[Show abstract][Hide abstract] ABSTRACT: We defined associations among immune cell subsets in G-CSF (G)-mobilized allografts and clinical outcomes following allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-mobilized allografts were extensively characterized by immunophenotype. Subset-specific transplanted cells were correlated with acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), malignant disease relapse, non-relapse mortality (NRM), and overall survival (OS). Of 238 evaluable alloHCT recipients, 78% (185) patients received reduced-intensity conditioning (RIC); and 64% (152) patients received anti-thymocyte globulin (ATG)-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range: 1.4 to 41.1 months). In multivariable analyses adjusted for relevant clinical factors, allograft activated NK cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with significantly lower risk of aGVHD [p=0.0016, HR 0.51 (95% confidence interval 0.33 - 0.78) while late-activated HLADR(+) CD3(+) cells associated with significantly higher aGVHD [p<0.0005, HR 2.31 (95% confidence interval 1.55 - 3.43)]. In a subgroup of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), receipt of an allograft from an older donor (≥ 40 years) was associated with a higher incidence of relapse (p=0.0042, HR: 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); p=.0024, HR: 0.4) and NKT cells (CD3(+)CD56(+); p=0.0006; HR: 0.54) cells were associated with a lower incidence of relapse. Presence of HLA-Bw4-80Ile(+) genotype was associated with lower relapse-incidence. In conclusion, activated NK cells within PBSC allografts associate with lower aGVHD risk, while HLA-DR(+) T cells associate with higher aGVHD and cGVHD risk; NKT cells and early activated T cells are associated with lower relapse risk in AML and MDS patients. These findings may have implications in therapeutic targeting of select populations in the allograft to minimize incidence of GVHD.
Full-text · Article · Dec 2015 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukemia (CLL) is frequently complicated by secondary autoimmune cytopenias (AIC). Ibrutinib is an irreversible inhibitor of Bruton's Tyrosine Kinase approved for treatment of relapsed CLL and CLL with del(17p). The effect of ibrutinib treatment on the incidence of AIC is currently unknown. We reviewed medical records of 301 patients treated with ibrutinib as participants in therapeutic clinical trials at the Ohio State University Comprehensive Cancer Center between July 2010 and July 2014. Subjects were reviewed with respect to past history of AIC, and treatment emergent AIC cases were identified. Prior to starting ibrutinib treatment, 26% of patients had experienced AIC. Information was available for a total of 468 patient-years of ibrutinib exposure, during which there were six cases of treatment emergent AIC. This corresponds to an estimated incidence rate of 13 episodes for every 1000 patient-years of ibrutinib treatment. We further identified 22 patients receiving therapy for AIC at the time ibrutinib was started. Of these 22 patients, 19 were able to discontinue AIC therapy. We found that ibrutinib treatment is associated with a low rate of treatment emergent AIC. Patients with an existing AIC have been successfully treated with ibrutinib and subsequently discontinued AIC therapy.Leukemia accepted article preview online, 07 October 2015. doi:10.1038/leu.2015.273.
No preview · Article · Oct 2015 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
[Show abstract][Hide abstract] ABSTRACT: ABSTRACT Only a minority of patients with high risk lymphoma will be cured with autologous transplant, so maintenance with Vorinostat, an oral agent with activity in relapsed lymphoma, was studied starting day +60 for 21 consecutive days followed by a week off for up to 11 cycles. Twenty-three lymphoma patients were treated. Ten patients completed the full 11 cycle treatment plan per protocol, 4 patients were removed due to progressive disease, 7 withdrew or were removed from the study due to toxicities. Despite Prevnar vaccine administration every 2 months for 3 injections, the mean antibody concentration never reached protective levels (>0.35 mcg/mL). Fatigue and functional well-being measured by BFI and FACT-G improved significantly from cycle 1 to cycle 7, but the depression scores from the CES-D did not change. Given the toxicities observed, this broad spectrum deacetylase inhibitor at this schedule is not optimal for prolonged maintenance therapy.
No preview · Article · Sep 2014 · Leukemia and Lymphoma
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.
Patients and methods:
We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5-21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.
Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59-0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11-0.69) of patients.
Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
No preview · Article · Feb 2013 · Cancer Chemotherapy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Complex karyotype (CK) on metaphase cytogenetics discriminates poor outcome in chronic lymphocytic leukaemia (CLL) patients undergoing salvage treatment; we hypothesized that it might provide prognostic information for patients undergoing allogeneic stem cell transplant. Fifty-one CLL patients were analysed following transplant; 18-month overall survival (OS), event-free survival (EFS) and cumulative incidence of progression estimates were 35%, 14% and 63%, respectively, in patients with CK (n = 19) versus 83%, 68% and 29% in patients without (n = 32) (P ≤ 0·0001, P ≤ 0·0001, and P = 0·02). In patients with high-risk interphase cytogenetics, CK remained predictive of worse OS (P = 0·02) and EFS (P = 0·009). These findings support further evaluation of metaphase karyotype in transplant risk assessment.
Preview · Article · Jul 2012 · British Journal of Haematology