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 1 000 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.

Summary 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.

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. Results 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. Conclusions 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.

We defined associations among immune cell subsets in granulocyte colony-stimulating factor (G-CSF)-mobilized allografts and clinical outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Fresh peripheral blood stem cell (PBSC) aliquots from 238 G-CSF-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, nonrelapse mortality, and overall survival. Of 238 assessable alloHCT recipients, 185 patients (78%) received reduced-intensity conditioning and 152 (64%) antithymocyte globulin-based serotherapy. Incidences of aGVHD and cGVHD were 58% and 48%, respectively. Median follow-up was 21 months (range, 1.4 to 41.1). In multivariable analyses adjusted for relevant clinical factors, allograft activated natural killer (NK) cells (CD56(+)CD16(+)CD69(+)CD158b(+)) were associated with a significantly lower risk of aGVHD (P = .0016; HR, .51; 95% confidence interval, .33 to .78), whereas late-activated HLA-DR(+) CD3(+) cells were associated with significantly higher aGVHD (P < .0005; HR, 2.31; 95% confidence interval, 1.55 to 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 = .0042; HR, 2.99); allograft content of early activated CD3(+) cells (CD3(+)CD69(+); P = .0024; HR, .4) and NKT cells (CD3(+)CD56(+); P = .0006; HR, .54) 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, whereas 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.

Statins possess potent immunomodulatory effects that may play a role in preventing acute GVHD (aGVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We performed a Phase II study of atorvastatin for aGVHD prophylaxis when given to allo-HCT recipients and their HLA-matched sibling donors. Atorvastatin (40mg/day) was administered to sibling donors, beginning 14 days before the anticipated start of stem cell collection. Allo-HCT recipients (n=40) received atorvastatin (40mg/day) in addition to standard aGVHD prophylaxis. The primary endpoint was cumulative incidence of grades 2-4 aGVHD at day 100. Atorvastatin was well tolerated and there were no attributable grade 3-4 toxicities in donors or their recipients. Day 100 and 180 cumulative incidences of grade 2-4 aGVHD were 30% (95% CI 17- 45%) and 40% (95% CI 25-55%), respectively. One-year cumulative incidence of chronic GVHD was 43% (95% CI 32- 69%). One year non-relapse mortality and relapse incidences were 5.5% (95% CI 0.9-16.5%) and 38% (95% CI 18- 47%), respectively. One-year progression-free survival and overall survival were 54% (95% CI 38-71%) and 82% (95% CI 69-94%). One-year GVHD-free, relapse-free survival (GRFS) was 27% (95% CI 16-47%). These results did not differ from our historical controls (N=96). While safe and tolerable, the addition of atorvastatin did not appear to provide any benefit to standard GVHD prophylaxis alone.