Mutant PPM1D- and TP53-Driven Hematopoiesis Populates the Hematopoietic Compartment in Response to Peptide Receptor Radionuclide Therapy.

PURPOSE: Hematologic toxic effects of peptide receptor radionuclide therapy (PRRT) can be permanent. Patients with underlying clonal hematopoiesis (CH) may be more inclined to develop hematologic toxicity after PRRT. However, this association remains understudied. MATERIALS AND METHODS: We evaluated pre- and post-PRRT blood samples of patients with neuroendocrine tumors. After initial screening, 13 cases of interest were selected. Serial blood samples were obtained on 4 of 13 patients. Genomic DNA was analyzed using a 100-gene panel. A variant allele frequency cutoff of 1% was used to call CH. RESULT: Sixty-two percent of patients had CH at baseline. Persistent cytopenias were noted in 64% (7 of 11) of the patients. Serial sample analysis demonstrated that PRRT exposure resulted in clonal expansion of mutant DNA damage response genes (TP53, CHEK2, and PPM1D) and accompanying cytopenias in 75% (3 of 4) of the patients. One patient who had a normal baseline hemogram and developed persistent cytopenias after PRRT exposure showed expansion of mutant PPM1D (variant allele frequency increased to 20% after exposure from < 1% at baseline). In the other two patients, expansion of mutant TP53, CHEK2, and PPM1D clones was also noted along with cytopenia development. CONCLUSION: The shifts in hematopoietic clonal dynamics in our study were accompanied by emergence and persistence of cytopenias. These cytopenias likely represent premalignant state, as PPM1D-, CHEK2-, and TP53-mutant clones by themselves carry a high risk for transformation to therapy-related myeloid neoplasms. Future studies should consider CH screening and longitudinal monitoring as a key risk mitigation strategy for patients with neuroendocrine tumors receiving PRRT.

Survival outcomes of alternate dosing schedule of pemetrexed as maintenance therapy in NSCLC: Single institution experience.

BACKGROUND: Maintenance therapy with pemetrexed has shown survival benefit in patients with advanced stage non-small cell lung cancer (NSCLC). The recommended dose schedule is 500 mg/m 2 in 21-day cycles. Prolonged treatment with maintenance pemetrexed can result in cumulative toxicities. We sought to compare treatment outcomes in patients receiving an alternate maintenance schedule in realworld practice. METHODS: This single-center, retrospective study investigated patients with advanced stage (IIIB and IV) NSCLC receiving at least two doses of maintenance pemetrexed from May 1, 2011 to June 30, 2016. The objective was to compare time on treatment with maintenance pemetrexed therapy initiated at a standard schedule (q3 weeks) versus an alternate schedule (q4 weeks or longer). Also evaluated were progressionfree survival (PFS) and overall survival (OS) differences between the two groups. RESULTS: 129 patients were included, of whom 40 started the alternate schedule no later than cycle 3 of treatment (29 of 40 patients initiated maintenance treatment on the alternate schedule). Average time on maintenance treatment for patients appeared to be longer in the patients who received the alternate schedule regimen (195 vs 263 days, p =0.008). OS trended towards better survival among patients receiving the alternate schedule regimen (11.9 vs 18.1 months, p =0.3). Limiting the analysis to ALK wildtype, the patients showed a similar trend, with median PFS (7.6 vs 11.5 months, p =0.46) and OS (11.9 vs 17.6 months, p =0.38), still favoring the alternate schedule. CONCLUSIONS: The alternate dosing schedule of maintenance pemetrexed (q4 weeks or longer) is feasible and not detrimental to OS. Future investigations evaluating the optimal administration schedule of maintenance pemetrexed is warranted.

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

Outcomes of Adult Acute Myeloid Leukemia Treated With Gemtuzumab-Ozogamicin: Cue To Optimized Chemotherapy Backbone.

BACKGROUND: The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined. MATERIALS AND METHODS: We performed a retrospective analysis of the safety and outcomes of adult patients with newly diagnosed acute myeloid leukemia (AML) treated with GO with intensified versus standard anthracycline doses (daunorubicin dose 90 mg/m2 vs 60 mg/m2) ± FLT3 inhibitors. The χ2 test and Mann-Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan-Meier method and survival comparisons made using log-rank test. RESULTS: We report a 97% overall response rate in 34 patients with newly diagnosed AML with a median age of 54 years (19-75 years) treated with GO and standard induction. The 11 patients (100%) receiving GO plus daunorubicin dose 90 mg/m2 as part of 7 + 3 induction achieved complete response versus 91% (20/22) complete response in the standard daunorubicin dose group (P = NS). No increased toxicity was noted with the higher daunorubicin dose or when GO and 7 + 3 were combined with FLT3 inhibitors in 3 younger patients (<60 years). Two older patients treated with GO+7 + 3 and FLT3i experienced grade 3 or higher cardiotoxicity. We observed a longer estimated event-free survival for patients with newly diagnosed AML in our cohort (median, 24 months; 95% confidence interval, 17.2 to not reached) compared with historical data. CONCLUSION: We demonstrate that anthracycline dose intensification with GO may offer higher response rates without increased toxicity in younger patients presenting with de novo AML across European Leukemia Net risk categories.

Predictors of vascular disease in myelodysplastic syndromes.

The escalating link between somatic mutations commonly seen in myelodysplastic syndromes (MDS) and atherosclerotic vascular disease has increased the interest in management and associations of these conditions. We present a retrospective study examining clinical and molecular variables associated with vascular disease in patients with MDS. This study included a comprehensive evaluation of 236 patients with MDS. Our study has multiple findings. Mutations in ASXL1 correlated with increased risk of vascular disease for the entire cohort (P = .013). Though this has been replicated in other studies, there are no guidelines at this time for preventing vascular events in these patients. Our study also showed that lower ferritin levels may be linked to increased vascular events (P = .043), therefore the optimal use of supportive red blood cell transfusions in patients with MDS and the overall impact of inflammatory markers such as erythrocyte sedimentation rate and c-reactive protein should be re-addressed. Furthermore, our study showed that patients with Trisomy 8 in the low-risk MDS cohort (based on IPSS-R scores) were protected from vascular events (P = .036). Our findings of lower ferritin being linked with increased risk of vascular events as well as patients with Trisomy 8 being protected from vascular events may impact patient care. There do not appear to be any prior studies with these findings. In addition, given the connection between MDS and atherosclerotic vascular disease, we believe guideline-based management of cardiac risk factors among MDS patients may improve overall outcomes. Further studies with larger patient cohorts are needed to further investigate these findings.

Safety of Same-Day Vitamin B12 Supplementation in Patients Receiving Pemetrexed for the Treatment of Non-Small-Cell Lung Cancer or Pleural Mesothelioma: A Retrospective Analysis.

BACKGROUND: Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated. PATIENTS AND METHODS: This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed. RESULTS: Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 109/L vs. 5 × 109/L, P = .0003). CONCLUSION: Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.