Hepatitis B virus reactivation with clinical flare in allogeneic stem cell transplants with chronic graft-versus-host disease

We conducted a retrospective study with the aim of identifying risk factors and clinical characteristics associated with HBV reactivation and clinical flare after allogeneic stem cell transplantation (aSCT). We reviewed the King Faisal Specialist Hospital and Research Center International Bone Marrow Transplant Registry database from January 1998 to June 2000. Complete serological screening for HBV was available in 128 of 131 patients transplanted during that period. Fifty-four (42%) had evidence of prior infection and recovery from HBV before transplant (hepatitis B core antibody positive, B surface antigen negative). Forty-two were evaluable for HBV reactivation and clinical flare. Six (14%) reactivated with clinical flare as documented by seroconversion and/or positive HBV DNA in the serum with biochemical hepatitis at 5.5, 18, 18, 19, 21 and 23 months post-transplant. Five of fifteen patients with chronic graft-versus-host disease (cGVHD) reactivated with clinical flare in contrast to 1/27 without cGVHD (RR: 9.0, 95% CI: 1.2-70.1 P < 0.02). HBV reactivation with clinical flare occurred during immunosuppressive therapy tapering or withdrawal in all patients. In conclusion, hepatitis B core antibody positive allogeneic stem cell recipients with cGVHD are at significant risk of HBV reactivation with clinical flare.     

Assessment of sleepiness,fatigue, and depression among Gulf Cooperation Council commercial airline pilots

Purpose

No studies have assessed the prevalence of fatigue, depression, sleepiness, and the risk of obstructive sleep apnea (OSA) among commercial airlines pilots in the Gulf Cooperation Council (GCC).

Methods

This was a quantitative cross­sectional study conducted among pilots who were on active duty and had flown during the past 6 months for one of three commercial airline companies. We included participants with age between 20 and 65 years. Data were collected using a predesigned electronic questionnaire composed of questions related to demographic information in addition to the Fatigue Severity Scale (FSS), the Berlin Questionnaire, the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS).

Results

The study included 328 pilots with a mean age ± standard deviation of 41.4 ± 9.7 years. Overall, 224 (68.3%) pilots had an FSS score ≥ 36 indicating severe fatigue and 221 (67.4%) reported making mistakes in the cockpit because of fatigue. One hundred and twelve (34.1%) pilots had an ESS score ≥ 10 indicating excessive daytime sleepiness and 148 (45.1%) reported falling asleep at the controls at least once without previously agreeing with their colleagues. One hundred and thirteen (34.5%) pilots had an abnormal HADS depression score (≥ 8), and 96 (29.3%) pilots were at high risk for OSA requiring further assessment.

Conclusion

Fatigue, sleepiness, risk of OSA, and depression are prevalent among GCC commercial airline pilots. Regular assessment by aviation authorities is needed to detect and treat these medical problems.

     

Outcome of aplastic anemia in adolescence: a survey of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation

We analyzed the outcome of 537 adolescents (age 12–18 years) with idiopathic aplastic anemia included in the database of the Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation comparing: i) matched family donor hematopoietic stem cell transplantation performed as first-line treatment with ii) front-line immunosuppressive therapy not followed by subsequent transplant given for failure and with iii) hematopoietic stem cell transplantation performed after failed front-line immunosuppressive therapy. Overall survival was 86% in the matched family donor hematopoietic stem cell transplantation group, 90% in patients given front-line immunosuppressive alone (those who did not fail this treatment and who did not receive subsequent rescue with hematopoietic stem cell transplantation) and 78% in subjects who underwent hematopoietic stem cell transplantation post failed front-line immunosuppressive therapy (P=0.14). Event-free survival in the same groups was respectively 83%, 64% and 71% (P=0.04). Cumulative incidence of rejection was 8% in matched family donor hematopoietic stem cell transplantation and 9% in transplants post failed front-line immunosuppression (P=0.62). Cumulative incidence of acute graft-versus-host disease was 12% in matched family donor transplants and 18% in transplants post failed immunosuppression (P=0.18). Chronic graft-versus-host disease was higher in matched family donor hematopoietic stem cell transplantation (8%) than in transplants post failed immunosuppressive therapy (20%) (P=0.0009). Cumulative incidence of post-therapy malignancies was 0.7% in matched family donor transplantations, 7% in transplantations post failed immunosuppression and 21% after front-line immunosuppression (P=0.0017). In the whole cohort, under multivariate analysis, the diagnosis to treatment interval of two months or under positively affected overall survival whereas up-front immunosuppression alone (with no subsequent rescue transplants) negatively affected event-free survival. In transplanted patients an interval from diagnosis to treatment of 2 months or under, bone marrow as source of cells and first-line matched family donor transplants provided a significant advantage in overall and event-free survival. Aplastic anemia in adolescents has a very good outcome. If a matched family donor is available, hematopoietic stem cell transplantation using bone marrow cells is the first choice treatment. If such a donor is not available, immunosuppressive treatment may still be an acceptable second choice, also because, in case of failure, hematopoietic stem cell transplantation is a very good rescue option.     

