Basic characteristics and safety of donation in related and unrelated haematopoietic progenitor cell donors - first 10 years of prospective donor follow-up of Swiss donors.

Since July 2007 prospective life-long follow-up (FU) for unrelated (URD) and related donors (RD) is mandatory in Switzerland and data on every allogeneic haematopoietic progenitor cell (HPC) donation are collected prospectively. We report the real-world experience of HPC donation during a 10-year study period (01.07.2007-30.06.2017) with basic characteristics and FU data. 1105 donors underwent 1155 HPC donation procedures. Eighty percent of first donations performed by 802 (73%) RDs and 303 (27%) URDs were peripheral blood stem cells (PBSC), 20% bone marrow (BM). Male donors were over-represented as URD (60% male vs 40% female). Main differences between RDs and URDs concerned age and pre-existing health disorders. RDs were significantly older at first donation (median age 48 years) compared to URD (34 years, p < 0.0001) and had more pre-existing health problems: 25% vs 9% in URD (p < 0.0001). No fatal complications occurred, collection related severe adverse events (SAE) after first donation were not significantly different between groups (RD 1.2%, URD 0.99%), incidence rates for neoplastic and autoimmune diseases did not exceed the rates of the general population. RDs are a more heterogeneous and potentially more vulnerable group, but if donor evaluation is performed appropriately, HPC donation is still safe.

Prevalence of untreated and uncontrolled cardiovascular risk factors in survivors of allogeneic cell transplantation.

Cardiovascular risk factors (CVRF) are frequent among long-term survivors after allogeneic hematopoietic cell transplantation (HCT) but prospective data on CVRF are sparse. We conducted a cross-sectional single center study including patients who underwent a first HCT mostly for hematologic malignancies at our center between 2000 and 2016, surviving at least 1 year. 260 patients (median age 54 years [range 19-78], 40% female) who were median 6 years (range 1-16) after transplantation were included. Most patients (232, 89%) had peripheral blood stem cell transplantation. cGVHD was present in 41% at the time of study inclusion. Prevalence of hypertension, dyslipidemia, and diabetes was 58%, 63% and 9%, respectively. Untreated hypertension, dyslipidemia and diabetes was found in 15%, 35% and 2%. Among patients with treated hypertension, 38% did not have blood pressure controlled to levels ≤140/90 mmHg. 36% patients under lipid-lowering therapy did not reach their LDL target. Multivariable logistic regression analyses showed that age and diabetes increased the likelihood for hypertension and dyslipidemia, whereas body mass index, cGVHD and male sex predicted hypertension only. In summary, CVRF in long-term survivors are frequent and persisting after cessation of immunosuppression. A large proportion of CVRF are either untreated or uncontrolled.

Inability to work and need for disability pension among long-term survivors of hematopoietic stem cell transplantation.

Return to work is critical goal following HSCT. However, late effects may impede return to normal activity after HSCT. In the case of inability to work, patients may need a work disability pension to ensure a reasonable livelihood. This study evaluated inability to work and need for disability pension among long-term survivors and analyzed possible determinants of need for social support. This retrospective, single-center study included all HSCT patients surviving ⩾5 years seen at the outpatient clinic between January 2013 and August 2015. There were 203 patients, median age at HSCT 35 years, and 50 years at time of study; median time between HSCT and study control was 12 years; 178 had allo-HSCT, 187 had a malignant disease. At time of study, 156 (77%) were working full or part-time, 47 (23%) were not working. In total, 76 (37%) survivors were receiving a work disability pension compared to 3.17% of the Swiss working population. Patients with a disability pension were significantly older at HSCT, were more often living alone, had more active physical and mental late effects, and higher score of fatigue compared to patients without. These findings underline the importance of screening for employment and the social consequences of non-employment in long-term survivors after HSCT.

Cardiac autonomic functioning is impaired among allogeneic hematopoietic stem cell transplantation survivors: a controlled study.

Healthy cardiac autonomic functioning (CAF) is essential for maintaining homeostasis in response to the environmental demands of everyday life. Impaired CAF is associated with higher morbidity and higher mortality. To explore CAF in survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) 1-10 years after transplant (median=4.3 years), an ambulatory assessment was performed with 104 patients, and 45 age- and gender-matched healthy controls. Heart rate (HR) and respiratory sinus arrhythmia (RSA, that is, high-frequency HR variability) were measured in a laboratory setting and during a 12-hour naturalistic period of daily life. Cancer-related fatigue was assessed by the Functional Assessment of Chronic Illness - Fatigue questionnaire; physical fitness by bicycle-ergometry VO2max. In contrast to healthy controls, 4-year post-HSCT fatigue was greater in patients (P<0.0001, Cohen's d effect size [d]=1.14), and fitness was lower in patients (P<0.0001, d=1.09). In both laboratory and real-life ambulatory conditions, average HR was persistently higher (P<0.0001, d=0.88) and mean RSA magnitude lower (P<0.001, d=0.69) among patients, compared with controls. Severely fatigued patients showed higher HR and lower parasympathetic cardiac control than non-fatigued patients (HR: P=0.02, d=0.47; RSA: P=0.02, d=0.72), and this was unrelated to fitness. These findings may have important implications for predicting long-term treatment outcome and consequences for routine post-HSCT care.

