We previously demonstrated that autologous natural killer (NK)–cell therapy after hematopoietic cell transplantation (HCT) is safe but does not provide an antitumor effect. We hypothesize that this ...is due to a lack of NK-cell inhibitory receptor mismatching with autologous tumor cells, which may be overcome by allogeneic NK-cell infusions. Here, we test haploidentical, related-donor NK-cell infusions in a nontransplantation setting to determine safety and in vivo NK-cell expansion. Two lower intensity outpatient immune suppressive regimens were tested: (1) low-dose cyclophosphamide and methylprednisolone and (2) fludarabine. A higher intensity inpatient regimen of high-dose cyclophosphamide and fludarabine (Hi-Cy/Flu) was tested in patients with poor-prognosis acute myeloid leukemia (AML). All patients received subcutaneous interleukin 2 (IL-2) after infusions. Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells. In contrast, infusions after the more intense Hi-Cy/Flu resulted in a marked rise in endogenous IL-15, expansion of donor NK cells, and induction of complete hematologic remission in 5 of 19 poor-prognosis patients with AML. These findings suggest that haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to HCT.
Using multicenter data, we developed a novel acute graft-
-host disease Risk Score which more accurately predicts response to steroid treatment, survival and transplant related mortality than other ...published risk scores based upon clinical grading criteria.
To validate this Risk Score in a contemporary cohort, we examined 355 recent University of Minnesota patients (2007-2016) diagnosed with acute graft-
-host disease and treated with prednisone 60 mg/m
/day for 14 days, followed by an 8-week taper. Overall response complete response + partial response was higher in the 276 standard risk
79 high risk graft-
-host disease patients at day 14 (71%
56%,
<0.01), day 28 (74% versus 59%,
=0.02) and day 56 (68%
49%,
<0.01) after steroid initiation. Day 28 response did not differ by the initial graft-
-host disease grade. In multiple regression analysis, patients with high risk graft-
-host disease were less likely to respond at day 28 (odds ratio 0.5, 95% CI 0.3-0.9,
<0.01) and had higher risks of 2 year transplant related mortality (Hazard Ratio 1.8, 95% CI, 1.0-2.1,
=0.03) and overall mortality (Hazard Ratio 1.7, 95% CI, 1.2-2.4,
<0.01) than patients with a standard risk graft-
-host disease. This analysis confirms the Minnesota graft-
-host disease Risk Score as a valuable bedside tool to define risk in patients with acute graft-
-host disease. A tailored approach to upfront acute graft-
-host disease therapy based upon the Minnesota Risk Score may improve outcomes and facilitate testing of novel treatments in these patients.
We sought to study whether survival after haploidentical transplantation is comparable to that after matched unrelated donor transplantation for 822 patients aged 50-75 years with acute myeloid ...leukemia in first or second complete remission. One hundred and ninety-two patients received grafts from haploidentical donors (sibling 25%; offspring 75%) and 631 patients from matched unrelated donors aged 18-40 years. Patients' and disease characteristics of the two groups were similar except that recipients of matched unrelated donor transplantation were more likely to have poor risk cytogenetics and more likely to receive myeloablative conditioning regimens. Time from documented remission to transplant did not differ by donor type. Five-year overall survival was 32% and 42% after haploidentical and matched unrelated donor transplant, respectively (
=0.04). Multivariable analysis showed higher mortality (hazard ratio 1.27,
=0.04) and relapse (hazard ratio 1.32,
=0.04) after haploidentical transplantation, with similar non-relapse mortality risks. Chronic graft-
-host disease was higher after matched unrelated donor compared to haploidentical transplantation when bone marrow was the graft (hazard ratio 3.12,
<0.001), but when the graft was peripheral blood, there was no difference in the risk of chronic graft-
-host disease between donor types. These data support the view that matched unrelated donor transplant with donors younger than 40 years is to be preferred.
The novel bispecific ligand-directed toxin (BLT) DT2219 consists of a recombinant fusion between the catalytic and translocation enhancing domain of diphtheria toxin (DT) and bispecific single-chain ...variable fragments (scFV) of antibodies targeting human CD19 and CD22. We conducted a phase I dose-escalation study to assess the safety, maximum tolerated dose, and preliminary efficacy of DT2219 in patients with relapsed/refractory B-cell lymphoma or leukemia.
DT2219 was administered intravenously over 2 hours every other day for 4 total doses. Dose was escalated from 0.5 μg/kg/day to 80 μg/kg/day in nine dose cohorts until a dose-limiting toxicity (DLT) was observed.
Twenty-five patients with mature or precursor B-cell lymphoid malignancies expressing CD19 and/or CD22 enrolled to the study. Patients received median 3 prior lines of chemotherapy and 8 failed hematopoietic transplantation. All patients received a single course of DT2219; one patient was retreated. The most common adverse events, including weight gain, low albumin, transaminitis, and fever were transient grade 1-2 and occurred in patients in higher dose cohorts (≥40 μg/kg/day). Two subjects experienced DLT at dose levels 40 and 60 μg/kg. Durable objective responses occurred in 2 patients; one was complete remission after 2 cycles. Correlative studies showed a surprisingly low incidence of neutralizing antibody (30%).
