Sequential Fludarabine, Ara-C, Etoposide (FLAV) Followed By Fludarabine/ Busulfan Reduced Toxicity Conditioning Is Safe and Effective Salvage for Adult Patients with Refractory Acute Myeloid Leukemia and High Risk Myelodysplasia

Background A significant proportion of patients with acute myeloid leukemia (AML) will either be refractory to initial chemotherapy or will suffer refractory relapse. The role of allogeneic transplantation (SCT) in active disease is contentious. There is a growing body of literature that sequential chemotherapy, pioneered by the German FLAMSA regimen, followed by RIC SCT is a safe and efficacious modality in these patients, and there have been numerous modifications of this regimen, especially as amsacrineis not widely available. Fludarabine, cytarabineand and etoposide (VP16) (FLAV) have been reported as an effective salvage regimen. Here we report on single center outcomes of a variation of the FLAMSA regimen, substituting amsacrine for etoposide with mainly myeloablative conditioning. Methods Patients were offered this regimen if fit for allogenic HSCT and had AML which is refractory to two cycles of chemotherapy or refractory to one cycle and considered at high risk for complication with second cycles. Patients with MDS received this regimens if eligible for transplant with high or very high risk cytogenetics. All patients received cytoreductive chemotherapy consisted of fludarabine 30mg/m2/day x 4 days, Cytarabine 2g/m2/day x 4 days, etoposide 100mg/m2/day x 3days, commenced simultaneously. After 3 days of rest, conditioning chemotherapy consisted of fludarabine 30mg/m2 x 2 days and and IV busulfan 0.8mg/m2 q 6 hours; the number of busulfan doses varied between 8 - 12, depending on patient comorbidity. All patients received 2 doses of ATG at 2.5mg/m2/day on day -3 and -2. All patients received GCSF mobilized peripheral blood hematopoietic cells. Post-transplant GVHD prophylaxis consist of CsA and MMF. CsA was tapered from day+60 and stopped at day +90 in the absence of GVHD. MMF was discontinued between day +30 and day +40. Donor lymphocyte infusions were collected for planned prophylactic DLI. Results Twenty six patients received FLAV-SCT between March 2014 and July 2019. The median age was 38 (14-60); 16 (62%) female. Overall 12 (46%) pts had de novo AML, 10 (39%) pts had secondary or therapy related AML and 4 (15%) pts had MDS. Fourteen (54%) pts had adverse risk cytogenetics include 8 (31%) pts had complex or monosomal karyotype. Patients' characteristics are summarized in Table 1. All patients had active disease prior to FLAV-SCT. The median time for ANC and platelet engraftment was 14 (10 - 42) days and 17 (10 - 52) days respectively. Day 30 assessment shows CR in 16 (61%) pts and CR/CRi in 17 (65%) pts. Outcomes are summarized in Table 2. Three patients (12%) developed veno-occlusive disease. Acute GVHD grade II-IV and III-IV occurred in 9 (35%) pts and 2 (8%) pts respectively. Three (12%) patients developed chronic GVHD. Cumulative incidence of NRM at 100 days and 2 years was 8% and 12% respectively. The median OS for all pts was 5.2 months with 2 years rate of 32% (15 - 50). Among responders, the median OS and RFS were 19.2 months and 8.7 months, 2y-OS and RFS were 47% and 25%, respectively (Figure 1). Conclusion Our result demonstrates that transplant is an effective therapeutic modality in this very high risk refractory AML/MDS patients. Sequential chemotherapy (FLAV) followed by SCT with busulfan at myeloablative dose is tolerable with an acceptable toxicities and encouraging results. Figure 1 Figure 1. Disclosures Chaudhri: Novartis: Honoraria; Abbvie: Honoraria; Astra Zeneca: Honoraria. Alzahrani: King Faisal Specialist Hospital and Research Centre: Current Employment; Novartis: Consultancy, Honoraria; Bayer: Consultancy, Honoraria, Speakers Bureau; Sobi: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau.

Molecular Evolutionary Process of Advanced Gastric Cancer During Sequential Chemotherapy Detected by Circulating Tumor DNA

Background: Chemotherapy is the major strategy for advanced gastric cancer (AGC) patients, whereits efficacy has largely plateaued. Tumor evolutionary theory provides a promising strategy to optimize paradigm of cancer treatment, while current data of molecular changes during sequential chemotherapy is too insufficient to understandevolutionary process in tumors. Methods: Here, we performed NGS analysison 100 circulatingtumor DNA (ctDNA) samples collected from 27 AGC patients during treatment of sequentialchemotherapy. We observed dynamic changes of copy number instability (CNI) and gene-level copy number variations (CNVs) during the treatment.Results: Gene-levelCNV profiles were similar between baseline and end oftreatment. Subsequent regimens did not significantly change the CNV profiles driven by first-line regimens. Based on changes of copy number values of genes during treatment, resistance related genes of all four regimens were identified, respectively. These genes could be enriched into several common oncologic pathways, while exhibited a high inter-patient heterogeneity. Genes with different copy number values between baseline and end of treatment could be the targets of by molecular matched therapy. Conclusions: Our study provides important information to understand molecular evolutionary process of AGS patients during sequential chemotherapy first and can help to optimize future treatment strategies.

