Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing's sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT) allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an event-free survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemotherapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results.
HLA-mismatched hematopoietic stem cell tranplantation; childhood; solid tumors.
Pediatric patients undergoing hematopoietic stem cell transplantation (HSCT) are at high risk of acquiring fungal infections. Antifungal prophylaxis shortly after transplantation is therefore indicated, but data for pediatric patients under 12 years of age are scarce. To address this issue, we retrospectively assessed the safety, feasibility, and initial efficacy of prophylactic posaconazole in children.
60 consecutive pediatric patients with a median age of 6.0 years who underwent allogeneic HSCT between August 2007 and July 2010 received antifungal prophylaxis with posaconazole in the outpatient setting. 28 pediatric patients received an oral suspension at 5 mg/kg body weight b.i.d., and 32 pediatric patients received the suspension at 4 mg/kg body weight t.i.d. The observation period lasted from start of treatment with posaconazole until its termination (maximum of 200 days post-transplant).
Pediatric patients who received posaconazole at 4 mg/kg body weight t.i.d. had a median trough level of 383 μg/L. Patients who received posaconazole at 5 mg/kg body weight b.i.d. had a median trough level of 134 μg/L. Both regimens were well tolerated without severe side effects. In addition, no proven or probable invasive mycosis was observed.
Posaconazole was a well-tolerated, safe, and effective oral antifungal prophylaxis in pediatric patients who underwent high-dose chemotherapy and HSCT. Posaconazole at a dosage of 12 mg/kg body weight divided in three doses produced consistently higher morning trough levels than in patients who received posaconazole 5 mg/kg body weight b.i.d. Larger prospective trials are needed to obtain reliable guidelines for antifungal prophylaxis in children after HSCT.
Posaconazole; Posaconazole trough levels; Pediatric patients; Antifungal prophylaxis; Stem cell transplantation
Invasive pulmonary aspergillosis (IPA) is one of the major complications encountered by patients receiving chemotherapy for hematologic malignancies. The prolonged period of intense immunosuppression following allogeneic hematopoietic stem cell transplantation (HSCT) may increase the risk of IPA recurrence in patients with a history of IPA. We evaluated the impact of a history of IPA on allogeneic HSCT outcome, and examined the incidence of IPA after HSCT.
This retrospective study included 22 patients with a history of IPA prior to receiving allogeneic HSCT at the Samsung Medical Center from 1995 to 2007. Diagnosis of IPA was defined as proven (N=5), probable (N=0), or possible (N=17).
All 22 patients received amphotericin-based regimens to treat pre-transplant IPA. Secondary antifungal prophylaxis was administered to 10 patients during HSCT. The development of post-transplant IPA was observed in 2 patients. One of the patients died from septic shock within 2 days of the diagnosis of possible IPA. The other patient recovered from IPA, but eventually had a relapse of the primary disease. Of the 22 patients, the overall 2-year survival rate was 63% (95% confidence interval [CI]: 41-85), and the transplant-related mortality rate was 19% (95% CI: 0-38).
Our results suggest that a history of IPA prior to HSCT does not have an adverse impact on transplant outcomes, although the small number of cases was a limitation in this study. Future studies involving a larger number of cases are needed to further examine this issue.
Invasive pulmonary aspergillosis; Allogeneic hematopoietic stem cell transplantation
This study was done to observe the alteration of the estimated glomerular filtration rate (eGFR) in multiple myeloma patients according to type of tandem hematopoietic stem cell transplantation (HSCT). Forty-one patients were enrolled in this study. Twenty patients underwent autologous HSCT (auto-HSCT) and 21 patients underwent allogeneic HSCT (allo-HSCT). The changes in eGFR after the two tandem HSCT modalities were different between the two groups, according to the donor of stem cells (P = 0.016). In the auto-HSCT group, the eGFR, recorded 12 months after secondary HSCT, was significantly decreased compared with the eGFR recorded before stem cell mobilization (P = 0.005). Although there was no significant difference, the trend showed that the eGFR after allo-HSCT decreased from the previous HSCT until a month after secondary HSCT. In addition, after 6 months of secondary HSCT, the eGFR recovered to the level recorded prior to the HSCT (P = 0.062). This difference may be due to total body irradiation, a calcineurin inhibitor, or maintemance therapy. Changes in renal function would be monitored closely for these patients. The recovery of the eGFR would be a main focus for the patients treated with the total body irradiation or the calcineurin inhibitor, a progressive decline of the eGFR would be also crucial for the patients treated with maintenance therapy.