We have determined the safety of a novel immunotoxin DT2219 and established its biologically active dose between 40 and 80 μg/kg/day ×4. A phase II study exploring repetitive courses of DT2219 is planned.
Background
A comprehensive assessment of morbidity after allogeneic bone marrow transplantation (BMT) performed in childhood remains understudied.
Methods
Seven hundred eighty‐nine allogeneic BMT ...recipients who had survived ≥2 years after BMT performed between 1974 and 2014 at age <22 years and 690 siblings completed a 255‐item survey self‐reporting sociodemographics and chronic health conditions. A severity score (grade 3 severe, 4 life‐threatening, or 5 fatal) was assigned to the conditions using Common Terminology Criteria for Adverse Events, version 5.0. For the BMT cohort, the cumulative incidence of chronic health conditions was calculated as a function of time from BMT. Proportional subdistribution hazards models were used to determine predictors of grade 3–5 conditions. Logistic regression was used to estimate the risk of grade 3–4 conditions in BMT recipients who were alive at the time of this study compared with siblings.
Results
The median age at transplantation was 11.3 years (range, 0.4–22.0 years), and the median length of follow‐up was 11.7 years (range, 2.0–45.3 years). The most prevalent primary diagnoses were acute lymphoblastic leukemia (30.7%), and acute myeloid leukemia/myelodysplastic syndrome (26.9%). At age 35 years, the cumulative incidence of a grade 3–4 condition was 53.8% (95% CI, 46.7%–60.3%). The adjusted odds ratio of a grade 3–4 condition was 15.1 in survivors (95% CI, 9.5–24.0) compared with siblings. The risk of a grade 3–5 condition increased with age at BMT (hazard ratio HR, 1.03; 95% CI, 1.01–1.05) and was higher among females (HR, 1.27; 95% CI, 1.02–1.59), patients who received total body irradiation (HR, 1.71; 95% CI, 1.27–2.31), and those reporting chronic graft‐versus‐host disease (HR, 1.38; 95% CI, 1.09–1.74).
Conclusions
Two‐year survivors of allogeneic BMT in childhood have an increased risk of grade 3–4 chronic health conditions compared with siblings, suggesting the need for long‐term follow‐up.
Two‐year survivors of allogeneic bone marrow transplantation in childhood have a substantially increased risk of chronic health conditions compared with siblings. By age 35 years, more than one half of bone marrow transplantation recipients had a severe or life‐threatening chronic health condition.
Reduced-intensity conditioning may reduce transplantation-related mortality in high-risk adults undergoing hematopoietic transplantation. We investigated unrelated donor umbilical cord blood (UCB) ...transplantation after such conditioning in 43 patients (median age, 49.5 years; range, 22-65 years) with a primary end point of donor engraftment. The first 21 patients received busulfan 8 mg/kg, fludarabine 200 mg/m2, and 200 cGy of total body irradiation (Bu/Flu/TBI). Subsequent patients (n = 22) received cyclophosphamide 50 mg/kg, fludarabine 200 mg/m2, and 200 cGy TBI (Cy/Flu/TBI). UCB grafts (93%) were 1-2 HLA antigen–mismatched with the recipient and contained a median cryopreserved cell dose of 3.7 × 107 (range, 1.6 × 107-6.0 × 107) nucleated cells per kilogram of recipient body weight (NC/kg). Graft versus host disease (GVHD) prophylaxis was cyclosporin A to day 180 plus mycophenolate mofetil to day 30. The cumulative incidence of sustained donor engraftment was 76% (95% confidence interval CI, 56%-96%) for Bu/Flu/TBI recipients and 94% (95% CI, 84%-100%) for Cy/Flu/TBI recipients. The median day of neutrophil recovery (at least 0.5 × 109/L) for engrafting Bu/Flu/TBI recipients was 26 days (range, 12-30 days) and for Cy/Flu/TBI recipients was 9.5 days (range, 5-28 days). Incidence of grades III-IV acute GVHD was 9% (95% CI, 1%-17%), and survival at 1 year was 39% (95% CI, 23%-56%). These data demonstrate that 0-2 antigen mismatched UCB is sufficient to engraft most adults after reduced-intensity conditioning and is associated with a low incidence of severe acute GVHD.