Durable Response of Induction Sequential Chemotherapy Combined With Nimotuzumab and Consolidative Carbon Ion Radiotherapy With Non-V600 BRAF Mutation Locally Advanced Pancreatic Cancer

Background: Pancreatic cancer remains a highly fatal malignancy among the most common cancers. Multidisciplinary systemic treatment is the vital method to prolong the survival of patients with locally advanced and advanced disease. Case presentation: We report a patient presented to the hospital with upper abdominal pain with occasional diarrhea for 6 months, diagnosed as locally advanced pancreatic cancer (LAPC). The patient was detected carrying with BRAF p.N486_P490del mutation and positive EGFR expression, receiving induction sequential chemotherapy of gemcitabine plus nab-paclitaxel and modified fluorouracil plus leucovorin, oxaliplatin and irinotecan, combined with nimotuzumab, followed by consolidative carbon ion radiotherapy. After the sequential treatment, the efficacy evaluation was partial response and progression-free survival was at least 20 months. Conclusions: LAPC patients with non-V600 BRAF mutation and positive EGFR expression might benefit from induction sequential chemotherapy combined with nimotuzumab and consolidative carbon ion radiotherapy. It is possible for patient with locally advanced disease to obtain better local control and further survival.

Cytostatic treatment with irinotecan liposomal in a patient with advanced pancreatic adenocarcinoma

Pancreatic cancer is one of the most common malignant neoplasms with a short survival time and a low cure rate. This neoplasm progresses quickly, it is often diagnosed in the advanced stage, which means that systemic treatment regimens are not sufficiently effective. A case of 65-year-old patient with metastatic pancreatic cancer who underwent sequential chemotherapy with the use of liposomal irinotecan was presented.

Case Report: Sequential Chemotherapy and Immunotherapy Produce Sustained Response in Osteosarcoma With High Tumor Mutational Burden

BackgroundImmunotherapy has provided an effective method for the treatment of many cancers. However, its efficacy in osteosarcoma is not satisfactory so far.Case PresentationHere, we presented a case of osteosarcoma treated with sequential chemotherapy and immunotherapy and showed promising therapeutic potential. The 29-year-old female patient presented 9th rib osteosarcoma with suspected right lung lower lobe metastasis. Surgery was performed to remove the primary lesion, and a series of chemotherapies were given afterward in consideration of the response and tolerance. The right lung lower lobe metastasis was under control first but progressed (PD) 9 months after the initiation of therapy. The lesion was surgically removed and subsequent chemotherapy was implemented. The patient had good tolerance with chemotherapy and maintained well for approximately 11 months before the discovery of 11th rib and right lung upper lobe metastases. Surgery was then performed on both lesions and achieved complete response. Post-surgical brief chemotherapy and subsequent long-term immunotherapy (pembrolizumab) maintained continuous remission for 33 months. The patient survived for 60 months with well-controlled disease from the time of confirmed diagnosis. Genetic alterations of all primary and metastatic lesions were investigated by whole-exome sequencing (WES). Substantial similarity in mutational landscape between the primary lesion and 11th rib metastasis and between the two lung metastases were revealed, while substantial heterogeneity was found between the rib lesions and lung metastases. The tumor mutational burden (TMB) for the 9th rib primary lesion, the metastatic 11th rib lesion, and the metastatic right upper and lower lobe nodule tissues was 8.02, 2.38, 4.61, and 0.14 mutations/Mb, respectively. The primary lesion exhibited the most diverse copy number variation (CNV) changes among all lesions. Furthermore, pathway enrichment analysis also suggested significant heterogeneity among the lesions.ConclusionsSurgery with sequential chemotherapy and maintenance immunotherapy was shown to have good response for the first time on osteosarcoma patient who had high TMB tumor lesions and good tolerance for chemotherapy and immunotherapy.

Optimizing the program of sequential chemotherapy for advanced gastric cancer based on gene-level CNVs called from ctDNA.

e16068 Background: Tumor evolutionary trade-offs under treatment pressure can be utilized to optimize therapy. We aimed to profile the dynamic pattern of gene-level copy number variations (CNVs) for advance gastric cancer (GCA) patients who underwent sequential chemotherapy and optimized the therapy program. Methods: 27 chemo-naive advanced GCA patients with distant metastasis were enrolled. Peripheral blood samples were collected at different time points, including pre-therapy and disease progression on a specific regimen. Gene-level CNVs were called from ctDNA of blood samples and drug modified score (DMS) was defined as the ratio of CNV value between samples of pre- and post-treatment for each gene. Positive and negative DMS of a gene represented its resistance and sensitivity to a selected regimen, respectively. Then, the best initial regimen was selected and the optimal program of sequential chemotherapy was designed for each patient. Results: DMS of gene was calculated for four chemotherapy regimens, including platinum-based doublet regimen (Pt-2d), oral-fluorouracil prodrug (O-FP), paclitaxel-based regimen (PTX) and irinotecan-based regimen (CPT-11). Based on DMS distribution, resistant and sensitive genes were determined for each regimen through a heuristic method. Functional enrichment analysis showed that resistant genes mainly involved in cellular response to oxygen-containing compound and regulation of cell proliferation, while sensitive genes mainly involved in positive regulation of macromolecule biosynthetic process and regulation of apoptotic process. Then, drug resistant score (DRS, defined as DMS weighted sum of CNV values of resistant genes) was calculated and the regimen with the lowest DRS was selected as the best initial treatment for each patient. The best initial treatment of 16 patients was CPT-11, of 8 patients was O-FP, of 2 patients was Pt-2d and of 1 patient was PTX. Following that, the optimal program of sequential chemotherapy was designed according to the percentage of shared resistant genes between regimens for each patient, where two regimens with the lowest percentage were recommended to use one by one. Finally, prognostic analysis showed that differences between the optimal and practical program of sequential chemotherapy were negatively correlated to overall survival of patients. Conclusions: Based on gene-level CNVs called from ctDNA of blood samples, we determined the best initial treatment and designed the optimal program of sequential chemotherapy for advanced GCA patients, pacing a key step toward precision medicine in GCA field.