidity, a decreased lifespan and a poor quality of life. While there is increasing evidence that hydroxyurea can improve the course of severe SCD, hematopoeitic stem-cell transplantation (HSCT) remains the only curative option for SCD. Multicenter trials have shown that HSCT after myeloablative conditioning has excellent outcomes in children with SCD, with an overall survival ranging from 93 to 97% and an event-free survival between 82 and 86%. With better understanding of the course of SCD in adulthood, there has been increasing interest in making HSCT a viable intervention in adults. Nonetheless, older patients with severe disease have not been considered suitable candidates because of the higher risks associated with myeloablative conditioning. Recently, reduced-intensity regimens have been used in adults with good results, albeit in a small number of patients. The main limitation of HSCT in both adults and children with SCD remains the lack of availability of fully matched HLA sibling donors for patients meeting transplant criteria.     

Treatment of pain in adults with sickle cell disease

The treatment of an adult patient with sickle cell disease whose clinical course is characterized by frequent painful crises creates a number of logistic problems in a tertiary care city hospital. Because such patients usually have no objective signs of painful crises, they are often considered to be malingerers and drug abusers. This paper reviews this controversial issue and presents one attempt at its resolution.     

Bone mass density in adults with sickle cell disease

Sickle cell disease (SCD) leads to many complications including osteoporosis and osteopenia. We studied the prevalence and predisposing factors of low bone mass density (BMD) in adults with SCD. In this retrospective study, dual X-ray absorptiometry bone scans were used to determine BMD in the lumbar spine, femoral neck and ultra distal radius of 103 patients (73 females, 30 males, aged 15-80 years). Chart reviews and a patient questionnaire were used to collect patient characteristics, disease course and severity, and low BMD risk factors. The 79.6% of patients (mean age 36.5 +/- 12.5 years) had an abnormal BMD, with a predilection for the lumbar spine (P = 0.001). Analysis by 3 (low BMD versus very low BMD versus normal) or by 2 groups (abnormal versus normal) showed that abnormal BMD was associated with lower body mass index (BMI) (P = 0.003), lower Hb level (P = 0.001) and higher ferritin (P = 0.003). Low BMD patients were more likely to be SS, SC or Sbeta(0)thal than Sbeta(+)thal (P = 0.022). Abnormal BMD was not related to age, sex, menarche, SCD complications, number of crises, iron overload, treatment with hydroxycarbamide or desferal, renal disease, smoking or alcohol. Patients treated with hydroxycarbamide for at least 6 months were more likely to have an abnormal BMD. In this SCD population, abnormal BMD seemed to be independent of sex, age and menopause, whereas BMI, ferritin level, Hb type and level appeared to play a major role.     

Acute chest syndrome in adults with sickle cell disease

STUDY OBJECTIVES: Acute chest syndrome (ACS) is a frequent and potentially severe pulmonary illness in sickle cell disease (SCD). The aim of the study was to report the clinical features and outcome of consecutive ACS episodes in adult patients in a French SCD center. All patients were treated according to an uniform therapeutic protocol applying transfusion only in the more severe clinical form of ACS. RESULTS: There were 107 consecutive episodes in 77 adult patients (mean age, 29 +/- 7 years; 78% hemoglobin [Hb] SS; 14% Hb SC; and 8% Hb Sbeta + thalassemia) over a 6-year period. Seventy-eight percent of our patients had an associated vaso-occlusive crisis that preceded the chest signs in half of the cases. Comparison between acute and baseline levels showed a statistically significant difference in Hb levels (drop of 1.6 to 2. 25 g/dL depending on Hb genotype), WBC count (increase of 9.2 +/- 8. 3 x 10(9)/L); platelet count (increase of 67 +/- 209 x 10(9)/L); and lactate dehydrogenase values (increase of 358 +/- 775 IU/L) in ACS patients. Hypercapnia was detected in 42% of patients without sign of narcotic abuse. We identified a high percentage of alveolar macrophages containing fat droplets in 31 of 43 (77%) patients who underwent BAL. Bacterial culture findings were almost always negative, but were performed after starting antibiotic therapy that was administered in 96 episodes. Transfusion was required in 50 of 107 ACS events (47%). Five patients died, and all were transfused. CONCLUSIONS: These results confirm that fat embolism is probably a frequent mechanism of ACS in adult patients. However, fat embolism was not associated with a more severe clinical course, suggesting that bronchoscopy and BAL have little impact on the management of these patients. Restricting transfusion to the most severe ACS cases does not seem to increase the mortality rate.     