Initial therapy of chronic graft-
-host disease is prednisone ± a calcineurin-inhibitor, but most patients respond inadequately. In a randomized, adaptive, phase II/III, multicenter trial we studied ...whether prednisone/sirolimus or prednisone/sirolimus/photopheresis was more effective than prednisone/sirolimus/calcineurin-inhibitor for treating chronic graft-
-host disease in treatment-naïve or early inadequate responders. Primary endpoints of this study were proportions of subjects alive without relapse or secondary therapy with 6-month complete or partial response in phase II, or with 2-year complete response in phase III. The prednisone/sirolimus/photopheresis arm closed prematurely because of slow accrual and the remaining two-drug
three-drug study ended in phase II due to statistical futility with 138 evaluable subjects. The two-drug and three-drug arms did not differ in rates of 6-month complete or partial response (48.6%
50.0%,
=0.87), or 2-year complete response (14.7%
15.5%,
=0.90). Serum creatinine values >1.5 times baseline were less frequent in the calcineurin-inhibitor-free arm at 2 months (1.5%
11.7%,
=0.025) and 6 months (7.8%
24.0%,
=0.016). Higher adjusted Short Form-36 Physical Component Summary and Physical Functioning scores were seen in the two-drug arm at both 2 months (
=0.02 and
=0.04, respectively) and 6 months (
=0.007 and
=0.001, respectively). Failure-free survival and overall survival rates at 2 years were similar for patients in the the two-drug and three-drug arms (48.6%
46.2%,
=0.78; 81.5%
74%,
=0.28). Based on similar long-term outcomes, prednisone/sirolimus is a therapeutic alternative to prednisone/sirolimus/calcineurin-inhibitor for chronic graft-
-host disease, being easier to administer and better tolerated.
Limited umbilical cord blood (UCB) cell dose compromises the outcome of adult UCB transplantation. Therefore, to augment graft cell dose, we evaluated the safety of the combined transplantation of 2 ...partially human leukocyte antigen (HLA)–matched UCB units. Twenty-three patients with high-risk hematologic malignancy (median age, 24 years; range, 13-53 years) received 2 UCB units (median infused dose, 3.5 × 107 nucleated cell NC/kg; range, 1.1-6.3 × 107 NC/kg) after myeloablative conditioning. All evaluable patients (n = 21) engrafted at a median of 23 days (range, 15-41 days). At day 21, engraftment was derived from both donors in 24% of patients and a single donor in 76% of patients, with 1 unit predominating in all patients by day 100. Although neither nucleated or CD34+ cell doses nor HLA-match predicted which unit would predominate, the predominating unit had a significantly higher CD3+ dose (P < .01). Incidences of grades II-IV and III-IV acute GVHD were 65% (95% confidence interval CI, 42%-88%) and 13% (95% CI, 0%-26%), respectively. Disease-free survival was 57% (95% CI, 35%-79%) at 1 year, with 72% (95% CI, 49%-95%) of patients alive if they received transplants while in remission. Therefore, transplantation of 2 partially HLA-matched UCB units is safe, and may overcome the cell-dose barrier that limits the use of UCB in many adults and adolescents.
Acute graft-versus-host disease (aGVHD) is the primary limitation of allogeneic hematopoietic cell transplantation. Corticosteroids remain the standard initial therapy, yet only 25% to 41% of ...patients completely respond. This randomized, 4-arm, phase 2 trial was designed to identify the most promising agent(s) for initial therapy for aGVHD. Patients were randomized to receive methylprednisolone 2 mg/kg per day plus etanercept, mycophenolate mofetil (MMF), denileukin diftitox (denileukin), or pentostatin. Patients (n = 180) were randomized; their median age was 50 years (range, 7.5-70 years). Myeloablative conditioning represented 66% of transplants. Grafts were peripheral blood (61%), bone marrow (25%), or umbilical cord blood (14%); 53% were from unrelated donors. Patients who received MMF for prophylaxis (24%) were randomized to a non-MMF arm. At randomization, aGVHD was grade I to II (68%), III to IV (32%), and (53%) had visceral organ involvement. Day 28 complete response rates were etanercept 26%, MMF 60%, denileukin 53%, and pentostatin 38%. Corresponding 9-month overall survival was 47%, 64%, 49%, and 47%, respectively. Cumulative incidences of severe infections were as follows: etanercept 48%, MMF 44%, denileukin 62%, and pentostatin 57%. Efficacy and toxicity data suggest the use of MMF plus corticosteroids is the most promising regimen to compare against corticosteroids alone in a definitive phase 3 trial. This study is registered at http://www.clinicaltrials.gov as NCT00224874.
Normal adults have a small number of circulating endothelial cells (CEC) in peripheral blood, and endothelial outgrowth has been observed from cultures of blood. In this study we seek insight into ...the origins of CEC and endothelial outgrowth from cultures of blood. Fluorescence in situ hybridization analysis of blood samples from bone marrow transplant recipients who had received gender-mismatched transplants 5-20 months earlier showed that most CEC in fresh blood had recipient genotype. Endothelial outgrowth from the same blood samples after 9 days in culture (5-fold expansion) was still predominantly of the recipient genotype. In contrast, endothelial outgrowth after approximately 1 month (102-fold expansion) was mostly of donor genotype. Thus, recipient-genotype endothelial cells expanded only approximately 20-fold over this period, whereas donor-genotype endothelial cells expanded approximately 1000-fold. These data suggest that most CEC in fresh blood originate from vessel walls and have limited growth capability. Conversely, the data indicate that outgrowth of endothelial cells from cultures of blood is mostly derived from transplantable marrow-derived cells. Because these cells have more delayed outgrowth but a greater proliferative rate, our data suggest that they are derived from circulating angioblasts.
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