Kwai Han Yoo

The impact of post-thaw colony-forming units-granulocyte/macrophage on engraftment following unrelated cord blood transplantation in pediatric recipients

We retrospectively reviewed the engraftment kinetics following unrelated cord blood transplantation (CBT) in association with the post-thaw colony-forming units-granulocyte/macrophage (CFU-GM) number along with the numbers of total nucleated cells (TNC), CD34+ cells and CD3+ cells. A total of 71 cord blood units prepared for 53 patients (double-unit CBT in 18 patients) were evaluated. Either the number of infused CFU-GM or CD34+ cells was significantly lower in patients who failed to achieve engraftment (P=0.028 and 0.005, respectively). Post-thaw CFU-GM, TNC and CD34+ cells correlated with the speed of neutrophil engraftment (P=0.004, 0.037 and 0.004, respectively), whereas only CFU-GM showed a significant correlation with platelet engraftment (r=−0.385, P=0.024). In double-unit transplants, the number of CFU-GM was the only significant factor predicting engraftment of the predominating unit (P=0.006). We conclude that the post-thaw CFU-GM number is a reliable predictor of rapid engraftment after CBT as well as of the predominating unit in double-unit transplants. Thus, it would be important to perform post-thaw CFU-GM assay on cryopreserved aliquots from several candidate cord blood units in advance before CBT to avoid selecting the unit that might possess a low clonogenic potential.

Hepatic veno-occlusive disease in children after hematopoietic stem cell transplantation: incidence, risk factors, and outcome

Four hundred and sixty-seven hematopoietic stem cell transplantations (HSCTs) (217 autologous and 250 allogeneic HSCT) were performed in 374 children at four pediatric HSCT centers in Korea from January 2005 to December 2007. Among 467 transplants, veno-occlusive disease (VOD) developed in 72 transplants (15.4%) at a median of 10 days after HSCT. Multivariate analysis showed that BU or TBI-containing regimen (P=0.002), VOD prophylaxis without lipo-prostaglandin E1 (PGE1) (P=0.012), number of previous HSCT (P=0.014), and pretransplant serum ferritin (P=0.018) were independent risk factors for developing VOD. Mean serum ferritin levels were significantly higher in HSCT with VOD (2109.6±2842.5u2009ng/ml) than in HSCT without VOD (1315.9±1094.4u2009ng/ml) (P<0.001). The relative risk of death within 100 days of HSCT in transplants with VOD compared with transplants without VOD was 3.39 (confidence interval: 1.78–6.45). Our results suggest that lipo-PGE1 might have a protective effect against the development of VOD, and pretransplant serum ferritin could act as a risk factor for VOD. A larger prospective study is needed to confirm a possible role of lipo-PGE1 and iron chelation therapy in reducing the incidence of VOD.

Tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma.

From June 1997 to August 2005, 52 consecutive newly diagnosed stage 4 neuroblastoma patients over 1 year of age were assigned to receive tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) as consolidation therapy. Fifty of the 52 patients underwent a first HDCT/ASCR and 44 patients underwent a second HDCT/ASCR. Eight patients (15.4%) died from treatment-related toxicity (seven during the second HDCT/ASCR). Total body irradiation (TBI) in the first HDCT/ASCR and a shorter interval (<12 weeks) between the first and second HDCT/ASCR were associated with a higher rate of treatment-related death in the second HDCT/ASCR (P=0.032 and 0.095, respectively). The tumor relapsed or progressed in 11 patients, and 33 patients remained event free with a median follow-up of 53 months (range 19–117) from diagnosis. The 5-year event-free survival (EFS) (±95% confidence interval) for all 52 patients was 62.1±13.7%. The application of TBI and local radiotherapy, and a longer interval between the first and second HDCT/ASCR were independently associated with a better EFS (P=0.026, 0.007 and 0.020, respectively). However, further studies will be needed to decrease the toxic death rate in the second HDCT/ASCR while reducing the relapse rate.

Acquired C797S Mutation upon Treatment with a T790M-Specific Third-Generation EGFR Inhibitor (HM61713) in Non–Small Cell Lung Cancer

T790M mutation is most common resistant mechanism to epidermal growth factor receptor gene (EGFR) tyrosin kinasexa0inhibitor (TKI). Several third-generation EGFR-mutant selective TKI, such as AZD9291 (AstraZeneca), Rociletinib (Clovis), or HM61713 (Hanmi) have been developed. Acquired resistant C797S mutation was known to be one of the resistance mechanisms of AZD9291, which has not been reported for HM61713 yet. This is the first case report of C797S mutation as resistance mechanism of HM61713.