Multiple Myeloma; Allogeneic Stem-Cell Transplantation; Autologous Stem-Cell Transplantation; Renal Function; Tandem Transplantation
In the last decades, the global epidemiological impact of invasive candidiasis
(IC) in patients with hematologic malignancies (HM) and in hematopoietic stem
cell transplant (HSCT) recipients has decreased and the incidence of invasive
aspergillosis exceeded that of Candida infections. The use of prevention
strategies, first of all antifungal prophylaxis with triazoles, contributed to
the reduction of IC in these populations as demonstrated by several
epidemiological studies. However, relatively little is known about the current
epidemiological patterns of IC in HM and HSCT populations, because recent
epidemiological data almost exclusively derive from retrospective experiences
and few prospective data are available. Several prospective, controlled studies
in the prophylaxis of invasive fungal diseases have been conducted in both the
HM and HSCT setting. On the contrary, most of the prospective controlled trials
that demonstrated the efficacy of the antifungal drugs echinocandins and
voriconazole in the treatment of candidemia and invasive candidiasis mainly
involved patients with underlying conditions other than HM or HSCT. For these
reasons, international guidelines provided specific indications for the
prophylaxis strategies in HM and HSCT patients, whereas the recommendations on
therapy of documented Candida infections are based on the results observed in
the general population and should be considered with caution.
All allogeneic (allo) and autologous (auto) hematopoietic stem cell transplantation (HSCT) recipients at St. Jude Children’s Research Hospital undergo pre-HSCT computed tomography (CT) of the sinuses, chest, and abdomen because they are at significant risk for opportunistic infections. We studied whether this extensive routine imaging is warranted to detect infection despite the risk of additional radiation exposure. We reviewed the medical records of all children receiving allo- and auto-HSCT at St. Jude in 2004 and 2005. Of the 184 eligible patients who received 187 transplants, 131 received allografts and 56 autografts. Solid tumors and lymphomas were removed from the final analysis of the chest and abdomen CT as this imaging is typically warranted as part of disease restaging; thus 111 allogeneic participants were included in this analysis. Both auto and allo-recipients were evaluated by sinus CT and included in this final analysis. Most allo- and auto-HSCT recipients (≥ 80%) did not have sinus, pulmonary, cardiac, or gastrointestinal symptoms; >85% of the evaluable allo-recipients had no prior fungal infection. Eighty-eight allo- and 31 auto-HSCT recipients had abnormal sinus CT findings, all unrelated to the underlying disease. Sixty-two (55.9%) of the allo-recipients had normal chest CT and 85 (76.6%) had normal abdominal CT. Of the 18 allo-recipients who began new therapy based on these findings, only 2 (11.1%) were related to chest CT findings and the other 16 were related to sinus findings. Our findings suggest that pre-HSCT routine CT imaging of the abdomen may not be warranted in a subset of allogeneic recipients who are asymptomatic and without previous infectious findings. Thus, these patients may be spared unnecessary radiation exposure. Recipients undergoing auto-HSCT or allo-HSCT for lymphomas or solid tumors will routinely undergo chest and abdominal CT imaging as part of their disease evaluation. The decision to perform chest CT should be made judiciously based on a careful history and physical examination. Sinus imaging, which was frequently abnormal, may be justified in all patients to plan post-HSCT care.
