Page 186 - 2018_12-Haematologica-web

F. Keklik et al.
Introduction
Pulmonary complications occur frequently in patients after hematopoietic stem cell transplantation (HCT). Diffuse alveolar hemorrhage (DAH) is a serious pul- monary complication with a high mortality rate after HCT.1,2 The incidence of DAH varies between 3% and 10% after allogeneic HCT.3,4
The clinical symptoms of DAH include cough, hypox- emia, fever, and rarely hemoptysis.5 Chest radiography shows non-specific bilateral areas of ground-glass attenu- ation and patchy areas of consolidation.6 Bronchoalveolar lavage findings are characteristic for the diagnosis of DAH with progressively bloodier lavage returns. The etiology of DAH remains unknown, but lung tissue injury, inflam- mation and cytokine release have all been implicated in the pathogenesis of DAH.5 Some may require that no microorganism is isolated from the bronchoalveolar lavage fluid; however, DAH syndromes after allogeneic HCT have been shown to have similar clinical character- istics and presentation with or without an associated infection.3,7
The reported outcomes of patients with DAH after allo- geneic HCT have been dismal. Generally, patients with DAH require intensive care unit support and often mechanical ventilation because of severe hypoxemia. The mortality rate can reach 70-100% in patients with DAH because of multiorgan failure and/or sepsis.5,8-10
Recent changes in allogeneic HCT and supportive care practices include: (i) more frequent use of alternative donor allografts [e.g., umbilical cord blood (UCB) and hap- loidentical donors]; (ii) use of reduced intensity condition- ing for older patients or those with comorbidities; (iii) advances in the use of antibiotics targeting fungal and viral infection; and (iv) improvements in intensive care unit support. We therefore evaluated the impact of these changes on the contemporary incidence, risks, and out- comes of DAH after allogeneic HCT.
Methods
All patients who received peripheral blood stem cells (PB), bone marrow (BM) or UCB HCT between 2008 and 2015 at the University of Minnesota were included. The data were prospec- tively collected in our institutional Blood and Marrow Transplant Database on patients who had provided written informed consent to Institutional Research Board-approved studies, supplemented by individual medical record review as needed.
Definitions
Patients received myeloablative or reduced intensity condition- ing regimens (based on age ≥55 years or significant comorbidities, as previously described).11 The dose of total body irradiation (TBI) differed, being 1320 cGy in fractionated doses for myeloablative conditioning and 200 cGy for reduced intensity conditioning regi- mens. UCB HCT grafts were matched at four to six loci of six HLA-A, -B (antigen level), and -DRB1 (allele level) to the recipient and in patients receiving two UCB units were generally similarly matched to each other.12 HLA-matched was defined as 6/6 (or 4- 5/6 + 5-6/6 for double UCB) and 8/8 for PB and BM graft sources with graft nucleated cell doses and CD34 content as previously described.13,14 Standard risk was defined as patients with leukemia, lymphoma or other malignancy in first or second complete remis- sion, chronic myelogenous leukemia in first chronic phase,
myelodysplastic syndrome without excess blasts, or nonmalig- nant diseases. All other patients were considered high risk.
DAH was diagnosed by strict clinical criteria and alveolar lavage in all patients during fiberoptic bronchoscopy. The criteria includ- ed acute onset of hypoxemia with presence of diffuse pulmonary infiltrates on a chest X-ray or computed tomography scan and the presence of progressively bloodier return with each subsequent bronchoalveolar lavage.2,15 Aliquots of saline were successively instilled and aspirated and then visually examined to detect the presence of hemorrhage. The bronchoalveolar lavage fluid was submitted for cytological and microbiological examination. Cytological evaluation included specimen review using potassium hydroxide, Giemsa, and Papanicolaou stains. Appropriate micro- biological and cytological examinations for bacteria, fungi, mycobacteria, Pneumocystis jiroveci, and viruses were also per- formed. For this study, we classified all patients as having DAH regardless of documented infection from bronchoalveolar lavage given our previous analysis demonstrating that infection-associat- ed alveolar hemorrhage and DAH were related clinical syndromes with similar clinical presentation and risks.3
Supportive measures for the management of alveolar hemor- rhage included correction of platelet and coagulation abnormali- ties, careful maintenance of fluid and electrolyte balance, and aggressive ventilator and oxygen support. All patients received prophylactic and empiric antimicrobial agents as clinically indicat- ed. Corticosteroids, administered in most patients (>90%), con- sisted of a standard regimen of high-dose methylprednisolone, 500 mg twice a day for 3 days, followed by 250 mg twice a day for3days,125mgtwiceadayfor3days,60mgtwiceadayfor 3 days, and then 60 mg once a day tapered off over a 2-month period. Pediatric patients also received a similar dose and schedule of methylprednisolone with the dose of methylprednisolone adjusted per body surface area (i.e., starting dose 250 mg/m2/dose intravenously, twice a day for 3 days).
Neutrophil engraftment was defined as the first of 3 consecutive days with an absolute neutrophil count ≥0.5×109/L. Event times for neutrophil and platelet recovery were measured from the date of transplantation and were censored for death or disease progres- sion before day 21 without neutrophil recovery. Platelet engraft- ment was defined as the first day when the platelet count was >20×109/L and subsequently remained so without transfusions for 7 days. Neutrophil counts that never decreased below 0.5×109/L and platelet counts that never decreased below 20×109/L (without transfusion support) were defined as indicating engraftment at day +1 for either cell lineage. Primary graft failure was defined as a lack of neutrophil recovery at day 42 or less than 10% marrow recon- stitution of donor origin, even with neutrophil recovery.
Statistical analysis
The baseline characteristics of the patients and their transplants and information on post-transplantation complications and out- comes were prospectively collected by the Biostatistical Support Group at the University of Minnesota using standardized collec- tion procedures. Demographic and transplant characteristics were summarized by standard descriptive statistical methods. The sta- tistical comparison of categorical variables was performed using a chi-square test, while the Kruskal-Wallis (Wilcoxon) rank-sum test was used for comparisons of continuous variables between patients with and without DAH.
A cumulative incidence estimator was used to calculate the probabilities of neutrophil engraftment, DAH and infection, reflecting non-event deaths as a competing risk. The cumulative incidence of treatment-related mortality was also calculated, reflecting relapse as a competing risk.16 Fine and Gray regression analysis was used to compare the differences between cumulative
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haematologica | 2018; 103(12)