Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.

Physical Activity and Sleep Measures Using a Fitness Tracking Device during Hematopoietic Cell Transplantation: A Pilot Study.

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices.

History of drug use in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use. The medical charts of 232 patients were reviewed. Recipients of matched unrelated donor (MUD) or matched related donor (MRD) transplants were included. Drug use was defined by either metabolic evidence or provider documentation prior to transplant. Transplants were MUD (n = 148) or MRD (n = 84). Median follow-up duration was 15.5 months. There were 35 (15%) patients in the drug use group and 197 (85%) patients in the control group; 49% and 60.4% were in remission at the time of transplant, respectively. In univariate analysis, drug use was associated with a 3-year cumulative incidence of NRM of 43% vs 29% for the control group (p = 0.048), and an HR of 1.75, (95% CI: 1.02-2.99). After controlling for age, sex, disease status, and graft type, drug use was associated with a hazard ratio (HR) of 1.6 (95% CI: 0.95-2.92) for NRM, and an HR 1.2 (95% CI: 0.74-1.94) for OS. Larger cohorts may be needed to further evaluate this association.

Interrogating the impact of KIR ligand mismatch in engraftment following HLA-disparate stem cell transplantation.

The effects of donor-derived natural killer (NK) cell alloreactivity on disease relapse and transplant-related mortality following allogeneic stem cell transplantation have been described while the impact of recipient-derived NK cell alloreactivity on donor engraftment is not well known. Epitopes of HLA Class I molecules act as ligands for NK cell killer immunoglobulin-like receptors (KIR) regulating their cytotoxicity. As such, NK cell alloreactivity is predictable from KIR ligand mismatches between donors and recipients. We analyzed the impact of KIR ligand mismatch (KIR-L-MM) on donor engraftment in 70 cord blood transplants (CBT) and 26 haploidentical transplants (HaploSCT). In CBT, host-versus-graft-directed KIR-L-MM predicted primary graft failure; an effect not mitigated by use of ATG. This trend was most significant with HLA-C KIR-L-MM. In addition, graft-versus-host-directed KIR-L-MM predicted the dominant cord blood unit in double CBT. In the limited HaploSCT cohort, host-versus-graft-directed KIR-L-MM did not predict graft failure. Time to neutrophil engraftment was unaffected by KIR-L-MM in either CBT or HaploSCT. The direction of KIR-L mismatch may be a parameter to consider when selecting CBT units to ensure successful engraftment. The role of KIR-L-MM in CBT and HaploSCT engraftment merits further exploration in a large transplant database.

Serum electrolyte dynamics in multiple myeloma patients undergoing autologous haematopoietic stem cell transplantation.

AIM: High-dose melphalan followed by autologous haematopoietic cell transplantation remains the standard-of-care therapy for multiple myeloma (MM). Gastrointestinal toxicity concomitant with electrolyte derangement is a primary cause of morbidity from transplant. Here, we assessed the dynamics of electrolyte imbalances and its role in hematologic counts and engraftment. Ω Patients and Methods One hundred and eighteen MM patients that received transplant were studied. RESULTS: Engraftment speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) and full engraftment defined as the first of three consecutive days with ANC > 500 × 106 /L. The defined median ES was 2 days (range 0-5 days) and 40 patients had ES ≤2 days. Engraftment occurred at a median of 10 days. The median time-to-nadir for phosphorus and potassium was 10 and 4.28 days, respectively. The drop in phosphorus and potassium serum level was statistically greater in patients with an ES ≤2 days compared to patients with ES ≥2 days. Magnesium level were not significantly affected and there was no significant difference between the drop in serum phosphorus and potassium based on severity of nausea or oral mucositis. CONCLUSION: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous levels and a steep rise in neutrophil counts around the engraftment period following stem cell transplant. These events indicate a "genesis syndrome" characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described after HCT for certain high-grade lymphomas and leukemias.

Low-Dose Azacitidine with DNMT1 Level Monitoring to Treat Post-Transplantation Acute Myelogenous Leukemia or Myelodysplastic Syndrome Relapse.