Hematopoietic stem cell transplantation (HSCT); autologous HSCT; allogeneic HSCT; computed tomography (CT); infection; pediatrics
Despite the availability of new antifungal compounds, invasive fungal infection remains a significant cause of morbidity and mortality in children and adults undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Allogeneic HSCT recipients suffer from a long lasting defect of different arms of the immune system, which increases the risk for and deteriorates the prognosis of invasive fungal infections. In turn, advances in understanding these immune deficits have resulted in promising strategies to enhance or restore critical immune functions in allogeneic HSCT recipients. Potential approaches include the administration of granulocytes, since neutropenia is the single most important risk factor for invasive fungal infection, and preliminary clinical results suggest a benefit of adoptively transferred donor-derived antifungal T cells. In vitro data and animal studies demonstrate an antifungal effect of natural killer cells, but clinical data are lacking to date. This review summarizes and critically discusses the available data of immunotherapeutic strategies in allogeneic HSCT recipients suffering from invasive fungal infection.
invasive fungal infection; allogeneic hematopoietic stem cell transplantation; immunotherapy; granulocyte; T cell; natural killer cell
This study was to analyze the infectious complications after hematopoietic stem cell transplantation (HSCT) according to the recent changes of HSCT. Medical records of 379 adult patients who underwent HSCT consecutively at Catholic HSCT Center from January 2001 to December 2002 were reviewed retrospectively. Allogeneic HSCT accounted for 75.7% (287/379) and autologous HSCT for 24.3% (92/379). During pre-engraftment period, bacterial infection was predominant, and E. coli was still the most common organism. After engraftment, viral infection was predominant. The incidence of invasive fungal infection showed bimodal distribution with peak correlated with neutropenia and graft-versus-host disease (GVHD). The overall mortality and infection-related mortality rates according to 3 periods were as follows; during pre-engraftment, 3.16% (12/379) and 1.8% (7/379); during midrecovery period, 7.9% (29/367) and 4.1% (15/367); during late-recovery period, 26.9% (91/338), and 15.9% (54/338). Risk factors for infection-related mortality were as follows; during pre-engraftment period, fungal infection and septic shock; during the mid-recovery period, hemorrhagic cystitis and delayed engraftment; during the late-recovery period, fungal infection, chronic GVHD, and relapse. In conclusion, infection was still one of the main complications after HSCT and highly contributes to mortality. The early diagnosis and the effective vaccination strategy are needed for control of infections.
Hematopoietic Stem Cell Transplantation; Complication, Infectious; Postoperative Complications; Bacterial Infections and Mycoses; Viral Diseases
The optimal form of treatment for children with relapsed or refractory acute promyelocytic leukemia (APL) is unclear. We retrospectively analyzed the results of 32 (11 autologous, 21 allogeneic) hematopoietic stem cell transplants (HSCT) performed for children originally treated on either the Eastern Cooperative Group E2491 Trial or the Cancer and Leukemia Group B C9710 Trial and subsequently diagnosed with relapsed or refractory APL. For autologous HSCT, the incidence of treatment-related mortality (TRM) and relapse were 0% (95% CI, 0-30%) and 27% (95% CI, 9-57%), respectively. The 5-year event-free survival (EFS) and overall survival (OS) following autologous HSCT was 73% (95% CI, 43-91%) and 82% (95% CI, 51-96%), respectively. For allogeneic HSCT, the incidence of TRM and relapse were 19% (95% CI, 7-41%) and 10% (95% CI, 2-30%) respectively. The 5-year EFS and OS following allogeneic HSCT was 71% (95% CI, 50-86%) and 76% (95% CI, 55-90%) respectively. There was no significant difference in EFS or OS between autologous and allogeneic HSCT. This data demonstrates that autologous and allogeneic HSCT are both effective therapies for treatment of children with relapsed or refractory APL. Autologous HSCT is associated with a low incidence of TRM, while allogeneic HSCT is associated with a low incidence of relapse, suggesting a strong GVL effect against residual APL.
Pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) often receive intravenous liposomal amphotericin B (L-AmB) as antifungal prophylaxis. There are no guidelines for antifungal prophylaxis in children in this situation. Caspofungin (CAS), a broad-spectrum echinocandin, could be an effective alternative with lower nephrotoxicity than L-AmB.
We retrospectively analyzed the safety, feasibility, and efficacy of CAS in our center, and compared the results with L-AmB as antifungal monoprophylaxis in pediatric patients undergoing HSCT. 60 pediatric patients received L-AmB (1 or 3 mg/kg bw/day) and another 60 patients received CAS (50 mg/m2/day) as antifungal monoprophylaxis starting on day one after HSCT. The median ages of patients receiving L-AmB and CAS were 7.5 years and 9.5 years, respectively.
