Denileukin diftitox for the treatment of steroid-resistant acute graft-versus-host disease.

Acute graft-versus-host disease (aGVHD) is partly mediated through activated T cells, and these cells are known to express the high-affinity receptor for interleukin 2 (IL-2R). Denileukin diftitox is composed of human IL-2 and diphtheria toxin that is cytotoxic to activated lymphocytes expressing the high-affinity IL-2R. We describe the results of a phase II study of denileukin diftitox in 22 patients with steroid-resistant aGVHD. Twenty patients were treated at dose level 1 (4.5 microg/kg daily on days 1-5 and then weekly on study days 8, 15, 22, and 29), and 2 patients were treated at dose level 2 (9.0 microg/kg delivered on the same schedule). Dose level 2 was associated with grade 3/4 renal and hepatic toxicity and vascular leak syndrome, and no further patients were treated at this level. Dose level 1 was generally well tolerated. The response of aGVHD was assessed at study days 36 and 100. Nine patients (41%) responded, all with a complete response at study day 36, and 6 patients (27%) responded at study day 100 (4 complete responses and 2 partial responses). Denileukin diftitox has promising activity in steroid-resistant aGVHD, and further study is warranted.     

Multiple Myeloma in Hispanics: Incidence,Characteristics, Survival,Results of Discovery,and Validation Using Real-World and Connect MM Registry Data

BackgroundMultiple myeloma (MM) in Hispanics has never been studied. We therefore sought to determine the clinical characteristics and overall survival in MM of Hispanics compared to non-Hispanic whites (NHW) and non-Hispanic blacks (NHB).Patients and MethodsA single-center analysis of 939 patients diagnosed with MM from 2000 to 2017 with a large representation of NHB (n = 489), Hispanics (n = 281), and NHW (n = 169) was conducted to evaluate outcomes and disease characteristics. We used the Connect MM Registry, a large US multicenter prospective observational study with newly diagnosed MM patients, as a validation cohort.ResultsHispanics had a higher incidence of MM compared to NHW. The median age at presentation was 5 years younger (median, 65 years) in Hispanics compared to NHW (median, 70 years), and patients were more likely to present with renal dysfunction (estimated glomerular filtration rate < 30 mL/min). Hispanics had a higher proportion of Revised International Staging System (R-ISS) stage I disease compared to NHW and NHB (P = .03), while there was no difference in cytogenetics between Hispanics and NHB/NHW. In the multivariate analysis, only high-risk disease and response to first-line therapy significantly affected survival.ConclusionIn this first and largest analysis of MM in Hispanics, we found that Hispanics present at a younger age, have a higher incidence of renal dysfunction, and have low R-ISS stage disease at presentation. With equal access to therapy, Hispanics have survival similar to NHW/NHB.     

A phase II trial evaluating the safety and effectiveness of the AastromReplicell system for augmentation of low-dose blood stem cell transplantation

To reduce the number of apheresis procedures and maintain the usual rate of hematopoietic recovery in patients treated with high-dose chemotherapy, we studied the effect of adding a small volume of ex vivo expanded bone marrow to low doses of CD34(+) blood stem cells. Thirty-four patients with breast cancer received G-CSF (10 microg/kg/day) priming followed by a limited volume (50-100 ml) bone marrow aspiration and standard 10-liter aphereses. Marrow was expanded ex vivo using the AastromReplicell system and infused along with low doses of blood-derived CD34(+) cells, collected in one apheresis. Thirty-one evaluable patients received a median CD34(+) blood stem cell dose of 0.7 x 10(6)/kg (range, 0.2-2.5) and 4.7 x 10(7) nucleated cells/kg (range, 1.98-8.7) of ex vivo expanded marrow. All patients recovered with normal blood counts and engrafted 500 neutrophils/microl and 20 000 platelets/microl in a median of 10 and 13 days, respectively. Multivariate analysis revealed that, in addition to CD34(+) lineage negative cell quantity, the quantity of stromal progenitors contained in the ex vivo expanded product correlated with engraftment outcome (r = 0.551, P = 0.004). Our results indicate that ex vivo expanded bone marrow is capable of facilitating engraftment when combined with low doses of mobilized blood derived CD34(+) cells.     

Granulocyte colony-stimulating factor mobilizes more dendritic cell subsets than granulocyte-macrophage colony-stimulating factor with no polarization of dendritic cell subsets in normal donors

Dendritic cells (DCs) are effective antigen-presenting cells. We hypothesized that increasing the DC populations in donor lymphocyte infusions (DLIs) may augment the graft versus malignancy effect, particularly if granulocyte-macrophage colony-stimulating factor (GM-CSF) mobilization resulted in increased precursor dendritic cell (pDC) 1 cells. Mature DCs, pDC1 cells, pDC2 cells, and CD34(+) cells from the same donor were compared after granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell collections and GM-CSF mobilized DLI collections. Mobilization with G-CSF resulted in up to a 10-fold larger number of CD34(+) cells per kg and a 3-5-fold larger number of mature DCs, pDC1 cells, and pDC2 cells within the same donor compared with GM-CSF. The ratio of pDC1 to pDC2 in each donor remained constant with either cytokine. In this small sample of normal donors, it appears that G-CSF mobilizes more CD34(+) cells, mature DCs, pDC1 cells, and pDC2 cells within the same donor than does GM-CSF, with no significant polarization by G-CSF or GM-CSF for either pDC1 or pDC2 cells.     