Cerebral oxygen metabolism in adults with sickle cell disease

In sickle cell disease (SCD), oxygen delivery is impaired due to anemia, especially during times of increased metabolic demand, and cerebral blood flow (CBF) must increase to meet changing physiologic needs. But hyperemia limits cerebrovascular reserve (CVR) and ischemic risk prevails despite elevated CBF. The cerebral metabolic rate of oxygen (CMRO₂) directly reflects oxygen supply and consumption and may therefore be more insightful than flow-based CVR measures for ischemic risk in SCD. We hypothesized that adults with SCD have impaired CMRO₂ at rest and that a vasodilatory challenge with acetazolamide would improve CMRO₂. CMRO₂ was calculated from CBF and oxygen extraction fraction (OEF), measured with arterial spin labeling and T₂-prepared tissue relaxation with inversion recovery (T₂-TRIR) MRI. We studied 36 adults with SCD without a clinical history of overt stroke, and nine healthy controls. As expected, CBF was higher in patients with SCD versus controls (mean ± SD: 74 ± 16 versus 46 ± 5 mL/100 g/min, P < .001), resulting in similar oxygen delivery (SCD: 377 ± 67 versus controls: 368 ± 42 μmol O₂/100g/min, P = .69). OEF was lower in patients versus controls (27 ± 4 versus 35 ± 4%, P < .001), resulting in lower CMRO₂ in patients versus controls (102 ± 24 versus 127 ± 20 μmol O₂/100g/min, P = .002). After acetazolamide, CMRO₂ declined further in patients (P < .01) and did not decline significantly in controls (P = .78), indicating that forcing higher CBF worsened oxygen utilization in SCD patients. This lower CMRO₂ could reflect variation between healthy and unhealthy vascular beds in terms of dilatory capacity and resistance whereby dysfunctional vessels become more oxygen-deprived, hence increasing the risk of localized ischemia.     

Hematopoietic stem cell transplantation in sickle cell disease

Since the first report of a young girl affected by sickle cell anemia, treated successfully by bone marrow transplantation (BMT) for acute myeloid leukemia, more than 200 patients have been transplanted worldwide for sickle cell anemia. The disease-free survival (DFS) is good (80-85% in several series), even though many children who received allografts had already significant sickle-related complications. The best results are obtained in young children who have HLA-identical sibling donors and are transplanted early in the course of the disease (DFS: 93%). Future directions in the field of stem cell transplantation of sickle cell anemia include (1) the establishment of new protocols with less toxicity, but still effective, (2) adapted conditioning regimen for adult patients, and (3) new sources of stem cells for broader application: umbilical cord blood and volunteer unrelated donors.     

Clinical follow-up of hydroxyurea-treated adults with sickle cell disease

Hydroxyurea-derived clinical and biological benefits and safety were retrospectively studied for 123 adult patients from 2 sickle cell disease referral centers during a total follow-up of 654 patient-years and total hydroxyurea exposure of 549 patient-years. Fifty-six adverse events occurred (incidence: 12%/patient-year), with leg ulcers being the most frequent. Adverse events could arise at any time and were usually reversible. No malignancy was observed. Clinical and biological benefits of our cohort were similar to those previously reported. Based on this relatively long retrospective study, the risk/benefit ratio for moderate hydroxyurea doses was satisfactory.     

Cryptococcal pneumonia in a patient with sickle cell disease

We present the findings in a patient having sickle cell disease who developed multilobar pneumonia. Cultures of bronchial aspirates and histologic specimens grew Cryptococcus neoformans. There was neither spontaneous clearing of the infection nor a response to bactericidal antibiotics. The patient had no underlying malignant neoplasm or immunodeficiency as indicated by history, physical examination, and specialized tests of humoral and cell-mediated immunity.     

Rheumatoid arthritis in a patient with sickle cell disease

Sickle cell disease has various articular manifestations. Coexistent rheumatoid arthritis (RA) and sickle cell disease has been reported rarely. We present a patient with sickle cell disease and seropositive erosive RA demonstrating characteristic radiographic findings of the 2 entities.     

Successful reduced-intensity stem cell transplantation in a patient with myelodysplastic syndrome combined with Sweet's syndrome

A 53-year-old male with myelodysplastic syndrome developed Sweet's syndrome extensively over his left iliac and inguinal regions that was refractory to standard treatment with corticosteroids and chemotherapy, received a stem cell transplant from an HLA-matched unrelated donor, conditioned by reduced-intensity regimen. The patient achieved complete hematological remission, and the cutaneous lesions improved gradually and then disappeared completely despite the patient receiving granulocyte colony-stimulating factor after transplantation and developing acute graft-versus-host disease.     

Surgical and obstetric outcomes in adults with sickle cell disease

Background

Sickle cell disease patients are more likely than the general population to undergo surgery and usually do so at a younger age. Female sickle cell disease patients also have special gynecological and obstetric issues related to their disease.

