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Background Hepatitis B core antibody (HBcAb) seropositivity has been associated with a higher rate of hepatitis B virus (HBV) reactivation after chemotherapy, even in patients who are hepatitis B surface antigen (HBsAg) negative. We evaluated the incidence of hepatitis B reactivation and liver toxicity in patients with multiple myeloma (MM) who received high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution. Methods We identified 107 MM patients with resolved HBV infection (HBcAb positive, HBsAg negative) and 125 patients with negative HBV serology (control) who were matched for age, time of auto-HCT, disease status and preparative regimen. Both groups received HDC and auto-HCT between 1991 and 2013. Primary endpoints were: 1) HBV reactivation defined as HBsAg positivity or ≥10-fold increase in HBV DNA; 2) hepatotoxicity, as defined in NCI CTCv3.0. Results Approximately 70% in each group received melphalan alone as preparative regimen. In the resolved HBV infection group, 52 patients (49%) were Hepatitis B surface antibody (HBsAb) positive, and 24 (22%) had detectable HBV DNA prior to auto-HCT. Serum HBV DNA level was <100 IU/m in 22 patients, and <300 IU/ml in 2 patients. Hepatitis B e antigen (HBeAg) was non-reactive in all 4 patients evaluated prior to auto-HCT. Only 1 patient with resolved HBV infection received pre-emptive antiviral therapy with Lamivudine, while 4 patients received Lamivudine (3) or Tenofovir (1) at reactivation for a median duration of 1 year. HBV reactivation was seen in 7 of 107 (6.5%) patients in the resolved HBV group. There was a ≥10-fold increase in HBV DNA in 5 of 7 patients with HBV reactivation, and 2 of 7 also became positive for HBeAg. Median time to HBV reactivation from auto-HCT was 16 months. The cumulative incidence of grade 2 or more hepatotoxicity in resolved HBV infection and the control groups was 30% and 22%, respectively (hazard ratio [HR] 1.3; 95% confidence interval [CI], 0.7–2.3; P = 0.4). There was a trend for higher NRM in the control group at 1 year 7% vs 1%, with a HR of 0.15 (95% CI 0.02–1.2, P = 0.08) and at 2 years 8% vs 1% with a HR of 0.13 (95% CI 0.02–1.1, P= 0.06) after auto-HCT. With a median follow up of 18 and 35 months in resolved HBV infection vs. control groups, the median progression free survival was 21 and 18 months (p=0.5), respectively. Median overall survival in resolved HBV infection and control groups was 53 vs. 67 months (p=0.2), respectively. Conclusion Resolved HBV infection is associated with a significant risk of HBV reactivation and hepatotoxicity in patients undergoing auto-HCT for MM. These complications were reversible and were not associated with a decrease in PFS or OS.

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Although the survival of patients diagnosed with breast cancer has greatly improved over the last decades, the metastatic stage of the disease still remains incurable. Blood circulating tumor cells (CTCs) are assumed to be the source for metastatic onset and the enumeration of CTCs has already proven its prognostic value for survival in metastatic breast cancer (mBC) patients. However, the biological profiles of CTCs are so far not considered in therapy selection, but hold the potential to display the disease stage in a minimally invasive procedure. Here we serially collect liquid biopsies of mBC patients throughout their course of therapy with the CDK4/6 inhibitor palbociclib to monitor treatment response and drug resistance development. To this end, we combine transcriptomic, genomic and proteomic analyses of primary CTCs on bulk but also on the single cell level. Furthermore, we generated patient-specific, in vitro expanded CTC cell lines to intensively study mechanisms of drug resistance and identify new therapeutic targets by drug sensitivity assays. By analyzing mBC CTCs of serial liquid biopsies we monitored cell cycle arrest upon palbociclib treatment and drug resistance development. Drug sensitivity and successive drug resistance can be observed in primary and in vitro expanded, patient-specific CTCs. As revealed by RNA-seq of bulk and single CTCs, acquired resistance to palbociclib in mBC CTCs is associated with altered transcriptional programs including RB transcriptional corepressor 1 (RB1) function and can be linked to a loss-of-function mutation in the RB1 gene. Interestingly, apart from altered RB1 function, we can identify a global transcriptional transition from palbociclib sensitivity to resistance. Based on the transcriptomic information, pathways that are upregulated in resistant CTCs were determined and the patient-derived CTC cell lines were used to validate and specifically target tumor cells that are resistant to CDK4/6 inhibitors. Using drug screening assays on the CTC-derived cell lines, we identified potential drugs that in combination with palbociclib could circumvent the acquired resistance and help to prolong patient survival. Our study indicates that information about the biological state of serially collected CTCs can help to earlier detect the onset of resistance and should be included in clinical disease management. This will help to spare the patient severe side effects from ineffective drug treatment. Citation Format: Andreas Trumpp, Lisa Becker, Michael Fletcher, Roberto Würth, Anand Thippeswamy, Simon Haas, Lars Velten, Laura Michel, Frederik Marme, Sarah Jauch, Mirjam Becker, Lars Steinmetz, Andreas Schneeweiss, Marc Zapatka, Peter Lichter, Martin Sprick. Exploring CDK4/6 inhibitor therapy response and drug resistance development at the single cell level in metastatic breast cancer CTCs [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD2-01.

to 8% and did not differ across regimens in multivariate analysis. There were a significant interaction between regimens and disease (HL and NHL). For patients with NHL, there was no significant difference in outcomes with BEAM, CBV low , BuCy, and TBI. In contrast, NHL patients treated with CBV high had higher progression (HR 1.28 [1.08, 1.50], p¼0.003), and mortality (HR 1.27 [1.08, 1.49], p¼0.003). For patients with HL, BuCy and TBI were associated with higher progression at 3 years compared to BEAM (47%, 57% vs. 36%) and shorter overall survival (65%, 47% vs. 79%). Multivariable results for HL are demonstrated in the table. Conclusion: The impact of specific high-dose regimens with AutoHCT on overall outcomes appears to be different in patients with NHL and HL. Use of CBV high in patients with NHL and BuCy or TBI-containing regimens in HL were associated with worse outcomes compared to BEAM. Future investigation should be geared towards guiding the choice of regimen based on specific patient and disease characteristics.

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