Patients with early relapse of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) after hematopoietic cell transplantation (HCT) have a poor prognosis, and no standard treatment. Twenty-nine patients with early disease recurrence post-transplantation were treated with azacitidine (AZA; median dose, 40 mg/m2/day for 5 to 7 days). At a median follow-up of 6.3 months (range, 1.3 to 41.1 months), 7 patients (27%) had a response to AZA, defined as complete remission, hematologic improvement, or improved donor chimerism. Response occurred after a median of 3 cycles, and the median duration of response was 70 days (range, 26 to 464 days). Median survival was 6.8 months (95% confidence interval, 3.8 to 11.1 months). Survival was similar in the patients receiving an AZA dose ≤40 mg/m2 and those receiving an AZA dose >40 mg/m2. Six patients receiving donor lymphocyte infusion with AZA had a response or stable disease without worsening graft-versus-host-disease. We retrospectively used a flow cytometry assay to explore DNA-methyltransferase-1 in blood mononuclear cells as a potential pharmacodynamic marker to assess intracellular drug targeting in 8 patients. No correlation with AZA dose or response was observed. Low-dose AZA appears to have comparable efficacy to higher-dose AZA post-HCT. A significant proportion of this poor-risk population responded to low-dose AZA, suggesting a dose-independent, noncytotoxic mechanism for antileukemic activity.

Comparison of Peripheral Blast Clearance and Day 14 Bone Marrow Biopsy in Predicting Remission Status and Survival After 7+3 Induction in Acute Myeloid Leukemia.

INTRODUCTION: Induction chemotherapy with cytarabine and an anthracycline (7+3) remains the standard of care for acute myeloid leukemia (AML). PATIENTS AND METHODS: We retrospectively analyzed 183 newly diagnosed AML patients to compare the utility of rapid peripheral blast clearance (PBC), day of peripheral blast disappearance, residual blasts, and cellularity at day 14 bone marrow biopsy (D14BM) in predicting clinical response to 7+3 induction, overall survival (OS), and relapse-free survival (RFS). RESULTS: In multivariable logistic regression analysis, day 2 PBC > 85% [P = .0016] was the only predictor of remission status, with sensitivity and specificity of 75%. Peripheral blast disappearance within 5 days after induction and < 10% cellularity in D14BM predicted superior OS and RFS in multivariate analysis. Median follow-up of patients was 28 months since diagnosis. Two-year OS and RFS for patients with ≤ 10% versus > 10% cellularity at D14BM was 60.6% [95% confidence interval (CI), 50.8%-72.2%] versus 32.5% [95% CI, 23.0%-45.8%], and 51.9% [95% CI, 41.9%-64.3%] versus 28.8% [95% CI, 19.1%-43.4%], respectively [P = .0003 for OS and .002 for RFS]. CONCLUSION: Rapid PBC after 7+3 induction showed a significant improvement in specificity compared with D14BM, with similar sensitivity. Neither of these methods were reliably specific tools for the decision of early reinduction, despite their prognostic value. Our findings indicate that morphological cellularity in D14BM is an independent prognostic factor for OS and RFS, regardless of blast percentage, and that ≤ 10% cellularity defines D14BM hypoplasia.

Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation.

Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II-IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD.

Outcomes of allogeneic hematopoietic stem cell transplantation for lymphomas: a single-institution experience

ABSTRACT Introduction: Allogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes. Methods: All patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied. Results: Forty-one patients were reviewed: 10 (24%) had Hodgkin's and 31 (76%) had non-Hodgkin lymphomas. The median age was 50 years and 23 (56%) were male. The majority of patients (68%) had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43%) patients were in complete and seven (17%) were in partial remission. Most (95%) patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival. Conclusions: Allogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.

Outcomes of allogeneic hematopoietic stem cell transplantation for lymphomas: a single-institution experience.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation offers the opportunity for extended survival in patients with Hodgkin's and non-Hodgkin lymphomas who relapsed after, or were deemed ineligible for, autologous transplantation. This study reports the cumulative experience of a single center over the past 14 years aiming to define the impact of patient, disease, and transplant-related characteristics on outcomes. METHODS: All patients with histologically confirmed diagnosis of Hodgkin's or non-Hodgkin lymphomas who received allogeneic transplantation from 2000 to 2014 were retrospectively studied. RESULTS: Forty-one patients were reviewed: 10 (24%) had Hodgkin's and 31 (76%) had non-Hodgkin lymphomas. The median age was 50 years and 23 (56%) were male. The majority of patients (68%) had had a prior autologous transplantation. At the time of allogeneic transplantation, 18 (43%) patients were in complete and seven (17%) were in partial remission. Most (95%) patients received reduced-intensity conditioning, 49% received matched sibling donor grafts, 24% matched-unrelated donor grafts, and 27% received double umbilical cord blood grafts. The 100-day treatment-related mortality rate was 12%. After a median duration of follow up of 17.1 months, the median progression-free and overall survival was 40.5 and 95.8 months, respectively. On multivariate analysis, patients who had active disease at the time of transplant had inferior survival. CONCLUSIONS: Allogeneic transplantation results extend survival in selected patients with relapsed/refractory Hodgkin's and non-Hodgkin lymphomas with low treatment-related mortality. Patients who have active disease at the time of allogeneic transplantation have poor outcomes.