No proven breakthrough fungal infection occurred in either group during the median treatment period of 23 days in the L-AmB group and 24 days in the CAS group. One patient receiving CAS developed probable invasive aspergillosis. During L-AmB treatment, potassium levels significantly decreased below normal values. Patients treated with L-AmB had more drug-related side effects and an increased need for oral supplementation with potassium, sodium bicarbonate and calcium upon discharge as compared with the CAS group. CAS was well-tolerated and safe in this cohort of immunocompromised pediatric patients, who underwent high-dose chemotherapy and HSCT.
Prophylactic CAS and L-AmB showed similar efficacy in this biggest cohort of pediatric patients after allogeneic HSCT reported, so far. A prospective randomized trial in children is warranted to allow for standardized guidelines.
Caspofungin; Liposomal amphotericin B; Antifungal prophylaxis; Pediatric patients; Allogeneic stem cell transplantation
Post-transplant lymphoproliferative disorder (PTLD) is a complication of solid organ and allogeneic hematopoietic stem cell transplantation (HSCT); following autologous HSCT only rare cases of PTLD have been reported.
Here, a case of Hodgkin's disease (HD), as unusual presentation of PTLD after autologous HSCT for malignant glioma is described.
60-years old man affected by cerebral anaplastic astrocytoma underwent subtotal neurosurgical excision and subsequent high-dose chemotherapy followed by autologous HSCT. During the post HSCT course, cranial irradiation and corticosteroids were administered as completion of therapeutic program.
At day +105 after HSCT, the patient developed HD, nodular sclerosis type, with polymorphic HD-like skin infiltration.
The clinical and pathological findings were consistent with the diagnosis of PTLD.
Hematopoietic stem cell transplantation (HSCT) requires significant infrastructure. Little is known on its use and the factors associated with it on a global level.
To determine current use of HSCT, to assess differences in its application and to explore associations of macroeconomic factors with transplant rates on a global level.
Structured worldwide collection of numbers of allogeneic and autologous HSCT by main indication, donor type and stem cell source for the year 2006.
Worldwide Network for Blood and Marrow Transplantation (WBMT), a global non-profit umbrella organization for clinical HSCT.
All patients with an allogeneic or autologous HSCT for any indication transplanted in 2006 within any of the participating countries.
Main Outcome measures
Transplant rates (number of HSCT per 10 million inhabitants) by indication, donor type and country; description of main differences in HSCT use; macroeconomic factors of reporting countries associated with transplant rates.
There were 50’417 first HSCT, 21’516 allogeneic (43%), 28’901 autologous (57%) reported from 1’327 centers in 71 countries for leukemia (17’049 (34%; 89% allogeneic)), lymphoma (27’492 (54%; 87% autologous)), solid tumors (2’925 (6%, 95% autologous)), non-malignant disorder (2’593 (5%; 92% allogeneic)) or, “others” 358 (1%). Use of allogeneic or autologous HSCT, use of unrelated or family donors for allogeneic HSCT and proportions of disease indications varied significantly between countries and continental regions. In linear regression analyses, Government Health Care Expenditures (r2 = 77.33), team density (r2 =76.28), Human Development Index (r2 = 74.36) and Gross National Income /Capita (r2 = 74.04) showed the highest association with transplant rates.
HSCT is an accepted therapy today with different use and needs worldwide. Availability of resources, Governmental support and, access for patients to a team were identified as key factors for higher transplant rates.
Hematopoietic stem cell transplantation; Global perspective; transplant rates; leukemia; lymphoma; solid tumors; non-malignant disorders; Gross National Income per capita; Human Development Index
Factors affecting the efficacy of platelet and red blood cell (RBC) transfusion in patients undergoing hematopoietic stem cell transplantation (HSCT) have not been studied extensively. We aimed to evaluate platelet and RBC transfusion efficacy by measuring the platelet corrected count increment and the hemoglobin increment, respectively, 24 h after transfusion in 105 patients who received HSCT.