Co-transplantation of third-party umbilical cord blood-derived MSCs promotes engraftment in children undergoing unrelated umbilical cord blood transplantation

Success of umbilical cord blood transplantation (UCBT) has been limited by a high rate of graft failure and delayed hematological recovery. It has been postulated that MSCs have hematopoiesis-supportive properties. Therefore, to overcome the limitation of UCBT, third-party UCB-derived MSCs were co-transplanted in recipients receiving unrelated UCBT. Seven patients received UCB and third-party UCB–MSCs. Hematopoietic recovery and transplantation outcomes were compared with historic controls. There was no acute toxicity associated with the infusion of MSCs. The median day to neutrophil engraftment was 19 days in patients, as compared with 24 days in controls (P=0.03). The median day of platelet engraftment was 47 days and 57 days in patients and controls, respectively (P=0.26). In addition, there was no engraftment failure in the MSC group. The incidence of acute and chronic GVHD was comparable between the two groups. However, veno-occlusive disease and TRM did not occur in the MSC group. Third-party UCB–MSCs infusion was safe and feasible. MSCs may also enhance the engraftment of UCBT and prevent rejection. In addition, MSCs may have a role in decreasing TRM. Randomized, controlled trials are required to confirm these results and longer follow-up will determine the effects of MSCs on the risk of relapse.

Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer

Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0–7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastoma

Although external-beam radiation therapy (EBRT) has been an effective treatment modality in patients with bilateral advanced retinoblastoma, it significantly increases the risk of second malignancies and facial deformities. This study aimed to evaluate the efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) for treatment, instead of EBRT, in children with bilateral advanced retinoblastoma. Fourteen patients with bilateral retinoblastoma received chemotherapy, and local therapy was provided whenever possible. When at least one functional eye could not be saved by chemoreduction and local therapy, tandem HDCT/ASCR was provided to avoid EBRT. As a result, nine patients received tandem HDCT/ASCR. The toxicities were tolerable and there was no TRM. All nine patients who received tandem HDCT/ASCR had at least one functional eye without EBRT, and in two patients, both eyes were saved. No second malignancy has developed to date. HDCT/ASCR might be an effective treatment for bilateral advanced retinoblastoma, especially in cases in which at least one functional eye could not be preserved with chemoreduction and local therapy alone, and where EBRT was unavoidable. Long-term follow-up and further studies are needed to evaluate the efficacy and toxicity of HDCT/ASCR as an alternative treatment to EBRT.

The impact of drug‐resistant cytomegalovirus in pediatric allogeneic hematopoietic cell transplant recipients: a prospective monitoring of UL97 and UL54 gene mutations

Cytomegalovirus (CMV) infection is a major cause of morbidity in allogeneic hematopoietic cell transplant (alloHCT) recipients. Little is known about the epidemiology of antiviral resistance in the pediatric population. We performed the prospective study to assess the impact of drug‐resistant CMV infections in pediatric alloHCT recipients.

Tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk neuroblastoma: results of SMC NB-2004 study.

From January 2004 to December 2008, 50 consecutive patients with high-risk neuroblastoma were assigned to receive tandem HDCT (high-dose chemotherapy)/auto-SCT after nine cycles of induction chemotherapy. CEC (carboplatin+etoposide+cyclophosphamide) regimen and TM (thiotepa+melphalan)-TBI regimen (or TM regimen for stage 3 patients) were the first and second HDCT regimens. Local radiotherapy, differentiation therapy with 13-cis-retinoid acid and immunotherapy with interleukin-2 were given after tandem HDCT/auto-SCT. Of the 50 patients, 49 underwent a first HDCT/auto-SCT and 47 underwent a second HDCT/auto-SCT. The tumor relapsed or progressed in 14 patients, secondary malignancy developed in one patient and one patient died from chronic lung disease. Therefore, 34 patients remained event free with a median follow-up of 54.5 months (range, 14–94 months) from diagnosis. The probabilities of 5-year OS and EFS for all 50 patients were 77.0% (95% confidence interval (CI), 63.7–90.3) and 71.4% (95% CI, 58.7–84.1), respectively. However, all patients who remained event free for >3 years after tandem HDCT/auto-SCT experienced late adverse effects. Chemotherapeutic dose-escalation strategy using tandem HDCT/auto-SCT was very encouraging for survival. However, further studies incorporating newer treatment modalities are needed to reduce late adverse effects without jeopardizing the survival rate.

Assessment of converting from intravenous to oral administration of cyclosporin A in pediatric allogeneic hematopoietic stem cell transplant recipients.

We studied the administration method during a transition period from continuous intravenous (i.v.) infusion to oral administration of cyclosporin A (CsA). Thirty-two pediatric hematopoietic stem cell transplant (HSCT) recipients, between the ages of 8 months and 15.6 years (median 7.1 years) participated in this study. The pharmacokinetic properties of CsA was evaluated during the transition period from i.v. to oral CsA. The daily oral dose of CsA was three times higher than the i.v. dose. Oral dosing began immediately after the continuous infusion was discontinued. Whole-blood CsA concentrations were measured by a monoclonal fluorescence polarization immunoassay (FPIA). The mean±s.d. value of bioavailability (F), maximum concentration (Cmax), half-life (t1/2) of CsA were 43.1±14.4%, 1135.3±340.6u2009ng/ml and 3.1±1.2u2009h, respectively. Mean clearance (CL)±s.d. was 480.9±103.7, 414.9±137.1 and 320±51.8u2009ml/h/kg in patients <20, 20–40 and >40u2009kg of body weight, respectively. The CsA CL of younger children was significantly greater than for older children (P=0.044). CsA trough levels were maintained within the therapeutic range throughout the transition period. Therefore, our findings suggest that the immediate administration of an oral formulation, after discontinuation of the continuous infusion, would be practical and effective for routine clinical use.