Outcomes of Autologous Hematopoietic Cell Transplantation Compared With Chemotherapy Consolidation Alone for Non–High-Risk Acute Myeloid Leukemia in First Complete Remission in a Minority-Rich Inner-City Cohort With Limited Access to Allografts

IntroductionIn the United States, autologous hematopoietic cell transplantation (autoHCT) has fallen out of favor over chemotherapy consolidation for non–high-risk acute myeloid leukemia (AML) when allogeneic hematopoietic cell transplantation (alloHCT) is unfeasible, which is common in racial minorities because of donor registry under-representation and socioeconomic challenges. We compared autoHCT consolidation outcomes with chemotherapy alone in a minority-rich cohort in the Bronx.Patients and MethodsWe identified adults with favorable or intermediate cytogenetic risk AML in first complete remission after induction at Montefiore Medical Center from 1999 to 2015, and analyzed 81 patients who received consolidation with ≥2 cycles of chemotherapy, of whom 28 received autoHCT.ResultsThe cohort predominantly consisted of ethnic/racial minorities (69%). Age, sex, race, presenting white cell count, and cytogenetic risk were similar between groups. The autoHCT group had longer relapse-free (RFS; 43 vs. 11 months; P = .003) and overall (OS) survival (not reached vs. 36 months; P = .043). Adjusted multivariable analysis showed significant benefit of autoHCT over chemotherapy alone for RFS (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.37-0.75; P < .001) and OS (HR, 0.61; 95% CI, 0.40-0.95; P = .027).ConclusionIn this inner-city non–high-risk AML cohort, autoHCT provided OS and RFS benefit compared with chemotherapy alone. AutoHCT might constitute a valuable option for ethnic/racial minorities affected by significant barriers to alloHCT, whereas integration of measurable residual disease can help select patients more likely to benefit.     

High white blood cell concentration in the peripheral blood stem cell product can induce seizures during infusion of autologous peripheral blood stem cells

Seizures as a complication of the infusion of autologous peripheral blood stem cells (PBSC) are rare. Seizures during infusion of autologous PBSC in 3 of our patients prompted us to review our cell therapy and cytapheresis protocols and procedures. We retrospectively analyzed 159 adult patients collected between January 2006 and July 2009. Patients were collected on either the COBE Spectra (Caridian BCT, Lakewood, CO) cell separator (n = 85) or Fresenius AS (Fresenius Kabi AG, Bad Homburg, Germany) 104 cell separator (n = 74) and mobilized with granulocyte-colony stimulating factor (G-CSF) alone (n = 47), G-CSF and Plerixafor (n = 36), or G-CSF and chemotherapy (n = 76). Patient characteristics (including age, weight, number of collections, volume processed, disease type, and mobilization strategy) did not differ significantly between the COBE and Fresenius cohorts, and adverse effects from infusion were similar except for 3 of 159 patients who experienced seizures upon infusion of PBSC; all 3 were collected on the COBE and had PBSC product white blood cell (WBC) counts of 590 × 10(3)/μL or above. We prospectively correlated WBC counts midcollection, with final WBC counts to identify products with high WBC concentration during cytapheresis. Fifty-one patients had 66 cytapheresis procedures using the COBE, with WBC counts midway and at the end of collection of 287 × 10(3) ± 150/μL and 273 × 10(3) ± 144/μL, respectively. Mid-WBC therefore correlated with WBC at the end of the collection. Finally, we prospectively collected mid-WBC from 65 patients who underwent 80 PBSC collections between June 2009 and January 2010 to identify products with midcollection WBC concentration >450 × 10(3)/μL. In those cases, additional autologous plasma was collected at the time of collection to dilute the final product before cryopreservation. Patients who received diluted products experienced no delays in engraftment and no additional seizure episodes occurred.     

Ex-vivo expansion of bone marrow progenitor cells for hematopoietic reconstitution following high-dose chemotherapy for breast cancer

The use of hematopoietic growth factors, stromal monolayers, and frequent medium exchange allows the expansion of hematopoietic progenitors ex-vivo. We evaluated the use of ex-vivo expanded progenitor cells for hematopoietic reconstitution following high dose chemotherapy (HDC) in breast cancer patients. Patients with high-risk Stage II or metastatic breast carcinoma underwent bone marrow aspirations using general anesthesia. A total of 675-1125 x 10(6) mononuclear cells (MNC) were seeded for ex-vivo expansion for 12 days in controlled perfusion bioreactors (Aastrom Biosciences, Inc.). The bone marrow cultures, which included the stromal cells collected with the aspirate, were supplemented with erythropoietin, granulocyte-macrophage-colony stimulating factor (GM-CSF)/IL-3 fusion protein (PIXY 321), and flt3 ligand. Stem cell transplant was performed with expanded cells after HDC. A median bone marrow volume of 52.9 mL (range 42-187 mL) was needed to inoculate the bioreactors. Median fold expansion of nucleated cells (NC) and colony forming unit granulocyte-macrophage (CFU-GM) was 4.9 and 9.5, respectively. The median fold expansion of CD34+lin- and long-term culture-initiating culture (LTC-IC) was 0.42 and 0.32, respectively. Five patients were transplanted with ex-vivo expanded NC. Median days to an absolute neutrophil count > 500/microL was 18 (range 15-22). Median days to a platelet count > 20,000/microl was 23 (range 19-39). All patients had sustained engraftment of both neutrophils and platelets. Immune reconstitution was similar to that seen after HDC and conventional stem cell transplantation. We conclude that ex-vivo expansion of progenitor cells from perfusion cultures of small volume bone marrow aspirates, allows hematopoietic reconstitution after HDC.