Using retrospective analysis, we studied whether factors, including gender, time of transplantation, the compatibility of ABO group between HSC donors and recipients, and autologous or allogenic transplantation, influence the efficacy of blood component transfusion. We found that the infection rate of HSCT patients positively correlated with the transfusion amount, and the length of stay in the laminar flow room was associated with transfusion. We found that platelet transfusion performed during HSCT showed significantly better efficacy than that performed before HSCT. The effect of platelet transfusion in auto-transplantation was significantly better than that in allo-transplantation. The efficacy of RBC transfusion during HSCT was significantly lower than that performed before HSCT. The efficacy of RBC transfusion in auto-transplantation was significantly higher than that in allo-transplantation. Allo-transplantation patients who received HSCs from compatible ABO groups showed significantly higher efficacy during both platelet and RBC transfusion.
We conclude that the efficacy of platelet and RBC transfusions does not correlate with the gender of patients, while it significantly correlates with the time of transplantation, type of transplantation, and ABO compatibility between HSC donors and recipients. During HSCT, the infection rate of patients positively correlates with the transfusion amount of RBCs and platelets. The total volume of RBC units transfused positively correlates with the length of the patients’ stay in the laminar flow room.
Hematopoietic stem cell transplantation (HSCT) activity was surveyed in the 9 countries in the WHO Eastern Mediterranean (EM) region that are reported to carry out transplants. Between the years of 1984 and 2007, 7933 transplants were reported. The total number of HSCT per year has continued to increase, with a plateau in allogeneic HSCT (allo-HSCT) between 2005 and 2007. Overall, a greater proportion of transplants were allogeneic HSCT (allo-HSCT) (n=5761, 77%) compared to autologous HSCT (ASCT) (n=2172, 23% ASCT). Of 5761 allo-HSCT, acute leukemia constituted the main indication (n=2124, 37%). There was a relatively high proportion of allo-HSCT for bone marrow failure (n=1001, 17%) and hemoglobinopathies (n=885, 15%). The rate of unrelated donor transplants remained low, with only 2 non-umbilical cord matched unrelated donor (MUD) allo-HSCT reported. One hundred umbilical cord (UCB) transplants were reported (0.017% of allo- HSCT). Peripheral blood stem cells (PBSC) were the main source of graft in allo-HSCT, and PBSCT increasingly constitutes the main source of stem cells. Reduced intensity conditioning was utilized in 5.7% of allografts over the surveyed period. ASCT numbers continue to increase. There has been a shift in the indication for ASCT from acute leukemia to lymphoproliferative disorders (45%) followed by myeloma (26%). The survey reflects transplantation activity according to the unique health settings of this region. Notable differences in transplant practices as reported to the European Group for Blood and Marrow Transplantation (EBMT) over recent years are addressed.
Hematopoietic stem cell transplantation; EMRO; stem cell source; conditioning
Relapse and transplant-related complications are leading causes of mortality after hematopoietic stem cell transplantation (HSCT). Suicides and accidents have not been studied in these patients. This study sought to determine whether there is an excess of suicide and accidental deaths after HSCT, and to determine risk factors.
The incidence of suicidal and accidental death in patients after undergoing HSCT, standardized mortality ratio (SMR), and absolute excess risk (AER) of suicide and accidental deaths was determined, compared with the general European population. A case-control analysis was done to define factors associated with suicide and accidental deaths. Data were derived from the European Group for Blood and Marrow Transplantation Registry, including 294,922 patients who underwent autologous or allogeneic HSCT from 1980 to 2009.
The 10-year cumulative incidence of suicide and accidental deaths was 101.8 and 55.6 per 100,000 patients, respectively. SMR and AER of suicide after HSCT were 2.12 (P < .001) and 10.91, higher than in the European general population for 100,000 deaths, respectively. SMR and AER of accidental death were 1.23 (P < .05) and 2.54, respectively. In the case-control study, relapses were more frequent among patients who committed suicide after autologous HSCT (37% versus 18%; P < .0001). Chronic graft-versus-host disease was higher among patients who committed suicide after allogeneic HSCT (64% versus 37%; P = .001).
