[Show abstract][Hide abstract]ABSTRACT: Background
The binding of CXCR4 with its ligand (stromal-derived factor-1) maintains hematopoietic stem/progenitor cells (HSPCs) in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT) promotes hematopoiesis by inducing HSC proliferation. Methods
We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. ResultsThirty patients received plerixafor following peripheral blood stem cell (n = 28) (PBSC) or bone marrow (n = 2) transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04) and platelet recovery >20 K (p = 0.04) compared to the controls. Conclusions
Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registrationClinicalTrials.gov NCT01280955
Full-text Article · Dec 2016 · Journal of Hematology & Oncology
[Show abstract][Hide abstract]ABSTRACT: Background
Respiratory viral infections (RVIs) are frequent complications of hematopoietic stem cell transplant (HSCT). Surgical masks are a simple and inexpensive intervention that may reduce nosocomial spread.
In this prospective single-center study, we instituted a universal surgical mask policy requiring all individuals with direct contact with HSCT patients to wear a surgical mask, regardless of symptoms or season. The primary endpoint was the incidence of RVIs in the mask period (2010–2014) compared with the premask period (2003–2009).
RVIs decreased from 10.3% (95/920 patients) in the premask period to 4.4% (40/911) in the mask period (P < .001). Significant decreases occurred after both allogeneic (64/378 [16.9%] to 24/289 [8.3%], P = .001) and autologous (31/542 [5.7%] to 16/622 [2.6%], P = .007) transplants. After adjusting for multiple covariates including season and year in a segmented longitudinal analysis, the decrease in RVIs remained significant, with risk of RVI of 0.4 in patients in the mask group compared with the premask group (0.19–0.85, P = .02). In contrast, no decrease was observed during this same period in an adjacent hematologic malignancy unit, which followed the same infection control practices except for the mask policy. The majority of this decrease was in parainfluenza virus 3 (PIV3) (8.3% to 2.2%, P < .001).
Requiring all individuals with direct patient contact to wear a surgical mask is associated with a reduction in RVIs, particularly PIV3, during the most vulnerable period following HSCT.
[Show abstract][Hide abstract]ABSTRACT: To compare leukemia-free survival (LFS) and other clinical outcomes in patients with acute myelogenous leukemia (AML) who underwent a myeloablative allogeneic stem cell transplant (allo-SCT) with and without total body irradiation (TBI).
[Show abstract][Hide abstract]ABSTRACT: Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor alpha, interferon gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells.
Full-text Article · May 2016 · European Journal Of Haematology
[Show abstract][Hide abstract]ABSTRACT: Purpose:
To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS).
Patients and methods:
We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT.
Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort.
The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.
Full-text Article · Apr 2016 · Journal of Clinical Oncology
[Show abstract][Hide abstract]ABSTRACT: Despite the advent of targeted therapies and novel agents, allogeneic hematopoietic stem cell transplantation remains the only curative modality in the management of hematologic disorders. The necessity to find an HLA-matched related donor is a major obstacle that compromises the widespread application and development of this field. Matched unrelated donors and umbilical cord blood have emerged as alternative sources of donor stem cells; however, the cost of maintaining donor registries and cord blood banks is very high and even impractical in developing countries. Almost every patient has an HLA haploidentical relative in the family, meaning that haploidentical donors are potential sources of stem cells, especially in situations where cord blood or matched unrelated donors are not easily available. Due to the high rates of graft failure and graft-versus-host disease, haploidentical transplant was not considered a feasible option up until the late 20th century, when strategies such as “megadose stem cell infusions” and posttransplantation immunosuppression with cyclophosphamide showed the ability to overcome the HLA disparity barrier and significantly improve the rates of engraftment and reduce the incidence and severity of graft-versus-host disease. Newer technologies of graft manipulation have also yielded the same effects in addition to preserving the antileukemic cells in the donor graft.