Methods

We collected data through standardized clinical report forms, patient interviews, and medical records from 509 adult sickle cell disease patients. Logistic regression was used to estimate the association between multiple variables and each of the surgery types. We also determined the prevalence and outcomes of pregnancy in 284 women with sickle cell disease in this population.

Results

Almost 50% of patients aged 18-27 years had had a cholecystectomy. Mean corpuscular hemoglobin, total bilirubin, and lactate dehydrogenase were significantly higher in the postcholecystectomy group; 9.5% of 504 individuals had undergone splenectomy. Hematocrit, body mass index, and red blood cell count were significantly higher in the postsplenectomy group. Hip replacement had been performed in 9.2% of individuals, with the prevalence increasing as early as the fourth decade and continuing to increase through the sixth decade of life. A history of pregnancy was present in 190 women (67%). Of 410 pregnancies, only 53.9% resulted in live births, 16.6% were voluntarily terminated, and 29.5% were complicated by miscarriage, still birth, or ectopic implantation.

Conclusions

Sickle cell disease continues to have a strong effect on the mean age for common surgeries and impacts pregnancy outcomes. We conclude that this population has a unique surgical and obstetric history that should be further studied to provide insight into potentially more effective preventive approaches to end-organ damage.     

Acute splenic sequestration crises in adults with sickle cell disease

Reports of acute splenic sequestration crises in adults with sickle cell hemoglobin C disease or sickle cell thalassemia are rare, although an enlarged and distensible spleen persists in half of these patients. Seven episodes of acute splenic sequestration crises in four adults, two with sickle C disease and two with sickle thalassemia, are described. The crises were life-threatening and recurrent in all, but there were no fatalities. One patient had mild steady-state thrombocytopenia suggesting hypersplenism. Technetium 99m/sulfur colloid scanning of the spleen during the acute splenic sequestration crises in three patients showed almost total lack of splenic uptake or decreased uptake with intrasplenic filling defects thought to be splenic infarcts or hematomas on follow-up computed tomographic scanning. The scanning abnormalities resolved following recovery from the crises. Acute splenic sequestration crises probably are common in adults with sickle C disease and sickle thalassemia but may be underdiagnosed or misdiagnosed as splenic infarctions. The hematologic and splenic findings during acute splenic sequestration crises resemble those following splenic vein ligation in animals.     

Oscillatory haematopoiesis in adults with sickle cell disease treated with hydroxycarbamide

Hydroxycarbamide therapy has been associated with significant oscillations in peripheral blood counts from myeloid, lymphoid and erythroid lineages in patients with polycythaemia vera and chronic myeloid leukaemia. We retrospectively evaluated serial blood counts over an 8‐year period from 44 adult patients with sickle cell disease receiving hydroxycarbamide. Platelet counts, leucocyte counts, haemoglobin values and reticulocyte counts, apportioned by hydroxycarbamide status, were analysed using a Lomb‐Scargle periodogram algorithm. Significant periodicities were present in one or more counts in 38 patients receiving hydroxycarbamide for a mean duration of 4·81 years. Platelet and leucocyte counts oscillated in 56·8% and 52·3% of patients, respectively. These oscillations generally became detectable within days of initiating therapy. During hydroxycarbamide therapy, the predominant periods of oscillation were 27 ± 1 d for platelet counts and 15 ± 1 d for leucocyte counts. Despite an absolute decrease in leucocyte and platelet counts during hydroxycarbamide treatment, the amplitudes between nadirs and zeniths remained similar regardless of exposure. Our observations appear consistent with previously proposed models of cyclic haematopoiesis, and document that hydroxycarbamide‐induced oscillations in blood counts are innocuous phenomena not limited to myeloproliferative disorders as described previously. We speculate the known cell cycle inhibitory properties of hydroxycarbamide may accentuate otherwise latent constitutive oscillatory haematopoiesis.     

Current status of reduced-intensity stem cell transplantation; survey in the Kinki area

The status of reduced-intensity stem cell transplantation (RIST) in the Kinki area was investigated by questionnaires. We sent out questionnaires to 72 institutions and received 51 replies (72.2%). RIST was performed in 16 institutions (31.4%). A total of 91 cases were included of whom approximately 70% were non-remission or advanced hematological malignancies. Various conditioning regimens were used for RIST, most often consisting of fludarabine, busulfan and antithymocte globulin. Acute GVHD developed in 57% of all patients. Relapse or disease progression developed in 42.7% of evaluable patients. The overall survival rate was 54.6%, and 80% of low risk patients were alive at the time of analysis.