Influence of Age on Acute and Chronic GVHD in Children Undergoing HLA-Identical Sibling Bone Marrow Transplantation for Acute Leukemia: Implications for Prophylaxis

Relapse remains the major cause of mortality after hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research has suggested that reducing the intensity of calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis may be an effective strategy for abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that the benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk factors for GVHD, to risk-stratify patients based on age. Patients age <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor-based GVHD prophylaxis between 2000 and 2013 and were entered into the Center for International Blood and Marrow Transplant Research registry were included. The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 19%, that of grade II-IV aGVHD 7%, and that of chronic GVHD (cGVHD) was 16%. Compared with age 13 to 18 years, age 2 to 12 years was associated with a lower risk of grade II-IV aGVHD (hazard ratio [HR], .42; 95% confidence interval [CI], .26 to .70; P?=?.0008), grade II-IV aGVHD (HR, .24; 95% CI, .10 to .56; P?=?.001), and cGVHD (HR, .32; 95% CI, .19 to .54; P?<?.001). Compared with 2000-2004, the risk of grade II-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .36; 95% CI, .20 to .65; P?=?.0007) and in 2009-2013 (HR, .24; 95% CI. .11 to .53; P?=?.0004). Similarly, the risk of grade III-IV aGVHD was lower in children undergoing transplantation in 2005-2008 (HR, .23; 95% CI, .08 to .65; P?=?.0056) and 2009-2013 (HR, .16; 95% CI, .04 to .67; P?=?.0126) compared with those doing so in 2000-2004. We conclude that aGVHD rates have decreased significantly over time, and that children age 2 to 12 years are at very low risk for aGVHD and cGVHD. These results should be validated in an independent analysis, because these patients with high-risk malignancies may be good candidates for trials of reduced GVHD prophylaxis.     

Second Allogeneic Bone Marrow Transplantation after Myeloablative Conditioning Analysis of 43 Cases from Single Institution

Between March 1984 and December 1999, a total of 43 second related allogeneic BMT procedures after myeloablative conditioning were carried out in our institution, 37 following allogeneic, and 6 following autologous BMT. Thirty one patients were males (72%). At 1st BMT (BMT<PRE>1</PRE>), median age was 11.5 years (range, 0.16-45 years). BMT<PRE>1</PRE> was carried out for the diagnosis of AML in 13 patients (30%), SAA in nine (21%), ALL in six (14%), CML in six (14%), immunodeficiency in three (7%), NHL in two, β-thal in two, HD in one, Red cell aplasia in one. HLA matching status for allogeneic BMT<PRE>1</PRE> was full match in 33, one antigen mismatch in two and haplo identical in two patients. Median age at the 2nd BMT (BMT<PRE>2</PRE>) was 14 years (range, 0.41-46.7 years). Indications for BMT<PRE>2</PRE> were recurrent hematologic neoplasm in 23 patients (53%), primary graft failure in 12 (28%) and late graft failure in 8 (19%). Median time from BMT<PRE>1</PRE> to recurrence of hematologic neoplasm or late graft failure was 10 months (range, 2.5- 88 months). Median BMT<PRE>1</PRE> to BMT<PRE>2</PRE> interval was 13 months (range, 1-107 months). For BMT<PRE>2</PRE>, the same donor was used in 29 patients, while 14 patients had alternate related donor (12 full match, 1-one Ag mismatch, 1 haplo identical). A different conditioning regimen was used in the majority of the patients (39, 91%). Radiation containing conditioning regimen were used mostly for patients previously conditioned with chemotherapy only for BMT<PRE>1</PRE> and chemotherapy conditioning±ATG for those who received radiation containing conditioning at BMT<PRE>1</PRE>. Bone marrow was the stem cell source for all patients at BMT<PRE>2</PRE> and all except three autologous peripheral stem cell transplantation patient at BMT<PRE>1</PRE>. Significant organ toxicity leading to procedure related death in 13 patients (30%) was observed after BMT<PRE>2</PRE>. At a median follow up of 36 months after BMT<PRE>2</PRE>, 22 patients (51%) are alive (20 free of disease, 2 with recurrent disease) with overall median survival of 47.5 (SD±9) months. Univariate analysis of relevant clinical factors identified the following variables as the only statistically significant favorable prognostic factors for overall survival: BMT<PRE>1</PRE>-BMT<PRE>2</PRE> interval of ≥6 months (P=0.0007) and age at BMT<PRE>2</PRE> ≤10 years (P=0.041). The nature of underlying disease (neoplastic or non-neoplastic) was not statistically significant (P=0.23). There was no statistically significant difference in survival outcome of BMT<PRE>2</PRE> using same donor vs. alternate related donor (P=0.51). Due to the relatively limited sample size, multivariate analysis was not attempted. This single institution study suggests that second allogeneic BMT after myeloblative conditioning has an acceptable treatment related morbidity/mortality and favorable outcome if performed at age ≤10 years and with an interval of ≥6 months after the first BMT. Additionally same donor can successfully be used for the second transplant with similar survival outcome to alternate donor.     

Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients.

Bone marrow transplant (BMT) recipients are prone to bacterial, viral and fungal infections. Mycobacterium tuberculosis infection can occur in these patients, but the incidence is lower than that of other infections. This report describes four patients with Mycobacterium tuberculosis infection identified from 641 adult patients who received a BMT over a 12-year period (prevalence 0.6%). The pre-transplant diagnosis was AML in two patients and CML in the other two. Pre-transplant conditioning consisted of BU/CY in three patients and CY/TBI in one. Graft-versus-host disease (GVHD) prophylaxis was MTX/CsA in three patients and T cell depletion of the graft in one patient. Sites of infection were lung (two), spine (one) and central nervous system (one). Onset of infection ranged from 120 days to 20 months post BMT. Two patients had co-existing CMV infection. One patient had graft failure. The two patients who received anti-tuberculous (TB) therapy recovered from the infection. Although the incidence of tuberculosis in BMT patients is not as high as in patients with solid organ transplants, late diagnosis due to the slow growth of the bacterium can lead to delay in instituting anti-TB therapy. A high index of suspicion should be maintained, particularly in endemic areas.     

Defective assembly of membrane proteins in erythroid precursors of beta- thalassemic mice

beta-Thalassemic mice provide a useful model for studying the pathophysiology of human beta-thalassemia in that one can perform experiments that are difficult to perform in humans. The ease of access to beta-thalassemic mouse marrow provided the opportunity to explore the cause of the ineffective erythropoiesis that characterizes severe beta-thalassemia in mouse and man. We hypothesized that the accumulation of excess alpha-globin might interfere with the normal assembly of red blood cell (RBC) membrane proteins, thus contributing to the severe intramedullary lysis. Femoral marrow was obtained from normal and beta-thalassemic mice, and RBC precursors were purified (> 90%) by panning and harvesting CD45- cells. The assembly of RBC membrane proteins was assessed by observing immunofluorescence patterns obtained on fixed permeabilized precursors using rabbit polyclonal antibodies directed against human spectrin, and band 4.1, and murine band 3. The distribution of the proteins was shown with a fluorescein- tagged goat antirabbit antibody. In contrast to normal mice, about 30% of intermediate and late stage erythroblasts in beta-thalassemic mice appear abnormal. Neither spectrin nor band 4.1 formed crisp rim fluorescence in these erythroid precursors of thalassemic mice, whereas assembly of band 3 appeared normal. Therefore, the assembly of membrane skeletal proteins is abnormal in murine beta-thalassemic erythroid precursors perhaps because of the deposition of unmatched alpha-globin chains.     

Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study

Fifty-five years after publication of the first hematopoietic stem cell transplantation this technique has become an accepted treatment option for defined hematologic and non-hematologic disorders. There is considerable interest in understanding differences in its use and trends on a global level and the macro-economic factors associated with these differences. Data on the numbers of hematopoietic stem cell transplants performed in the 3-year period 2006–2008 were obtained from Worldwide Network for Blood and Marrow Transplantation member registries and from transplant centers in countries without registries. Population and macro-economic data were collected from the World Bank and from the International Monetary Fund. Transplant rates were analyzed by indication, donor type, country, and World Health Organization regional offices areas and related to selected health care indicators using single and multiple linear regression analyses. Data from a total of 146,808 patients were reported by 1,411 teams from 72 countries over five continents. The annual number of transplants increased worldwide with the highest relative increase in the Asia Pacific region. Transplant rates increased preferentially in high income countries (P=0.02), not in low or medium income countries. Allogeneic transplants increased for myelodysplasia, chronic lymphocytic leukemia, acute leukemias, and non-malignant diseases but decreased for chronic myelogenous leukemia. Autologous transplants increased for autoimmune and lymphoproliferative diseases but decreased for leukemias and solid tumors. Transplant rates (P<0.01), donor type (P<0.01) aand disease indications (P<0.01) differed significantly between countries and regions. Transplant rates were associated with Gross National Income/capita (P<0.01) but showed a wide variation of explanatory content by donor type, disease indication and World Health Organization region. Hematopoietic stem cell transplantation activity is increasing worldwide. The preferential increase in high income countries, the widening gap between low and high income countries and the significant regional differences suggest that different strategies are required in individual countries to foster hematopoietic stem cell transplantation as an efficient and cost-effective treatment modality.