Full-text Article · Feb 2016 · Advances in Hematology
[Show abstract][Hide abstract]ABSTRACT: This open-label, Phase-2 study investigated the safety of LY2090314 (GSK-3 inhibitor) in AML patients. Twenty patients received 40-mg LY2090314 (50-mg ranitidine pretreatment) as follows: Cohort 1 - days 1, 8, and 15 of a 28-d cycle (n = 7); Cohort 2 - days 1, 5, and 9 of a 21-d cycle (n = 6); Cohort 3 - days 1, 5, 9, and 12 of a 21-d cycle (n = 7). Decreased appetite (n = 7) and nausea (n = 4) were the most frequently reported possibly drug-related non-hematologic treatment-emergent adverse events (TEAEs). Hematologic TEAEs included febrile neutropenia (n = 2), thrombocytopenia (n = 1), and anemia (n = 1). Atrial flutter (n = 1), QT interval prolongation (n = 3), and visual disturbances (n = 2) were observed, but were not clinically significant (investigator assessed). Although β-catenin levels indicated an on-target effect, no complete or partial remissions were observed. Pharmacokinetics were consistent with a previous Phase 1 study. These data suggest that single-agent LY2090314 has acceptable safety but limited clinical benefit in AML patients at the dose/frequencies investigated.
[Show abstract][Hide abstract]ABSTRACT: Natural Killer (NK) cells are lymphoid cells that exhibit an innate response against virus-infected cells. These cells are also capable of mounting an immune response against tumor cells after education through major histocompatibility complex (MHC) class I molecules. NK cell regulation is mediated through IFN-gamma and IL-15, important cytokines which can drive NK cell expansion in vivo. Previous studies have shown effective infusion of allogeneic NK cells after lymphodepleting regimens with induction of remission of poor prognosis acute myeloid leukemia (AML). Challenges remain in the expansion of these NK cells once infused and in their education to recognize tumor targets. A principal mechanism of tumor recognition is through KIR mismatch in cells lacking self MHC I molecules. Activating KIRs exist, though their ligands are unknown at this time. Impacting NK cell expansion and education in vivo has been challenging, and thus far clinical applications of NK cells have shown promise in helping to maintain remission in humans, though this remission has not been maintained. Future efforts to utilize NK cells clinically are focusing on developing more consistency in successful expansion of NK cell and educating them to recognize their tumor targets. Additional efforts to utilize novel antibody-based therapy to engage NK cells to their tumor targets are also in development.
[Show abstract][Hide abstract]ABSTRACT: Purpose:
Peripheral blood stem cell mobilization using growth factors is a common method of stem cell collection for transplantation, however, little is reported concerning safety of continued growth factor delivery in exceptional responders with very high white blood cell (WBC) counts in preparation for pheresis. We performed a retrospective study of the safety of growth factor delivery for leukapheresis in those with WBC counts greater than 60,000/µl.
Allogeneic donors received 5 days of granulocyte colony-stimulating factor (G-CSF) at a daily dose of 10 or 16 µg/kg. Autologous donors received G-CSF 10 µg/kg/day +/- chemotherapy until peripheral blood CD34(+) count reached 10/µl. Granulocyte donors received 300 µg dose of G-CSF the day prior to donation.
Out of 3,037 leukapheresis collections from 1998 to 2005, we identified 303 collections from 204 donors or patients who had a WBC > 60,000/µl. WBC counts were ≥100,000/µl in seven of these subjects. If inadequate stem cell dose was obtained with pheresis with WBC counts this high, patients had growth factor dosing decreased 50% but still received a dose till stem cell collection was completed. Of the 204 subjects, 122 were patients and 82 were donors. These 204 donors/patients had no serious adverse events reported other than the common reports of myalgia, bone pain, and headache associated with administration of growth factors. Pain levels ranged from mild to severe and usually were managed by over the counter analgesics.
Continuing ½ the dose of neupogen to complete the pheresis process appears safe in subjects with very high white blood counts.
Article · Feb 2015 · Journal of Clinical Apheresis