Therapy-related myeloid leukemia following Pleuropulmonary blastoma: A case report

The development of secondary malignancy (SM) is the most worrisome long-term complication of childhood cancer. Acute myeloid leukemia is the most prevalent neoplasm that occurs after treatment with alkylating agents and topoisomerase II inhibitors. Pleuropulmonary blastoma (PPB) is a rare lung neoplasm in children. Type II and type III of this cancer are markedly aggressive and have a recurrent nature. Chemotherapy, radiation therapy, and hematopoietic stem cell transplant (HSCT) are treatment modalities that make these patients prone to secondary malignancy. Here was presented and discussed a case of myeloid leukemia 3.5 years after treatment of Pleuropulmonary blastoma in a 5.5-year-old boy who was a candidate for high dose chemotherapy and autologous stem cells transplant (auto-SCT) because of frequent recurrence and lack of response to chemotherapy and radiation therapy. It seems this is the first reported case of therapy-related myeloid leukemia (t-AML) after PPB in children. Awareness of the creation of this complication following administration of cytotoxic therapies in the treatment of solid tumors will increase physician attention in the selection of treatment modality as well as the counseling of patients at the time of diagnosis.

Nonmyeloablative Allogeneic Transplantation in First Remission for Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia with Post-Transplantation Cyclophosphamide: Outcomes By Receipt of Pre-Transplant Blinatumomab

Background: The benefit of allogeneic blood or marrow transplantation (alloBMT) following myeloablative conditioning (MAC) in first complete remission (CR1) compared to chemotherapy has been demonstrated in a randomized trial for adults with acute lymphoblastic leukemia (ALL). Persistence of measurable residual disease (MRD) prior to alloBMT confers an increased risk of relapse. Blinatumomab eradicates persistent or recurrent MRD at levels ≥10 -3 in 78% of B ALL. However, post-hoc analyses of patients who have undergone alloBMT following blinatumomab for MRD demonstrate non-relapse mortality (NRM) of 36.5%. NRM following nonmyeloablative (NMAC) alloBMT with high-dose post-transplantation cyclophosphamide (PTCy) is just 11%. Given broadly similar outcomes between HLA-matched MAC alloBMT and HLA-haploidentical NMAC alloBMT following PTCy, we have shifted to using exclusively NMAC alloBMT with PTCy and sought to explore outcomes depending on receipt of pre-transplant blinatumomab. Methods: The bone marrow transplant database at Johns Hopkins was queried for adult patients with Ph-negative B-ALL who received NMAC alloBMT in CR1 using PTCy between January 2008 and July 2020. Characteristics of patients were summarized and compared using the student's T test for continuous variables and Fisher's exact test for categorical variables. Estimators of OS and RFS were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model for OS and RFS, and Fine and Gray's model for cumulative incidence of relapse (CIR)/NRM considering competing events. Results: Among the 50 identified patients undergoing 1 st transplant in CR1 with NMAC, all received conditioning with fludarabine and cyclophosphamide followed by total body irradiation (TBI). In addition to PTCy, all patients received mycophenolate mofetil and either tacrolimus or sirolimus as GVHD prophylaxis. Sixteen patients (32%) received blinatumomab in CR1 or achieved CR1 following blinatumomab and proceeded to transplant without intervening therapy, while 34 patients (68%) did not. At the time of treatment with blinatumomab; 3 patients had >5% blasts after chemotherapy, 8 had persistent or recurrent MRD >10 -4 after chemotherapy, and 5 had no evidence of MRD at a sensitivity of 10 -4. Among the 5 MRD- patients treated with blinatumomab; 1 had been refractory to their first course of chemotherapy (67% blasts), 3 had MRD >10 -4 at the first MRD response assessment following chemotherapy, and 1 had CNS involvement at diagnosis. The demographics of these two groups are presented in Table 1 and separated by pre-transplant blinatumomab status. The groups were well balanced in terms of gender, age, WBC at diagnosis, CNS involvement at diagnosis, and donor type. Patients who received blinatumomab were more likely to have been refractory to their initial course of chemotherapy and were transplanted later after their initial diagnosis than those who did not. All patients who received blinatumomab were MRD-negative at a sensitivity of 10 -4 prior to their transplant, while 11.8% of patients who did not receive blinatumomab were MRD-positive. Relapse-free and overall survival, cumulative incidence of relapse, and non-relapse mortality by receipt of blinatumomab prior to transplant are shown in Figure 1. Non-relapse mortality was not increased among patients who received pre-transplant blinatumomab (HR=1.06, p=0.94). The causes of non-relapse mortality included GVHD (1) and secondary malignancy (1) in patients who received blinatumomab; and infection (1), bleeding (1), secondary malignancy (1), and other (1) in patients who did not receive blinatumomab. Receipt of pre-transplant blinatumomab was associated with a decreased cumulative incidence of relapse (HR=0.15, p=0.07) and improved relapse-free survival (HR=0.32, p=0.07). Overall survival (HR=0.63, p=0.5) between the two groups was similar, likely reflecting the efficacy of salvage therapies such as CD19 CAR T cells; blinatumomab; and inotuzumab in the relapsed, post-transplant population. Conclusions: Treatment with blinatumomab prior to NMAC alloBMT with PTCy in CR1 for Ph-negative B ALL did not increase NRM and produced a 3-year RFS of 81%. The low CIR and NRM of NMAC alloBMT in an MRD-negative CR1 following blinatumomab suggest it could be a viable alternative to MAC. Figure 1 Figure 1. Disclosures Webster: AmGen: Consultancy; Pfizer: Consultancy. DeZern: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levis: Takeda: Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Astellas and FujiFilm: Research Funding; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ghiaur: Syros Pharmaceuticals: Consultancy; Menarini Richerche: Research Funding. Hourigan: Sellas: Research Funding. Jain: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy. Ali: Janssen: Consultancy; BMS: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Amgen: Consultancy; Aduro: Consultancy; Poseida: Research Funding; Aduro: Research Funding; BMS: Research Funding.

