Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Upfront multi-bipolar radiofrequency ablation for HCC in transplant-eligible cirrhotic patients with salvage transplantation in case of recurrence.

INTRODUCTION: We aim to assess the long-term outcomes of percutaneous multi-bipolar radiofrequency (mbpRFA) as the first treatment for hepatocellular carcinoma (HCC) in transplant-eligible cirrhotic patients, followed by salvage transplantation for intrahepatic distant tumour recurrence or liver failure. MATERIALS AND METHODS: We included transplant-eligible patients with cirrhosis and a first diagnosis of HCC within Milan criteria treated by upfront mbp RFA. Transplantability was defined by age <70 years, social support, absence of significant comorbidities, no active alcohol use and no recent extrahepatic cancer. Baseline variables were correlated with outcomes using the Kaplan-Meier and Cox models. RESULTS: Among 435 patients with HCC, 172 were considered as transplantable with HCCs >2 cm (53%), uninodular (87%) and AFP >100 ng/mL (13%). Median overall survival was 87 months, with 75% of patients alive at 3 years, 61% at 5 years and 43% at 10 years. Age (p = .003) and MELD>10 (p = .01) were associated with the risk of death. Recurrence occurred in 118 patients within Milan criteria in 81% of cases. Local recurrence was observed in 24.5% of cases at 10 years and distant recurrence rates were observed in 69% at 10 years. After local recurrence, 69% of patients were still alive at 10 years. At the first tumour recurrence, 75 patients (65%) were considered transplantable. Forty-one patients underwent transplantation, mainly for distant intrahepatic tumour recurrence. The overall 5-year survival post-transplantation was 72%, with a tumour recurrence of 2.4%. CONCLUSION: Upfront multi-bipolar RFA for a first diagnosis of early HCC on cirrhosis coupled with salvage liver transplantation had a favourable intention-to-treat long-term prognosis, allowing for spare grafts.

Microvascular invasion of hepatocellular carcinoma predicts microvascular invasion of its recurrence: potential implications for salvage liver transplantation?

Background: Microvascular invasion (MVI) can only be assessed on a full surgical specimen. We aimed at evaluating, whether the histology of the primary tumor is predictive of MVI in a hepatocellular carcinoma (HCC) recurrence. Methods: Patients, who underwent liver resection or orthotopic liver transplantation (OLT) for recurrent HCC from January 2001 until June 2018 were eligible for this retrospective analysis. Resected specimens were evaluated for HCC subtype/morphology, vessels encapsulating tumor clusters (VETC)-pattern and MVI. Dichotomous parameters were analyzed using χ2-test and ϕ-values, with P values <0.05 being considered significant. Results: Of 230 HCC recurrences, 37 (16.1%) underwent repeated liver resection (n=22) or OLT (n=15). Of these, 67.6% initially exceeded the Milan criteria. MVI correlated Milan criteria (P=0.005), tumor size (P=0.015) and VETC-pattern (P=0.034) in the primary specimen. The recurrences shared many features of the primary HCC such as tumor grade (P=0.002), VETC-pattern (P=0.035), and MVI (P=0.046). In recurrences, however, only the concordance with the Milan criteria correlated with MVI (P=0.018). No patient without MVI in the primary HCC revealed MVI on early recurrence (<2 years) (P=0.035). Conclusions: HCC recurrences share many biological features of the primary tumor. Moreover, early recurrences of MVI-negative HCC never revealed MVI. This finding offers novel concepts, e.g., patient selection for salvage OLT.

Sustained Hematopoietic Engraftment Potential after Prolonged Storage of Cryopreserved Hematopoietic Stem Cells Used in Salvage Autologous Stem Cell Transplantation.

Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Peripheral blood stem cells (PBSCs), a source of hematopoietic stem cells (HSCs), are collected before the first transplantation, and adequate quantities of PBSCs can be collected and stored potentially for years to support at least 2 transplantations for eligible patients. To ensure the safety of salvage HSCT in the treatment of patients in subsequent relapse, PBSCs must retain the potential to engraft even after several years of cryopreservation. Although PBSC viability has been studied extensively using in vitro techniques, few publications describe the most rigorous functional potency measure, of patients receiving a myeloablative conditioning regimen. This study describes a large single-institution experience evaluating the engraftment kinetics of PBSCs used in salvage transplantation after multiple years of storage compared with first transplantation for the same patients in the treatment of MM. A retrospective chart review of patients with MM undergoing HSCT between 2000 and 2021 identified 89 patients who received salvage autologous PBSCs stored for >1 year after first HSCT. PBSCs were cryopreserved and stored in vapor-phase liquid nitrogen refrigerators at ≤-150°C. All patients received a PBSC product from the same collection cycle for both transplantations. Differences in CD34+ cell doses and days to engraftment between the first and salvage transplantations were tested using the paired 2-tailed t-test and Wilcoxon signed-rank test. Univariate and multivariable linear regressions were used to determine the association between storage time and days to engraftment, adjusting for CD34+ cell dose and conditioning regimen in the multivariable model. The median duration of storage between the day of initial collection and salvage transplant was 5.4 years (range, 1.0 to 19.7 years). Engraftment kinetics demonstrated a sustained neutrophil engraftment (absolute neutrophil count >0.5 × 109 cells/L) at a median of 11 days after both the first and salvage transplantations (range, 8 to 15 days and 8 to 19 days, respectively; P < .05). The median time to sustained platelet engraftment (>20 × 109 cells/L without transfusion support) was 13.5 days after the first HSCT and 14 days after salvage HSCT (range, 9 to 27 days and 10 to 56 days, respectively; P = .616). After adjusting for CD34+ cell doses and conditioning regimens, there was no association between the duration of cryopreservation and days to neutrophil engraftment (r = 0.178, P = .130) or platelet engraftment (r = 0.244, P = .100). Engraftment kinetics of the salvage HSCT are comparable to those of the first HSCT even when products are stored in vapor-phase nitrogen refrigerators for a median of 5.4 years. There is no association between the duration of storage and time to engraftment when controlling for CD34+ cell dose and conditioning regimen. Prolonged storage of cryopreserved HSC products is a safe practice for MM patients undergoing salvage autologous HSCT.