There is an excess of deaths due to suicide and accidents in patients after undergoing HSCT as compared with the European general population. Relapse was associated with more suicide and accidental deaths after autologous HSCT, and chronic graft-versus-host disease was associated with more deaths by suicide after allogeneic HSCT. Cancer 2013;119:2012–2021. © 2013 American Cancer Society.
hematopoietic stem cell transplantation; late effects; suicides; accidents; long-term; survivorship
High risk patients with active fungal infection who had undergone hematopoietic stem cell transplantation (HSCT) with the support of granulocyte transfusions (GTX) as an adjunct to antifungal agents are reviewed retrospectively. Patients requiring immediate allogeneic HSCT for their primary hematological disorders (two severe aplastic anemia, one T cell acute lymphoblastic leukemia (ALL) in second complete remission, one acute myeloid leukemia (AML)-in first complete remission, one T-ALL in refractory relapse) but were denied by other transplant programs due to active invasive fungal infections had undergone HSCT with the support of GTX at the stem cell transplantation unit of Gazi University. Five patients who had undergone six transplants were included in the study and received a total of 38 (3–13) granulocyte transfusions during these six transplants. The median granulocyte concentration was 3.4 × 1011 per apheresis bag. Full clinical and radiological recovery was achieved in three of the five high risk patients with active invasive fungal infection with the combination of antifungal agents and GTX. Even a very high risk patient with aplastic anemia who had undergone two consecutive transplants due to secondary graft failure was also cured of his primary disease despite the presence of multiple pulmonary fungus balls. Three of the five patients with very high risk features due to the underlying hematological disease and the associated active fungal infection were rescued with allogeneic HSCT performed with the support of GTX combined with antifungal agents. Despite the limitations of this report due to its retrospective nature, it suggests that GTX might be an alternative in patients with active fungal infections who otherwise are denied by the transplant programs. However, prospective randomized studies are required to draw a solid conclusion regarding the role of GTX in HSCT recipients in desperate situations such as active fungal infections.
Stem cell transplantation; Granulocyte transfusion; Fungal infection; Anti-fungal treatment
We examined the role of hematopoietic cell transplantation (HSCT) for patients aged ≤18 years with refractory or recurrent Burkitt (n=41), lymphoblastic (n=53), diffuse large B cell (n=52) and anaplastic large cell lymphoma (n=36), receiving autologous (n=90) or allogeneic (n=92 – 43 matched sibling and 49 unrelated donor) HSCT in 1990–2005. Risk factors affecting event-free survival (EFS) were evaluated using stratified Cox regression. Characteristics of allogeneic and autologous HSCT recipients were similar. Allogeneic donor HSCT was more likely to use irradiation-containing conditioning regimens, marrow stem cells, be performed in more recent years, and for lymphoblastic lymphoma. EFS rates were lower for patients not in complete remission at HSCT, regardless of donor type. After adjusting for disease status, 5-year EFS were similar after allogeneic and autologous HSCT for diffuse large B cell (50% vs. 52%), Burkitt (31% vs. 27%) and anaplastic large cell lymphoma (46% vs. 35%). However, EFS was higher for lymphoblastic lymphoma, after allogeneic HSCT (40% vs. 4%, p<0.01). Predictors of EFS for progressive or recurrent disease after HSCT included disease status at HSCT and use of allogeneic donor for lymphoblastic lymphoma. These data were unable to demonstrate a difference in outcome by donor type for the other histologic sub-types.
Non-Hodgkin lymphoma; allogeneic HSCT; autologous HSCT
Invasive fungal infections (IFI) are a major cause of morbidity and mortality among both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. Candida is the most common cause of IFI in SOT recipients and the second most common cause of IFI in HSCT recipients. We determined susceptibilities to fluconazole, voriconazole, itraconazole, posaconazole, amphotericin B, and caspofungin for 383 invasive Candida sp. isolates from SOT and HSCT recipients enrolled in the Transplant-Associated Infection Surveillance Network and correlated these results to clinical data. Fluconazole resistance in C. albicans, C. tropicalis, and C. parapsilosis isolates was low (1%), but the high percentage of C. glabrata and C. krusei isolates within this group of patients increased the overall percentage of fluconazole resistance to 16%. Voriconazole resistance was 3% overall but was 8% among C. glabrata isolates. On multivariable analysis, among HSCT recipients fluconazole nonsusceptibility was independently associated with C. glabrata, non-Hodgkin's lymphoma, cytomegalovirus (CMV) antigenemia, diabetes active at the time of the IFI, and any prior amphotericin B use; among SOT recipients, fluconazole nonsusceptibility was independently associated with any fluconazole use in the 3 months prior to the IFI, C. glabrata, ganciclovir use in the 3 months prior to the IFI, diabetes acquired since the transplant, and gender.
