Joerg Halter

Severe events in donors after allogeneic hematopoietic stem cell donation

The risk for donors of allogeneic hematopoietic stem cells transplants is generally considered negligible. This study shows that hematopoietic stem cell donation is associated with a small but definite risk of fatalities and serious adverse events Background The risk for donors of allogeneic hematopoietic stem cells transplants is generally considered negligible. Scattered reports of severe complications and a recent controversy on hematopoietic malignancies after granulocyte colony-stimulating factor administration have challenged this opinion. Design and Methods Three hundred and thirty-eight allogeneic transplant teams from 35 primarily European countries were asked to report numbers of fatalities, severe adverse events and hematologic malignancies occurring among their hematopoietic stem cell donors. Results Two hundred and sixty-two of the 338 teams (77.5%) responded to a first survey (1993–2002) and 169 of the 262 responder teams (65%) to a second survey (2003–2005). They had performed a total of 51,024 first allogeneic hematopoietic stem cell transplantations, of which 27,770 were bone marrow and 23,254 peripheral blood. They observed five donor fatalities, one after a bone marrow donation and four after peripheral blood donation (incidence 0.98 per 10,000 donations; 95% CI 0.32–2.29), 37 severe adverse events (7.25/10,000; 95% CI 5.11–9.99), of which 12 in bone marrow donors (4.32/10,000; 95% CI 2.24–7.75) and 25 in peripheral blood donors (10.76/10,000; 95% CI 6.97–15.85; p<0.05) and 20 hematologic malignancies (3.92/10,000; 95% CI 2.39–6.05), of which 8 after donating bone marrow and 12 after donating peripheral blood stem cells. The observed incidence rate of hematologic malignancies did not exceed the expected incidence in an age- and sex-adjusted general population. Conclusions Hematopoietic stem cell donation is associated with a small but definite risk of fatalities and serious adverse events. True incidences might be higher, due to potential underreporting by study design. A continuous, standardized donor follow-up is needed to define donor risk groups and to monitor intermediate and long-term sequelae.

The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome–negative acute lymphoblastic leukemia in first and second complete remission

We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m(2) or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.

Risk Factors for Acute Graft-Versus-Host Disease After Human Leukocyte Antigen–Identical Sibling Transplants for Adults With Leukemia

PURPOSE Acute graft-versus-host disease (GVHD) causes substantial morbidity and mortality after human leukocyte antigen (HLA)-identical sibling transplants. No large registry studies of acute GVHD risk factors have been reported in two decades. Risk factors may have changed in this interval as transplant-related techniques have evolved. PATIENTS AND METHODS Acute GVHD risk factors were analyzed in 1,960 adults after HLA-identical sibling myeloablative transplant for acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), or chronic myeloid leukemia (CML) reported by 226 centers worldwide to the Center for International Blood and Marrow Transplant Research from 1995 to 2002. Outcome was measured as time from transplant to onset of grade 2 to 4 acute GVHD, with death without acute GVHD as a competing risk. RESULTS Cumulative incidence of grade 2 to 4 acute GVHD was 35% (95% CI, 33% to 37%). In multivariable analyses, factors significantly associated with grade 2 to 4 acute GVHD were cyclophosphamide + total-body irradiation versus busulfan + cyclophosphamide (relative risk [RR] = 1.4; P < .0001), blood cell versus bone marrow grafts in patients age 18 to 39 years (RR = 1.43; P = .0023), recipient age 40 and older versus age 18 to 39 years receiving bone marrow grafts (RR = 1.44; P = .0005), CML versus AML/ALL (RR = 1.35; P = .0003), white/Black versus Asian/Hispanic race (RR = 1.54; P = .0003), Karnofsky performance score less than 90 versus 90 to 100 (RR = 1.27; P = .014), and recipient/donor cytomegalovirus-seronegative versus either positive (RR = 1.20; P = .04). Stratification by disease showed the same significant predictors of grade 2 to 4 acute GVHD for CML; however, KPS and cytomegalovirus serostatus were not significant predictors for AML/ALL. CONCLUSION This analysis confirmed several previously reported risk factors for grade 2 to 4 acute GVHD. However, several new factors were identified whereas others are no longer significant. These new data may facilitate individualized risk estimates and raise several interesting biologic questions.

Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia

Imatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM(+)) and 900 subjects who did not receive IM before HCT (IM(-)) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM(+) and IM(-) groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Outcome of influenza infections in outpatients after allogeneic hematopoietic stem cell transplantation

Background. Influenza can cause significant morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT). The diagnostic methods and antiviral treatment have scarcely been investigated.

Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach.

Allogeneic hematopoietic SCT (HSCT) has been proposed as a treatment for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). HSCT has been performed in nine patients using different protocols with varying success. Based on this preliminary experience, participants of the first consensus conference propose a common approach to allogeneic HSCT in MNGIE. Standardization of the transplant protocol and the clinical and biochemical assessments will allow evaluation of the safety and efficacy of HSCT as well as optimization of therapy for patients with MNGIE.

ABO blood group-incompatible living donor kidney transplantation: a prospective, single-centre analysis including serial protocol biopsies

BACKGROUND ABO incompatible kidney transplantation using antigen-specific immunoadsorption is increasingly performed but data on outcome, complications and protocol biopsies are still scarce. The present prospective single-centre study was aimed at these issues. METHODS This was a prospective single-centre cohort study of 10 successive ABO incompatible living donor kidney transplantations at the University Hospital Basel from September 2005 to October 2007. The following parameters were closely monitored during the whole follow-up: graft function, albuminuria, blood group antibody titres, CD19+ cell count, total IgG and IgG subclasses, CMV antigenaemia, decoy cells in the urine, EBV and polyoma BK virus PCR in the blood. Protocol biopsies were performed on Days 0 and 7 after 3, 6, 12 and 18 months. RESULTS Patient and graft survival is 100% after a median follow-up of 489 days (range 183-916 days). Median serum creatinine is 137 micromol/l (range 70-215 micromol/l), and median urine albumin-creatinine ratio (UACR) is 3.1 mg/ mmol (range 0.6-7.8 mg/mmol) at the time of the last follow-up. All patients had sustained diminished CD19+ cell count and/or total IgG concentrations. Neither CMV antigenaemia nor EBV replication in the blood was observed. Seven patients had positive polyoma BK virus replication in the blood but none developed polyoma virus-associated nephropathy (PVAN). Protocol biopsies revealed rejection Banff IIa in three patients on Day 7, and in one patient after 3 and 6 months. Banff Ia rejection was found in five patients. All rejection episodes resolved. Mild signs of chronic antibody-mediated rejection were observed in five patients. CONCLUSIONS ABO-incompatible kidney transplantation seems to be successful and safe. Modifications of the current protocol may be possible and may further reduce potential side effects and costs.

Pregnancy after Hematopoietic Cell Transplantation: A Report from the Late Effects Working Committee of the Center for International Blood and Marrow Transplant Research (CIBMTR)

Preservation of fertility after hematopoietic cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N = 99) and nonmalignant disorders (N = 79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative (MA) allogeneic HCT (12 women, 50 men), and nonmyeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were MA in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5 to 10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or MA conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility, and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.

Classifying Cytogenetics in Patients with Acute Myelogenous Leukemia in Complete Remission Undergoing Allogeneic Transplantation: A Center for International Blood and Marrow Transplant Research Study

Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.