Iron deficiency and thrombocytosis.

According to many textbooks, iron deficiency (ID) is associated with reactive thrombocytosis. In this study, we aimed to investigate the correlation between serum ferritin levels and platelet counts in a large cohort of healthy blood donors. We included all whole blood and apheresis donors aged 18 years or older with at least one ferritin measurement and one platelet count performed at the same visit between 1996 and 2014. A total of 130 345 blood counts and ferritin measurements obtained from 22 046 healthy donors were analysed. Overall, no correlation between serum ferritin and platelet count was observed (r = -0.03, ρ = 0.04 for males, and r = 0.01, ρ = -0.02 for females, respectively). Associations remained clinically negligible after adjusting for age, time since previous blood donation, number of donations and restricting the analysis to ferritin deciles. In this large, retrospective single-centre study, correlations between low ferritin and platelet count in a large and homogeneous cohort of healthy donors were negligible. Further studies in patients with more severe anaemia and patients with inflammation are warranted.

Synergistic effect of sorafenib and cGvHD in patients with high-risk FLT3-ITD+AML allows long-term disease control after allogeneic transplantation.

The multikinase inhibitor sorafenib has shown a strong anti-leukemic effect in FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML); however, remission is often transient. To better understand the role of sorafenib, we performed a retrospective analysis of all patients who received sorafenib in combination with allogeneic hematopoietic stem cell transplantation (HSCT) at our center. Seventeen patients with FLT3-ITD positive AML were treated with sorafenib in combination with allogeneic HSCT. Seven patients received sorafenib therapy pre- and posttransplant, and 10 patients were given sorafenib only posttransplant. Median duration of sorafenib treatment was 13 months (range 1-42); median dose was 600 mg (range 100-1200). Fourteen patients (82 %) achieved a complete remission (CR), while 5 patients (29 %) eventually developed progressive disease. Developing chronic graft-versus-host disease (GvHD) had a strong protective influence on the risk of sorafenib resistance (p = 0.028, HR 0.08, 95 % CI 0.01-0.76). In a total of 8 patients, sorafenib had to be stopped, paused or dose-reduced due to toxicity. In 5 patients with pronounced toxicity, we switched to an alternating dosing schedule with 1 month on/1 month off sorafenib. These patients subsequently remained in sustained complete molecular remission, with a median follow-up of 20 months. Our data indicate that sorafenib can achieve high rates of sustained remission in high-risk patients treated in combination with HSCT.

Lower dose anti-thymocyte globulin for GvHD prophylaxis results in improved survival after allogeneic stem cell transplantation.

In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched-related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II-IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival.

Clinical guidelines for gynecologic care after hematopoietic SCT. Report from the international consensus project on clinical practice in chronic GVHD.

Despite similarities relevant age- and gender-specific issues exist in the care of patients after allogeneic hematopoietic SCT (HSCT). Female genital chronic GVHD (cGVHD) has been markedly underreported in the past but has a significant impact on the patients' health and quality of life. Data on prevention and treatment of this complication are still limited. Here we present a comprehensive review summarizing the current knowledge, which was discussed during several meetings of the German, Austrian and Swiss Consensus Project on clinical practice in cGVHD. In this report, we provide recommendations for post-transplant gynecological care of cGVHD manifestations agreed upon by all participants. This includes guidelines for diagnosis, prevention, and therapeutic options and topical treatments in female patients with genital cGVHD and hormonal replacement treatment of premature ovarian failure for adult and pediatric patients and underlines the necessity for regular gynecological care and screening programs for women after HSCT.

Differences in health behaviour between recipients of allogeneic haematopoietic SCT and the general population: a matched control study.