Use of Backup Stem Cells for Stem Cell Boost and Second Transplant in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation.

Autologous hematopoietic stem cell transplantation (ASCT) is a standard treatment for multiple myeloma (MM). Consensus guidelines recommend collecting sufficient stem cells in case there is a need for stem cell boost for delayed/poor engraftment or for future second ASCT. However, collecting and storing backup stem cells in all patients requires significant resources and cost, and the rates of backup stem cell utilization are not well studied. We sought to examine the utilization of backup stem cells (BSCs) in patients with MM undergoing ASCT. Patients with MM aged ≥18 years old who underwent first ASCT at our institution from January 2010 through December 2015 and collected sufficient stem cells for at least 2 transplants were included in this single-center retrospective study. This timeframe was selected to allow for adequate follow-up. A total of 393 patients were included. The median age was 58 years (range, 25-73). After a median follow-up of 6 years, the median progression-free survival (PFS) of the cohort was 3 years. Sixty-one percent (n = 240) of patients progressed or relapsed. Chemotherapy-based mobilization was used in almost all patients (98%). The median total CD34+ cells collected was 18.2 × 106/kg (range, 3.4-112.4). A median of 5.7 × 106 CD34+ cells/kg (range, 1.8-41.9) was infused during the first ASCT, and a median of 10.1 × 106 CD34+ cells/kg (range, 1.5-104.5) was cryopreserved for future use. Of the patients, 6.9% (n = 27) used backup stem cells, with 2.3% (n = 10) using them for stem cell boost, 4.6% (n = 18) for a second salvage ASCT, including 1 patient for both stem cell boost and second ASCT. Rates of backup stem cell use among patients aged <60, 60-69, and ≥70 years were 7.8%, 5.7%, and 5.9%, respectively. There was a trend toward higher rates of backup stem cell use for second ASCT in patients who were younger, had suboptimal disease control at time of first ASCT, and longer PFS. The median dose of stem cell boost given was 5.6 × 106 CD34+ cells/kg (range, 1.9-20). The median time from stem cell boost to neutrophil, hemoglobin, and platelet engraftment was 4 (range, 2-11), 15 (range, 4-34), and 12 (range, 0-34) days, respectively. Lower CD34+ dose and older age at time of ASCT predicted need for stem cell boost. With new salvage therapies for relapsed MM, the rates of second ASCT are very low. The low rates of use suggest that institutional policies regarding universal BSC collection and long-term storage should be reassessed and individualized. However, need for stem cell boost in 2.3% of patients may present a challenge to that.

[Salvage liver transplantation for hepatocellular carcinoma]. / Salvage-transplantatsiia pecheni pri lechenii gepatotselliuliarnoi kartsinomy.

OBJECTIVE: To analyze clinical course and the results of salvage liver transplantation in patients with recurrent hepatocellular carcinoma (HCC) after liver resection. MATERIAL AND METHODS: A 54-year-old man with HCV-infection and HCC and 22-year-old woman with fibrolamellar variant of HCC underwent resection of the right and left liver lobe, respectively. The first patient experienced recurrent HCC four times with an interval of 3-6 months within 2 years after surgery. Repeated liver resection was made in first three cases, right liver lobe transplantation - after the fourth recurrence. In the second patient, HCC recurred in 4 months after resection and was accompanied by subtotal portal vein thrombosis. Therefore, repeated liver resection was excluded and patient underwent right liver lobe transplantation. RESULTS: Patients are alive in 5 and 3.5 years after liver resection and in 2.5 and 3 years after transplantation, respectively. There are currently no signs of recurrent HCC in the graft.

Long-term survival comparison between primary transplant and upfront curative treatment with salvage transplant for early stage hepatocellular carcinoma.

