Mark R. Litzow

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

BACKGROUND: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission. METHODS: -negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point. RESULTS: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group. CONCLUSIONS: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.).

Hematopoietic stem cell transplantation (HSCT) is used for the INCIDENCE treatment of hematologic and solid tumors as well as for various The frequency of DAH has varied among reported series bebenign diseases worldwide. The International Bone Marrow cause of differences in patient mix, diagnostic approaches, and Transplant and the Autologous Blood and Marrow Transplant diagnostic criteria. The factors that influence the incidence of Registries estimate that approximately 50,000 hematopoietic DAH have changed over time and varied among HSCT centers. stem cell transplants were performed in 1998. Approximately Although bronchoscopy and surgical lung biopsy have been used 17,000 of these were allogeneic, and over 30,000 were autologous. for decades, their application in HSCT recipients with pulmonary Pulmonary complications develop in 30 to 60% of HSCT recipiinfiltrates has not been well standardized. Because underlying ents (1, 2). Because of graft-versus-host disease and immunosupconditions may prohibit invasive procedures, some clinicians pressant medications, both infectious and noninfectious pulmoprefer to initiate empiric antibiotics for suspected infection leadnary complications are more common in allogeneic than in ing to underdiagnosis of DAH. Moreover, although BAL is autologous HSCT recipients. Compared with bone marrow, the widely used for the diagnosis of DAH, the diagnostic criteria use of peripheral blood as the source of stem cells may lead to have elements of subjectivity and are not uniformly applied. fewer infectious pulmonary complications and bleeding during In seven studies that included 3,806 HSCT recipients, 204 the early post-HSCT period because of its association with a cases of DAH were reported, for a frequency of 5%, with a shorter neutrophil and platelet recovery time (3). The late-onset range between 2% and 14% (8–14). The reported frequency of noninfectious pulmonary complications have been addressed in DAH varies from 1 to 21% in autologous and from 2 to 17% a recent publication (4). Although alveolar hemorrhage can be in allogeneic HSCT recipients (1, 2, 5, 9–12, 15–22). DAH has caused by infections, diffuse alveolar hemorrhage (DAH) is conbeen reported in 123 of 2,616 (5%) autologous and 91 of 1,748 sidered to be a noninfectious pulmonary complication that usu(5%) allogeneic HSCT recipients (1, 2, 5, 9–12, 15–22). The ally occurs in the early posttransplant period. This commentary recent increase in the incidence of DAH has not been associated focuses on the frequency, risk factors, pathogenesis, clinical manwith uses of granulocyte colony-stimulating factor and peripheral ifestation, treatment, and prognosis of DAH. blood stem cell source (10).

We examined the incidence and clinical outcome of late-onset noninfectious pulmonary complications (LONIPC) in a series of 234 patients who underwent allogeneic bone marrow transplantation at our institution between April 1982 and October 1996. The 179 patients who survived 3 months or more were evaluated. Clinical, radiologic, pulmonary function, and pathologic tests were reviewed to identify 18 patients (10%) who fulfilled the diagnostic criteria of LONIPC. Accordingly, the pulmonary processes included bronchiolitis obliterans (BO, five patients), bronchiolitis obliterans with organizing pneumonia (BOOP, three patients), diffuse alveolar damage (DAD, one patient), lymphocytic interstitial pneumonia (LIP, one patient), and nonclassifiable interstitial pneumonia (NCIP, eight patients). Various methods of enhanced immunosuppressive therapy resulted in marked durable remission in nine patients (50%) (3/3 with BOOP, 3/8 with NCIP, 1/1 with DAD, 1/1 with LIP, 1/5 with BO). The presence of chronic graft-versus-host disease (cGVHD) and prophylaxis for GVHD with cyclosporine and prednisone were the only variables significantly associated with the development of LONIPC (P = 0.0001 and 0.008, respectively). Regardless of histology, a reduction in the forced expiratory volume to < 45% of the predicted range was associated with poor response to treatment. These findings suggest a strong association between cGVHD and LONIPC and that the risk of LONIPC development may be influenced by the particular method of GVHD prophylaxis. Most patients with BOOP or mild airflow limitation at diagnosis achieved durable remissions.