The efficacy and the safety of the administration of multipotent mesenchymal stromal cells (MMSCs) for acute graft-versus-host disease (aGVHD) prophylaxis following allogeneic hematopoietic cell transplantation (HSCT) were studied. This prospective clinical trial was based on the random patient allocation to the following two groups receiving (1) standard GVHD prophylaxis and (2) standard GVHD prophylaxis combined with MMSCs infusion. Bone marrow MMSCs from hematopoietic stem cell donors were cultured and administered to the recipients at doses of 0.9–1.3 × 106/kg when the blood counts indicated recovery. aGVHD of stage II–IV developed in 38.9% and 5.3% of patients in group 1 and group 2, respectively, (P = 0.002). There were no differences in the graft rejection rates, chronic GVHD development, or infectious complications. Overall mortality was 16.7% for patients in group 1 and 5.3% for patients in group 2. The efficacy and the safety of MMSC administration for aGVHD prophylaxis were demonstrated in this study.
A prospective observational registry assessed real world experience with caspofungin monotherapy or combination therapy for the initial or salvage treatment of proven or probable invasive aspergillosis (IA).
Data were collected from April 2006 to September 2007 for patients treated with caspofungin for a single episode of IA. Clinical effectiveness was categorized as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT).
Consecutive patients (n = 103) with proven or probable IA (per EORTC/MSG criteria) were identified from 11 countries. Malignancy (76.7%), neutropenia (64.1%), allogeneic hematopoietic stem cell transplantation (HSCT, 22.3%), solid organ transplantation (8.7%), autologous HSCT (4.9%), and HIV/AIDS (2.9%) were the most common underlying conditions. Most patients (84.5%) had pulmonary IA. Aspergillus fumigatus was the most frequently isolated species. The majority of patients received caspofungin monotherapy (82.5%) primarily as salvage therapy (82.4%). The main reason for switching to salvage therapy was clinical failure of the first-line therapy (69%). A favorable response at EOCT was seen in 56.4% (57/101) of patients overall, including 56.5% (48/85) and 56.3% (9/16) of patients receiving caspofungin monotherapy and combination therapy, respectively. Favorable response rates in clinically relevant subgroups were: malignancy, 51.9% (41/79); allogeneic HSCT, 56.5% (13/23); and neutropenia at time of hospitalization, 53.0% (35/66). There was a 72.3% (73/101) survival at 7 days after EOCT. Serious adverse events related to caspofungin were reported in 4 cases (3.9%); 3 patients (2.9%) discontinued treatment due to an adverse event related to caspofungin.
Caspofungin was both effective and well tolerated among high-risk patient groups such as those with neutropenia and active malignancies.
The indolent lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) remain incurable with standard therapy. Autologous hematopoietic stem cell transplantation (HSCT[JHA1]) is feasible and has low treatment related mortality in follicular lymphoma, but there are questions relating to optimal timing of the procedure, conditioning regimen and late effects. Myeloablative allogeneic HSCT is associated with high treatment related morbidity and mortality, few late relapses, but is applicable to only a small number of patients. The major focus of HSCT in these lymphomas has been with reduced intensity conditioning (RIC) allogeneic HSCT, which is applicable to the age distribution of these diseases and which exploit the graft versus lymphoma effect in these diseases. Steps to further decrease the morbidity and mortality of the RIC HSCT and in particular to reduce the incidence of chronic extensive graft versus host disease while maintaining tumor control remain the major focus. Many potential treatments are available for indolent lymphomas and CLL, and appropriate patient selection and the timing of HSCT remain controversial. The use of HSCT must always be weighed against the risk of the underlying disease, particularly in a setting where improvements in treatment are leading to improved outcome.
Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P <0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P<0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P<0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals.
stem-cell transplant; azoles; invasive fungal disease; mould infections; yeast infections
Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has become a valuable strategy for some intractable diseases, a number of problems remain to be resolved. We have developed a new HSCT method, HSCT + thymus transplantation (TT) from the same donor, which induces elevated T cell function with mild graft-versus-host disease (GVHD) in comparison to conventional HSCT alone and HSCT + donor lymphocyte infusion (HSCT + DLI). This new method is effective in the treatment of several intractable diseases and conditions, such as autoimmune diseases in aging, advanced malignant tumors, exposure to supralethal irradiation, multiple organ transplantation from different donors, and type 2 diabetes mellitus, for which conventional methods are ineffective. Our findings suggest that allo-HSCT + TT is preferable to conventional allo-HSCT alone or allo-HSCT + DLI. This method may become a valuable next-generation HSCT technique.
AIM: To investigate the frequency of occult hepatitis B, the clinical course of hepatitis B virus (HBV) reactivation and reverse seroconversion and associated risk factors in autologous hematopoietic stem cell transplantation (HSCT) recipients.
METHODS: This study was conducted in 90 patients undergoing autologous HSCT. Occult HBV infection was investigated by HBV-DNA analysis prior to transplantation, while HBV serology and liver function tests were screened prior to and serially after transplantation. HBV-related events including reverse seroconversion and reactivation were recorded in all patients.
RESULTS: None of the patients had occult HBV prior to transplantation. Six (6.7%) patients were positive for HBV surface antigen (HBsAg) prior to transplantation and received lamivudine prophylaxis; they did not develop HBV reactivation after transplantation. Clinical HBV infection emerged in three patients after transplantation who had negative HBV-DNA prior to HSCT. Two of these three patients had HBV reactivation while one patient developed acute hepatitis B. Three patients had anti-HBc as the sole hepatitis B-related antibody prior to transplantation, two of whom developed hepatitis B reactivation while none of the patients with antibody to HBV surface antigen (anti-HBs) did so. The 14 anti-HBs- and/or anti-HBc-positive patients among the 90 HSCT recipients experienced either persistent (8 patients) or transient (6 patients) disappearance of anti-HBs and/or anti-HBc. HBsAg seroconversion and clinical hepatitis did not develop in these patients. Female gender and multiple myeloma emerged as risk factors for loss of antibody in regression analysis (P < 0.05).
CONCLUSION: Anti-HBc as the sole HBV marker seems to be a risk factor for reactivation after autologous HSCT. Lamivudine prophylaxis in HbsAg-positive patients continues to be effective.
Autologous stem cell transplantation; Hepatitis B reactivation; Occult hepatitis; Multiple myeloma; Lymphoma
Respiratory viruses (RVs) are known to be major causes of morbidity and mortality in recipients of hematopoietic stem cell transplants (HSCTs), but prospective long-term studies are lacking. We prospectively screened all adult HSCT recipients (172 allogeneic [alloHSCT] and 240 autologous [autoHSCT]) who underwent transplantation during a 4-year period (1999 to 2003) for the development of a first episode of symptomatic upper respiratory tract infections and/or lower respiratory tract infections (LRTI) by an RV. RVs studied were influenza A and B viruses (n = 39), human respiratory syncytial virus (n = 19), human adenoviruses (n = 11), human parainfluenza viruses 1 to 3 (n = 8), human enteroviruses (n = 5), human rhinoviruses (n = 3), and the recently discovered human metapneumoviruses (n = 19). During the study, 51 and 32 cases of RV symptomatic infections were identified of alloHSCT and autoHSCT recipients (2-year incidence, 29% and 14%, respectively). Risk factors for progression of upper respiratory tract infection to LRTI included severe (<0.2 × 109/L) and moderate (<0.2 × 109/L) lymphocytopenia in alloHSCT (P = .02) and autoHSCT (P = .03). Death from LRTI was attributed to an RV in 8 alloHSCT recipients. Symptomatic RV had no effect on 2-year outcomes, with the possible exception of influenza A and B virus infections in autoHSCT: these were associated with nonrelapse mortality (P = .02). In conclusion, this prospective trial allows an estimation of the minimum incidence of a first RV infection in adult HSCT recipients and identifies risk factors for acquisition of an RV infection and progression to LRTI; this should aid in the design of future studies. In addition, human metapneumovirus should be added to the potentially serious causes of RV infections in HSCT.
Respiratory viruses; Hematopoietic stem cell transplantation; Respiratory tract infection; Prospective study