Breast metastasis from rectal carcinoma: A case report and review of the literature

BackgroundMetastasis from extramammary primary tumor to breast is extremely rare. Case SummaryA 59-year-old woman with 1-year history of rectal cancer presented with asymptomatic breast mass. At 16 months after the diagnosis of rectal mucinous adenocarcinoma, a breast mass was confirmed by ultrasonography and identified by pathology and immunohistochemistry as a metastasis from the rectal cancer. Treatments included chemotherapy (6 cycles: 300 mg irinotecan on day 1, 4.5 mg raltitrexed on day 2, 450 mg bevacizumab on day 3), radiotherapy, and surgical resection. Two years of follow-up examinations (6-months intervals) showed no evidence of recurrence or novel distant metastasis. ConclusionBreast metastasis from rectal carcinoma is a rare secondary malignancy. Final diagnosis can be established by histopathology and immunohistochemistry.

Survival of pediatric Hodgkin lymphoma patients treated with doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC) versus Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) at a single institution

Background: ABVD, the standard-of-care in adult Hodgkin lymphoma (HL), has not been directly compared to ABVE-PC, a pediatric regimen designed to reduce late-effects. We aimed to compare the effectiveness and associated toxicities of these two regimens used in the same institution. Methods: This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children’s Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n=46) or ABVE-PC (n=47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student’s t-test or Fisher’s exact test. Survival analysis used the Kaplan-Meier method. Events included: death, relapse, secondary malignancy, need for radiation therapy, pulmonary toxicity and cardiomyopathy determined by shortening fraction <29%. Analyses followed an intention-to-treat principle. Results: There was no difference in baseline characteristics between the patients receiving ABVE-PC or ABVD in regard for stage, risk group or prognostic variables, such as the presence or absence of “B” symptoms, bulky disease, and extra-nodal involvement. A greater proportion of patients treated with ABVE-PC received consolidating external beam radiation treatment (XRT) either by randomization or by response compared to ABVD (59.6% vs 32.6% respectively, p=0.01). While not statistically significant, response to therapy, assessed by PET/CT where available, mirrored the need for radiation (rapid response 58.3% vs 90.0%, n=34, p=0.11). There was no difference in event-free survival (p=0.63) or overall survival (p=0.37) with a median follow up length of 3.9 years. Conclusion: ABVD and ABVE-PC achieved similar survival outcomes in our single-institution cohort

A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor

Background Li-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia. Case report We present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity. Conclusions The knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.

Secondary Malignancy in Giant Cell Tumor: A Single-Center Study

Giant cell tumor of bone (GCTB) uncommonly undergoes sarcomatous transformation. Secondary malignancy in giant cell tumor (MGCT) develops at the prior treatment site, and is associated with radiotherapy and dismal prognosis. The objective of this study is to investigate the clinicopathological characteristics of MGCT patients. We reviewed medical records of patients with secondary MGCT. Twelve patients were analyzed including six females and six males, with a median age of 42.5 years. Benign recurrence occurred in five GCTB patients, who were not treated with radiotherapy. No pulmonary implants were observed. The median latency was 63 months. Nine patients were AJCC stage IIB, and three were stage IVA. The median follow-up period after malignant transformation was 62.5 months. Five patients developed local recurrence and six had metastasis. Five-year overall, recurrence- and metastasis-free survivals were 61.9%, 66.7% and 58.3%. The local recurrence of GCTB was a potential factor for metastasis-free survival. Difference in overall survival according to benign local recurrence was almost significant. In our series, the occurrence of secondary MGCT did not follow radiotherapy, contrary to the Western literature. The prognosis was better than the findings reported in previous studies. The local recurrence of benign GCTB could reflect the prognosis of MGCT.

Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.

Survival analysis of patients with primary breast duct carcinoma and lung adenocarcinoma: a population-based study from SEER

The appeal to enroll patients with primary breast and lung cancer in clinical trials is increasing, but survival of these two primary cancers remains to be elucidated. This study analyzed the prognosis of primary breast duct carcinoma with subsequent lung adenocarcinoma (BCLA) and primary breast duct carcinoma with prior lung adenocarcinoma (LABC). Cohorts of 3,515 patients with BCLA and 654 patients with LABC were identified from the Surveillance, Epidemiology, and End Results database. Patients were classified into simultaneous two primary cancer (sTPC), metachronous two primary cancer (mTPC1), or mTPC2 groups when the interval times between breast and lung cancer were within 6 months, between 7 and 60 months, or over 60 months, respectively. The propensity score matching program (PSM) was applied to determine the survival of BCLA/LABC relative to single breast/lung cancer. Cox proportional hazard regression model and competing risk modes were performed to identify confounders associated with all-cause and cancer-specific death, respectively. Survival of patients with LABC/BCLA relative to single breast/lung cancer was accessed via median survival time. The survival of patients with BCLA/LABC was generally poor compared with the survival of those with single breast cancer. The PSM-estimated HR in the sTPC group with BCLA and in the mTPC1 and mTPC2 groups with LABC were 0.75 (95% CI 0.62–0.90), 0.52 (95% CI 0.27–0.98), and 0.36 (95% CI 0.20–0.65), respectively, whereas the SHRs were 0.80 (95% CI 0.66–0.97), 0.68 (95% CI 0.34–1.34), and 0.46 (95% CI 0.27–0.80), respectively, compared with those in the single lung cancer group. By contrast, the survival rates of the remaining patients did not differ. The median survival times since secondary malignancy were 42, 23, and 20 months in the sTPC, mTPC1, and mTPC2 groups with BCLA, respectively, and 18, 60, and 180 months in those with LABC, respectively. For patients with BCLA, the adjusted Cox regression suggested incidences of all-cause deaths in mTPC1group were statically higher than those in sTPC group, whereas the incidences of all-cause and cancer-specific death in the mTPC1 and mTPC2 groups were statistically lower than those in the sTPC group. The prognosis of patients with breast cancer and subsequent lung cancer of over 18 months was not significantly different than that of single lung cancer, which supported the profound appeal to increase the involvement of these two primary cancers in potential beneficial clinical trials. For patients with lung cancer and prior breast cancer of within 6 months and subsequent breast cancer of over 18 months, prognosis was improved relative to single lung cancer. Therefore, additional attention is needed to eliminate the potential bias may when these patients are recruited in the clinical trials.

Patient-reported late effects of single fraction total body irradiation for non-malignant haematological disease transplant conditioning

Introduction: Patients with severe complications of non-malignant haematological disease are considered as candidates for curative treatment with an allogenic bone marrow transplant (ABMT). A non-myeloablative conditioning regimen is used; consisting of an alkylating agent and single fraction total body irradiation (SFTBI) at a dose of 2-4.5 Gy (dose rate 150mu/min). This is distinct from high dose fractionated total body irradiation (TBI) used in a myeloablative conditioning regimen; for which the late effects are well documented. There is however no dedicated study on the late effects associated with low dose SFTBI. Methods: We undertook a single institution study focusing on patient reported outcomes after SFTBI (January 2003 – January 2019) delivered more than 1-year previously, prior to an AMBT in patients aged under 16-years for non-malignant haematological conditions. A 19-point questionnaire was conducted with study subjects over the phone. The primary outcome was late effects as reported by patients. Secondary outcomes were patient demographics. Results: Fifty patients were screened, 31 were invited to take part and 24 consented to participate. Pulmonary toxicity was the most common visceral effect reported (5 patients), followed by kidney (3) and cardiac (2). No patients reported cataracts, diabetes or secondary malignancy. Two patients were on sex hormone replacement although no evidence of female menstrual delay was demonstrated. The majority (21) were enrolled in mainstream schools. Conclusion: Late effects do occur after SFTBI, but are mild and occur less frequently compared to high dose TBI. The consent process with children/parents prior to SFTBI should reflect this.