Iron Overload is Associated with Delayed Engraftment and Increased Non-Relapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
The negative impact of Iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well-recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin level (SF) of 2000 ng/ml. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/ml was 26.1% (95%CI: 10.6%-44.7%) and 52.1% (95%CI: 40.1%-62.8%), respectively; HR=2.26 (95%CI: 1.28-4.00, P=0.005). Two-year non-relapse mortality rate was higher among patients with SF >2000 ng/ml (56.5%, 95%CI: 33.3%-74.4%) compared to SF ≤2000 ng/ml (30.1%, 95%CI: 20.0%-40.9%); HR=2.18, (95%CI: 1.10-4.31, P=0.025). Neutrophil engraftment at 42 days was 78.3% (95%CI: 53.5%-90.8%) in patients with SF >2000 ng/ml, versus 91.8% (95%CI: 82.1%-96.4%) in patients with SF ≤2000 ng/ml; HR=0.58 (95%CI: 0.35-0.96, P=0.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95%CI: 29.4%-70.8%) for SF>2000 ng/ml versus 80.8% (95%CI: 69.5%-88.3%) for SF ≤2000 ng/ml; HR=0.48 (95%CI: 0.23-0.98, P=0.044). In conclusion, IO defined by SF of 2000 ng/ml is a strong adverse prognostic factor for UCB-HCT and should be a considered when UCB is chosen as the graft source for patients without a fully matched donor.
Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial
Annals of internal medicine. 2020
Background: Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT). Objective: To determine the safety and efficacy of Triplex. Design: First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933). Setting: 3 U.S. HCT centers. Participants: 102 CMV-seropositive HCT recipients at high risk for CMV reactivation. Intervention: Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens. Measurements: The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection. Results: A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients. Limitation: The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. Conclusion: No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia. Primary Funding Source: National Cancer Institute and Helocyte.
CMV-seropositive HCT recipients at high risk for CMV reactivation (n=102)
Intramuscular injections of Triplex CMV vaccine (n=51)
Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.
Long-term outcome of allogeneic hematopoietic stem cell transplantation from unrelated donor using tacrolimus/sirolimus-based GVHD prophylaxis: impact of HLA mismatch
BACKGROUND While Tacrolimus/Sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor (URD) HCT (2005 - 2013) with T/S-based GvHD prophylaxis. RESULTS With a median follow-up of 6.2 years (range=2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95%CI: 43.0-52.0) and 43.6% (95%CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of non relapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% vs. 50.7% at 5 years, p=0.034), primarily due to greater risk of NRM (33.5% vs. 21.7%, p=0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% vs. 12.8%, p=0.022) and infection (33.0% vs. 18.1%, p<0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (HR= 2.21, 95%CI: 1.16-4.23; p<0.01) and mMUD (HR=1.55, 95%CI:.1.15-2.08; p=0.004) were independent predictive factors for OS. CONCLUSIONS T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.
Protective effect of HLA-DPB1 mismatch remains valid in reduced-intensity conditioning unrelated donor hematopoietic cell transplantation
Bone marrow transplantation. 2019
A mismatch at HLA-DPB1 locus is associated with higher acute GVHD and lower relapse rate after myeloablative (MAC) allogeneic hematopoietic cell transplantation (alloHCT). Also, in MAC setting, mismatch permissiveness and expression level impact alloHCT outcomes. However, in reduced intensity conditioning (RIC), DP mismatch effect on transplant outcomes is unknown. We retrospectively evaluated DP mismatch influence (number, permissiveness, and expression) on HCT outcomes in 310 patients with high-resolution typing (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1), who underwent RIC HCT. By multivariable analysis, 11/12 had better overall survival (OS) and relapse vs. 12/12 (HR = 1.61 and 2.02; p = 0.04 and 0.01, respectively) and better OS vs. 10/12 (HR = 1.68; p = 0.02). Within the 11/12, nonpermissive (NoPR) mismatch was associated with higher risk of grade II-IV acute GVHD (HR = 1.97; p = 0.005) and nonrelapse mortality (HR = 2.13; p = 0.02) vs. permissive (PR). Grouping 11/12 based on the DP expression conferred higher mortality (HR = 3.78; p = 0.003) when low expressers received a graft from high expressers (AG) vs. low expressers (AA). Better OS was achieved in PR 11/12, when expression was low in patient and donor (AA) vs. all other combinations. Therefore, in RIC HCT, a single-DP mismatch has a protective role, especially in permissive setting, when donor and recipient are low expressers.
