Biology of Blood and Marrow Transplantation最新文献

We investigated risk factors for the development of mixed chimerism in 131 patients who underwent transplantation for myelofibrosis and determined the impact of lymphoid (CD3+) and myeloid (CD33+) chimerism on transplant outcome. Disease risk included DIPSS plus categories low to high. The median patient age was 58 years. Patients were conditioned with high-intensity (myeloablative) or low/reduced-intensity (nonmyeloablative) regimens and received a transplant from a related or unrelated donor. Mixed CD3⁺ chimerism was observed earlier after HCT, whereas CD33⁺ chimerism occurred later. Mixed chimerism was more frequent with low-intensity regimens than with high- intensity regimens. Mixed CD3⁺ chimerism did not lead to graft failure and was associated with a reduced incidence of acute GVHD and improved overall survival (OS) and relapse-free survival, whereas mixed CD33⁺ chimerism was associated with an increased incidence of relapse and reduced OS and relapse-free survival, independent of the CD34⁺ cell dose transplanted. Thus, mixed CD3⁺ chimerism in patients with myelofibrosis had a favorable impact on transplantation outcome and does not require therapeutic interventions.

A paucity of randomized phase III clinical trials in primary central nervous system lymphoma (PCNSL) has resulted in no uniform consensus on the optimal strategy for consolidation and conditioning regimens for autologous stem cell transplant (ASCT). The past 2 decades have witnessed a preference for thiotepa (TT)-based conditioning regimens due to superior central nervous system penetration. We retrospectively evaluated outcomes of patients with PCNSL who underwent ASCT at Mayo Clinic, Rochester over the past 2 decades, and the impact of TT-based conditioning regimens. Fifty-six patients underwent transplant for PCNSL, with 25 and 31 patients receiving BEAM (non-thiotepa) and carmustine (BCNU)/TT-based conditioning, respectively. All patients received high-dose methotrexate-based induction therapy. While the BCNU/TT group had higher risk disease features such as high International Extranodal Lymphoma Study Group prognostic score, elevated cerebrospinal fluid protein, and older patient population, there was no significant difference at 2 years post-transplant in progression-free survival (BEAM 68.0% [46.1% to 82.5%] versus BCNU/TT, 65.5% [45.2% to 79.8%], P = .99) or overall survival (OS) (84.0% [62.8% to 93.7%] in the BEAM group versus 81.6% [61.3% to 91.9%] in the BCNU/TT group, P = .95). Disease response status before transplant significantly affected the outcomes as those in complete remission had an OS at 2 years post-transplant of 94.7% (68.1% to 99.2%) in the BEAM group and 90.5% (67.0% to 97.5%) in the BCNU/TT group compared with those in partial response, 57.1% (17.2% to 83.7%) in BCNU/TT group and 50.0% (11.1% to 80.4%) in the BEAM group, respectively (P < .0001). Our retrospective cohort adds to the currently available literature and identifies the disease status before transplant as a significant factor affecting survival.

For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.

Fanconi anemia is the most common inherited bone marrow failure syndrome, and hematopoietic stem cell transplantation (HSCT) is the only curative option. Post-transplant cyclophosphamide (PTCy) is challenging in this group of children, given their increased sensitivity to chemotherapy. We performed a retrospective analysis of the data on children diagnosed with Fanconi anemia who underwent a haploidentical HSCT with PTCy from January 2014 to December 2019. Nineteen children (male/female, 0.75:1) underwent 21 haplo-HSCTs with PTCy. Fludarabine, low-dose cyclophosphamide, and 200 centi-gray total body irradiation were included in the conditioning regimen with 25 mg/kg PTCy on days +3 and +4. Haplo-graft was from a sibling in 38% and father in 57% of transplants. The source of stem cells was peripheral blood stem cells in 81% and bone marrow in 19% of transplants, with a median CD34 dose of 5.0 × 10⁶/kg. We documented engraftment in 84% and primary graft failure in 10% of transplants. N-acetylcysteine (NAC) was infused concomitantly during cyclophosphamide in 13 children. Grade 2 and 3 mucositis was lower among those who received NAC as compared to those who did not (30% and 15% versus 33% and 50%), while transaminitis was higher among those who did not receive the infusion. The incidence of acute graft-versus-host disease (GVHD) was 68%, and 81% of these were steroid responsive (grade I/II). We documented chronic GVHD in 25% children, predominantly involving the skin and mouth, which responded to low-dose steroids and ruxolitinib. Serum ferritin was monitored twice weekly as a surrogate marker for cytokine release syndrome due to nonavailability of IL-6 levels. A 1- or 2-log increase in the titers of ferritin associated with clinical features guided the early addition of steroids in the periengraftment period. The mean survival was found to be less among those with high serum ferritin (>10,000 ng/dL) in the periengraftment period as compared to those with ferritin <10,000 ng/dL (mean survival of 25 ± 10 months versus 50 ± 6 months, respectively). The overall survival in our cohort was 68.4%, with a mean survival time of 41.5 months (95% confidence interval, 29.3 to 53.8 months), with a statistically significant correlation between inferior outcome and having received over 15 transfusions before HSCT (P = .01). PTCy can be considered a viable option in children with Fanconi anemia, particularly in resource-limited settings given the high costs of HSCTs. Focused interventions in this subset of children help improve survival outcomes. Early identification of cytokine release syndrome and risk-adapted steroid therapy during engraftment helps prevent mortality. The concomitant use of NAC during cyclophosphamide infusion helps reduce oxygen free radical related tissue damage and regimen-related toxicity.