Little is known of health-relevant behaviour among long-term survivors of haematological disorders treated with haematopoietic SCT. This comparative cross-sectional multicentre study aimed (1) to explore the prevalence of selected behaviours in this group and (2) to compare them with those of the general population. Self-reported data of 376 survivors (mean age: 50.4 (s.d. = 12.8); median 7 years postallogeneic SCT (interquartile range (IQR) = 8.9; range 1-33) were compared with controls derived from the Swiss Health Survey 2007 by propensity score matching. Survivors were more physically inactive (26.8% vs 12.5%; P ⩽ 0.001) and consumed fewer portions of vegetables (⩾ 3 pieces: 10% vs 21.6%; P < 0.001), fruits (⩾ 3 pieces: 6.5% vs 10.6%; P < 0.001) and fish (31.2% vs 60.9% weekly fish dish; P < 0.001). More survivors consumed dairy products daily (92.5% vs 62.9%; P < 0.001), used sun protection regularly (94.5% vs 85.3%, P < 0.001) and had received influenza vaccinations in the past year (58.4% vs 21.5%; P < 0.001); fewer survivors smoked (13.4% vs 35.4%; P < 0.001). Survivors' weekly alcohol consumption was lower (median 1.5 servings (IQR 4) vs median 4.5 (IQR 10.3); P < 0.001). Of those taking immunosuppressants, 65.7% were non-adherent. Similar to the general population, survivors experience problems executing several health-enhancing behaviours, warranting corrective interventions.

Allogeneic hematopoietic stem cell donation-standardized assessment of donor outcome data: a consensus statement from the Worldwide Network for Blood and Marrow Transplantation (WBMT).

The number of allogeneic hematopoietic SCTs performed globally each year continues to increase, paralleled by an increased demand for donors of therapeutic cells. Donor characteristics and collection procedures have undergone major changes during recent decades, and further changes are foreseen. Information on short- and long-term donor outcomes is of crucial importance to ensure maximal donor safety and availability. Current data, predominantly from unrelated donors, give reliable information on the frequent early events associated with donation-most of them of mild-to-moderate intensity. Information on the type and relative risk of serious adverse reactions is more limited. Moreover, only few data exist on long-term donor outcome. On the basis of this need, recommendations for a minimum data set for prospective donor follow-up were developed in a workshop with the participation of an international group of investigators actively involved in allogeneic stem cell donation under the auspices of and approved by the Worldwide Network for Blood and Marrow Transplantation. Establishment of a standardized global follow-up for both, related and unrelated, donors will enable monitoring of the short- and long-term safety profiles of hematopoietic cell donation and form a solid basis for future donor selection and counseling.

Human metapneumovirus infection after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: The clinical characteristics of human metapneumovirus (hMPV)-associated lower respiratory tract infection (LRTI) after allogeneic hematopoietic stem cell transplantation (HSCT) is not well described. We describe the clinical course in eight HSCT recipients suffering from hMPV infection. METHODS: We prospectively included all patients with hMPV-associated LRTI after allogeneic HSCT during a period of 1 year. hMPV was diagnosed by multiplex polymerase chain reaction (PCR) from bronchoalveolar lavage (BAL). RESULTS: Eight patients with hMPV-associated LRTI were identified from 93 BAL samples. Three of the eight patients had co-infections with other pathogens. The median age of the patients was 45 years [interquartile range (IQR) 36.8-53.5], the median time posttransplant was 473 days (IQR 251-1,165), 5/8 patients had chronic graft-versus-host disease (cGvHD), and 6/8 patients received immunosuppression. Chest computed tomography (CT) scanning showed a ground-glass pattern in 7/8 patients. Seven of eight patients required hospitalization due to severe symptoms and hypoxemia. All were treated with intravenous immunoglobulin (IVIG), which was combined with oral ribavirin in six patients. The mortality rate was 12.5 % (1/8). CONCLUSIONS: hMPV-associated LRTI in allogeneic HSCT recipients are not uncommon and present with unspecific respiratory symptoms, ground-glass pattern in CT scanning, and co-infection.

Punctal occlusion is safe and efficient for the treatment of keratoconjunctivitis sicca in patients with ocular GvHD.

The use of punctal plugs in the treatment of keratoconjunctivitis sicca (KCS) in inflammatory eye disease remains controversial because of the potentially increased retention time of tears enriched with inflammatory cytokines that may aggravate eye inflammation. We describe the safety and efficacy of punctal occlusion in a retrospective analysis of 19 patients (16 men) with KCS due to chronic GvHD (cGvHD). Efficacy and safety were assessed by subjective and objective criteria (symptoms, corneal fluorescein staining, tear film break-up time (BUT), Schirmer I test, Jones test and visual acuity). Follow-up was from plug insertion until maximum one year after punctal occlusion. After punctal occlusion, patients reported a significant increase in subjective comfort (1.10 vs 0.59 on a scale ranging from no symptoms (0) to severe impairment (2), P<0.001). Pathological corneal fluorescein staining decreased significantly (P<0.001) and tear film BUT remained unchanged (5.98 vs 4.0 s, P=0.79). Measurement of tear secretion or retention time showed a non-significant trend for improvement in the Schirmer I (3.0 vs 3.40 mm, P=0.08) and Jones (1.36 vs 2.8 mm, P=0.08) tests. The logMAR visual acuity remained unchanged. Punctal occlusion achieved a significant improvement in subjective symptoms and objective findings in ocular GvHD without increasing ocular inflammation.