Melphalan-Based Reduced Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
Allogeneic hematopoietic stem cell transplantation (AlloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study, we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent AlloHCT with melphalan (Mel)-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with "semi-ablative" nature of this regimen. With a median follow up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative Incidence (CI) of relapse at 1- and 2-years were 17.0% and 19.3%, respectively. 100-day CI of grade II-IV acute GVHD was 37.7% (grade III-IV: 18.9%), and 2-year CI of chronic GVHD was 61.9% (45.9% extensive). The only significant predictor for poor OS was high/very high disease risk index (DRI). Transplant-related complication/morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion; AlloHCT with Mel-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse and favorable OS and PFS in patients with 70 years of age or older.
Provisional Title: Safety Analysis of Brentuximab Vedotin From the Phase 3 AETHERA Trial in Hodgkin Lymphoma in the Posttransplant Consolidation Setting
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
The phase 3 AETHERA trial demonstrated brentuximab vedotin's (BV) efficacy as consolidation therapy in patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression following autologous hematopoietic stem cell transplant (auto-HSCT; hazard ratio [HR]=0.57; P<0.001). The objective of this analysis is to provide further detail on the most common and clinically important treatment-emergent adverse events (TEAEs) in the AETHERA BV arm including their occurrence and management. AEs of clinical importance occurring in patients who participated in AETHERA (BV + best supportive care [BSC], n=165; placebo + BSC, n=164) were evaluated for time to onset, manageability through dose modification, and resolution. As previously reported, peripheral neuropathy (PN; 67%), infections (60%), and neutropenia (35%) were the most common BV-associated TEAEs. Neutropenia was managed with dose delays and granulocyte colony-stimulating factor; no dose reductions or discontinuations were required. The majority (57%) of PN cases were managed with dose delays and reductions. The median time to PN onset was 13.7 (range, 0.1-47.4) weeks. After end of treatment, PN continued to resolve; symptom resolution was similar to that in the placebo arm at 3 years, demonstrating reversibility. BV had no significant impact on preexisting PN. Patients with PN-related dose modifications had progression-free survival (PFS) comparable to patients without. Other less common but serious AEs, including pulmonary toxicities, hepatotoxicity, and cardiotoxicity, were rare in both arms and managed with BV dose modifications or discontinuations. Secondary malignancies were rare and reported in patients with comorbidities or other risk factors. Consolidation therapy with BV for patients with HL at high risk of relapse after auto-HSCT is associated with sustained PFS. The most common AEs in the BV arm were manageable and reversible. Awareness of these AEs and management approaches will enable healthcare providers and patients to plan the safest and most effective treatment plan.
Engraftment and outcomes following autologous stem cell transplantation in Hodgkin lymphoma patients mobilized with plerixafor
Hematological Oncology. 2017;35(3):281-287
Plerixafor has been used to improve peripheral blood stem cell (PBSC) mobilization in multiple myeloma, non-Hodgkin lymphoma, and very recently in Hodgkin lymphoma (HL) patients. Because prior studies have suggested that mobilization with plerixafor affects the composition of mobilized cells, there are concerns that this may in turn adversely impact the immune reconstitution and longer term outcomes of transplanted patients. However, data on the engraftment characteristics and long-term post-transplant outcomes in patients transplanted with plerixafor-mobilized PBSCs are lacking. This retrospective study examined the post-transplant outcomes of 105 consecutive adult HL patients, and compared the post-transplant outcomes of 21 patients who received plerixafor in addition to G-CSF+/-chemotherapy because of poor mobilization with those of 84 patients who mobilized well without plerixafor. Despite collecting significantly lower CD34+ cell doses (median of 3.41 vs. 6.05x106 /kg, p<0.0001) than control patients and requiring more collection days, plerixafor-mobilized patients showed comparable early engraftment characteristics, except for slightly delayed neutrophil engraftment (median: 11 vs.10days, p=0.002) and lower median neutrophil counts (2.1 vs. 2.6x109 /L, p=0.04) at one month after transplant. No significant differences were observed in longer term post-transplant outcomes, including cell counts at 3, 6, and 12months, RBC and platelet transfusion support during the first 120days, relapse incidence, overall and progression-free survival rates up to two years post transplant. The use of plerixafor not only enabled poorly mobilizing HL patients to collect enough PBSCs to proceed to ASCT, but also to have similar post-transplant outcomes compared to patients who mobilized well with conventional regimens. Copyright © 2016 John Wiley & Sons, Ltd.
Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia
Biology of Blood & Marrow Transplantation. 2017;23(2):318-324
Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.
Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Chemotherapy in Mantle Cell Lymphoma Patients Is Associated with Higher Rates of Hematopoietic Progenitor Cell Mobilization Failure despite Plerixafor Rescue
Biology of Blood & Marrow Transplantation. 2017;23(8):1264-1268
Induction regimens for mantle cell lymphoma (MCL) can be categorized into highly intensive regimens containing cytarabine and less intense regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) or rituximab with bendamustine (R-bendamustine). Prior publications have shown rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) can be associated with stem cell mobilization failures. However, those studies did not include the use of plerixafor as rescue for stem cell mobilization failure. We examined our database of 181 consecutive MCL patients who received upfront therapy from 2005 to 2015 with either R-hyperCVAD or less intense chemotherapy (R-bendamustine and R-CHOP only) regimens to assess impact of frontline chemotherapy on collection of hematopoietic cell progenitors before autologous stem cell transplantation (ASCT). In the preplerixafor era (before August 16, 2009), a significant difference in peripheral blood stem cell (PBSC) collection failure between the R-hyperCVAD (12%) and other chemotherapy (11%) groups was not established. However, in the postplerixafor era, use of R-hyperCVAD chemotherapy was associated with significantly higher rates of hematopoietic progenitor cell collection failures (17%) compared with that observed in the other chemotherapy group (4%; P=.04). The rates of mobilization failure declined to 4% in the postplerixafor era from 11% in the preplerixafor era for patients receiving less intensive chemotherapy. Conversely, the rate of mobilization failure increased in the R-hyperCVAD group from 12% in the preplerixafor era to 17% in the postplerixafor era. Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT.
CD25 Blockade Delays Regulatory T Cell Reconstitution and Does Not Prevent Graft-versus-Host Disease After Allogeneic Hematopoietic Cell Transplantation
Biology of Blood & Marrow Transplantation. 2017;23(3):405-411
Daclizumab, a humanized monoclonal antibody, binds CD25 and blocks formation of the IL-2 receptor on T cells. A study of daclizumab as acute graft-versus-host disease (GVHD) prophylaxis after unrelated bone marrow transplantation was conducted before the importance of CD25+FOXP3+ regulatory T cells (Tregs) was recognized. Tregs can abrogate the onset of GVHD. The relation between Tregs and a graft-versus-malignancy effect is not fully understood. An international, multicenter, double-blind clinical trial randomized 210 adult or pediatric patients to receive 5 weekly doses of daclizumab at 0.3mg/kg (n=69) or 1.2mg/kg (n=76) or placebo (n=65) after unrelated marrow transplantation for treatment of hematologic malignancies or severe aplastic anemia. The risk of acute GVHD did not differ among the groups (P=.68). Long-term follow-up of clinical outcomes and correlative analysis of peripheral blood T cell phenotype suggested that the patients treated with daclizumab had an increased risk of chronic GVHD (hazard ratio [HR],1.49; 95% confidence interval [CI], 1.0 to 2.3; P=.08) and a decreased risk of relapse (HR, 0.57; 95% CI, 0.3 to 1.0; P=.05), but similar survival (HR,0.89; 95% CI, 0.6 to 1.3; P=.53). T cells from a subset of patients (n=107) were analyzed by flow cytometry. Compared with placebo, treatment with daclizumab decreased the proportion of Tregs among CD4 T cells at days 11-35 and increased the proportion of central memory cells among CD4 T cells at 1 year. Prophylactic administration of daclizumab does not prevent acute GVHD, but may increase the risk of chronic GVHD and decrease the risk of relapse. By delaying Treg reconstitution and promoting immunologic memory, anti-CD25 therapy may augment alloreactivity and antitumor immunity. Copyright © 2017. Published by Elsevier Inc.