BACKGROUND: Whether primary liver transplantation (PLT) or upfront curative treatment with salvage liver transplantation (SLT) is a better treatment option for early hepatocellular carcinoma (HCC) is controversial. This study aims to compare the long-term survival starting from the time of primary treatment between the two approaches for early HCC using propensity score matching (PSM) analysis. METHODS: From 1995 to 2014, 175 patients with early HCC undergoing either PLT (n = 149) or SLT (n = 26) were retrospectively reviewed in a prospectively collected database. Patients' demographic data, tumor characteristics, short-term and long-term outcome were compared between two groups after PSM. RESULTS: After matching, the baseline characteristics were comparable between mPLT group (n = 45) and mSLT group (n = 25). The tumor recurrence rate after transplant was significantly higher in mSLT group than mPLT group (28% vs. 15.6%). Calculating from the time of primary treatment, the 1, 3, and 5-year overall survival rates were comparable between mPLT group (97.8%, 91.1% and 86.3%) and mSLT group (100%, 95% and 85%). However, the 1, 3, and 5-year recurrence-free survival rates were significantly better in mPLT group than mSLT group (95.6% vs. 90%, 86.6% vs. 80% and 84.3% vs. 70%). SLT approach and high pre-treatment serum alpha-fetoprotein level (>200 Î·g/mL) were poor prognostic factors for recurrence-free survival after transplant. CONCLUSIONS: PLT may be a better treatment option for early HCC, whereas SLT approach for HCC should be cautiously considered under the circumstance of organ shortage.

When to consider liver transplantation in hepatocellular carcinoma patients?

Orthotopic liver transplantation (LT) has been regarded as the best cure among the three curative treatment modalities. However, when to consider LT in hepatocellular carcinoma (HCC) patients remains a complicated clinical question. In this article, we will look into the recent updates in the context of LT for HCC, including the timing of orthotopic LT (primary or salvage LT), patient selection criteria, newer prognostic markers and scoring systems, down-staging and bridging therapy, salvage LT and treatment option of post-LT HCC recurrence. Evolution of immunosuppressive therapy and future development of the LT for HCC will also be discussed.

Primary liver transplantation vs liver resection followed by transplantation for transplantable hepatocellular carcinoma: Liver functional quality and tumor characteristics matter.

Liver resection (LR) and primary liver transplantation (LT) are two potentially curative treatment modalities for patients with hepatocellular carcinoma (HCC). If an underlying chronic liver disease exists, however, making a decision on which method should be selected is difficult. If a patient has no chronic liver disease, LR may be the preferable option with salvage transplantation (ST) in mind in case of recurrence. Presence of a moderate-to-severe liver failure accompanying HCC usually warrants primary LT. The treatment of patients with HCC and early-stage chronic liver disease remains controversial. The advantages of "LR-followed-by-ST-if-needed" strategy include less complicated index operation, no need for immunosuppression, use of donor livers for other patients in today's organ shortage setting and comparable survival rates. However, primary LT has its own advantages as it also treats underlying chronic liver disease with carcinogenic potential, removes undetected tumor nodules and potentially eliminates need for a ST. An article recently published by Fuks et al in Hepatology offers an approach by which selecting between LR-followed-by-ST and immediate LT might be easier. Here we discuss the results of the aforementioned report in the light of currently available knowledge.

The Usefulness of Salvage Transplantation in Patients with Hepatocellular Carcinoma / 대한이식학회지

PURPOSE: The treatment of choice for hepatocellular carcinoma (HCC) is either surgical resection or liver transplantation. Liver transplantation has the advantage of treating both the tumor and cirrhosis at the same time. However, due to the shortage of donors the availability of this treatment modality is limited. When recurrence is found after liver resection, liver transplantation (salvage transplantation) is an alternative treatment option, as well as in cases with hepatic failure after resection. We carried out this study to evaluate the usefulness of salvage transplantation in these cases. METHODS: From October 2000 to September 2007, among 305 patients who underwent living donor liver transplantation at Kangnam St. Mary Hospital, 119 underwent liver transplantation for HCC. Among them, 102 patients received a primary liver transplantation (PT) and 17 salvage liver transplantation (ST). Among those who underwent a ST, 7 had a major liver resection and 10 had a minor resection, prior to the transplantation. During the ST, all patients received right lobe grafts from living donors. Preoperative and postoperative clinical data were analyzed, as well as survival and disease free survival between the PT and ST groups. RESULTS: There were 5 cases (4.9%) of perioperative mortality in the PT group and 3 cases (17.7%) in the ST group; this difference was without statistical significance. The transfusion requirement for red blood cells was greater in the ST group; but this difference did not reach statistical significance (13.5+/-8.5 units in PT vs. 17.9+/-8.5 units in ST). In addition, there were no significant differences in the recipient operation time (640+/-111 mins in PT vs. 751+/-145 mins in ST), postoperative complication rate (32.3 % in PT vs. 58.8% in ST), reoperation rate (7.8 % in PT vs. 5.9% in ST), and postoperative hospital stay (30.9+/-9.9 days in PT vs. 29.2+/-11.5 days in ST). Furthermore, the 3- and 5-year intention to treat overall survival rate (70.0%, 65.1% in PT vs. 82.4%, 76.0% in ST) were not significantly different. CONCLUSION: The overall survival and disease free survival rates after ST were similar to those after PT. Salvage transplantation, therefore, may be a useful rescue therapy for patients that develop disease recurrence or deterioration of liver function after liver resection for HCC.