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs.

Ruxolitinib is an oral JAK1/2 inhibitor that is approved for use in patients with intermediate and high-risk myelofibrosis (MF) based on its proven spleen and symptom burden reduction. Its impact on hematopoietic stem cell transplantation (HSCT) outcomes is largely unknown, however. A significant number of patients proceeding to HSCT have been treated with ruxolitinib, and the specifics of its peritransplantation use vary widely in the published literature. Here we review the currently published data and experience to guide management of patients with MF on ruxolitinib proceeding to HSCT.

Cyclosporine (CsA) combined with short-course methotrexate is considered standard-of-care graft-versus-host disease (GVHD) prophylaxis for patients with severe aplastic anemia (AA) who undergo transplantation using cyclophosphamide (Cy) plus anti-thymocyte globulin (ATG) conditioning. However, there is no consensus on optimal post-transplant GVHD prophylaxis for patients undergoing matched related donor (MRD) transplantation using fludarabine (Flu)-based conditioning. We conducted a single-center retrospective analysis of patients with acquired AA (n = 106) undergoing MRD transplantation from July 2007 through January 2019. All patients received Flu-Cy-ATG conditioning and single-agent CsA as GVHD prophylaxis. Median age of the study cohort was 20 years (range, 3 to 52) and male to female ratio was 3.8:1. Median time from diagnosis to transplant was 11.5 months (range, 2.8 to 62). Graft source was bone marrow harvest in 71 (68%), combined bone marrow and peripheral blood stem cells in 34 (31%), and peripheral blood alone in 1 (1%) patient. Cumulative incidence of neutrophil engraftment at day 28 was 93.4% (95% confidence interval [CI], 87.3% to 97.1%) while that of platelet engraftment at day 100 was 90.5% (95% CI, 84% to 96%). Cumulative incidence of primary graft failure at day 28 was 6.6% (95% CI, 4% to 8%) while secondary graft failure occurred at a median of 190 days (range, 90 to 415) at a cumulative incidence of 3.7% (95% CI, 2% to 5%). Cumulative incidence of grade II to IV acute GVHD at day 100 was 3.8% (95% CI, 1.4% to 9.9%), while a 1-year probability of chronic GVHD was calculated as 7.5% (95% CI, 2.6% to 15%). Median follow-up post-transplant was 61 months (range, 6 to 144). Overall survival was 84.9%, disease-free survival was 80.2%, and GVHD-free relapse-free survival was 76.3%. This study indicates that single-agent cyclosporine is a feasible option for GVHD prophylaxis in MRD hematopoietic stem cell transplantation using Flu-Cy-ATG conditioning and is associated with very low rates of acute and chronic GVHD.

Granulocyte colony-stimulating factor (G-CSF) is administered after allogeneic hematopoietic cell transplantation (HCT) to aid neutrophil recovery. We compared the effect of empiric G-CSF administration on the duration of index inpatient hospitalization stay after HCT for patients aged ≥18 years with a hematologic malignancy. G-CSF was considered empiric if administered between day -3 and day +6 in relation to graft infusion. We studied 3562 HCTs (1487 HLA-matched sibling donor HCTs and 2075 HLA-matched unrelated donor HCTs) between 2007 and 2016. Three hundred and thirteen (21%) recipients of HLA-matched sibling donor HCT and 417 (20%) recipients of HLA-matched unrelated donor HCT received empiric G-CSF therapy. The effect of G-CSF therapy on the index hospitalization stay was examined in generalized linear models (GLMs) with adjustment for other patient, disease, and transplantation characteristics and acute graft-versus-host disease and infection post-transplantation. The duration of index hospitalization by treatment group did not differ for HLA-matched sibling donor HCT but was shorter with G-CSF for HLA-matched unrelated donor HCT (15 days versus 19 days; P < .001). Our GLMs confirmed shorter hospitalization with the use of G-CSF therapy for HLA-matched unrelated donor HCT (P = .01). G-CSF therapy was not associated with early survival for either donor type, and there was no benefit or disadvantage of giving G-CSF to promote neutrophil recovery.