| 1. |
- Guan, Jikui, et al.
(författare)
-
Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
- 2018
-
Ingår i: Cold Spring Harbor molecular case studies. - : Cold Spring Harbor Laboratory. - 2373-2873. ; 4:4
-
Tidskriftsartikel (refereegranskat)abstract
- Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
|
|
| 2. |
- Jensen, Karen Schow, et al.
(författare)
-
Temporal changes in incidence of relapse and outcome after relapse of childhood acute lymphoblastic leukemia over three decades : a Nordic population-based cohort study
- 2022
-
Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36, s. 1274-1282
-
Tidskriftsartikel (refereegranskat)abstract
- Relapse remains the main obstacle to curing childhood acute lymphoblastic leukemia (ALL). The aims of this study were to compare incidence of relapse, prognostic factors, and survival after relapse between three consecutive Nordic Society of Pediatric Hematology and Oncology trials. Relapse occurred as a primary event in 638 of 4 458 children (1.0–14.9 years) diagnosed with Ph-negative ALL between 1992 and 2018. The 5-year cumulative incidence of relapse was 17.3% (95% CI 15.4–19.2%) and 16.5% (95% CI 14.3–18.8%) for patients in the ALL1992 and ALL2000 trials, respectively, but decreased to 8.4% (95% CI 7.0–10.1%) for patients in the ALL2008 trial. No changes in duration of first complete remission and site of relapse were observed over time; however, high hyperdiploidy, and t(12;21) decreased in the ALL2008 trial. The 4-year overall survival after relapse was 56.6% (95% CI 52.5–60.5%) and no statistically significant temporal improvements were observed. Age ≥10 years, T-cell immunophenotype, bone-marrow involvement, early and very early relapse, hypodiploidy, and Down syndrome all independently predicted worse outcome after relapse. Improvements in the primary treatment of childhood ALL has resulted in fewer relapses. However, failure to improve outcome of remaining relapses suggests a selection of harder-to-cure relapses and calls for new therapeutic strategies.
|
|
| 3. |
- Remberger, Mats, et al.
(författare)
-
Improved survival after allogeneic hematopoietic stem cell transplantation in recent years : A single-center study
- 2011
-
Ingår i: Biology of blood and marrow transplantation. - : Elsevier BV. - 1083-8791 .- 1523-6536. ; 17:11, s. 1688-1697
-
Tidskriftsartikel (refereegranskat)abstract
- We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
|
|
| 4. |
- Svenberg, Petter, et al.
(författare)
-
Improved overall survival for pediatric patients undergoing allogeneic hematopoietic stem cell transplantation - A comparison of the last two decades.
- 2016
-
Ingår i: Pediatric Transplantation. - : Wiley. - 1397-3142 .- 1399-3046. ; 20:5, s. 667-74
-
Tidskriftsartikel (refereegranskat)abstract
- Pediatric protocols for allogeneic hematopoietic SCT have been altered during the last two decades. To compare the outcomes in children (<18 yr old), who underwent SCT at our center during 1992-2002 (P1) and 2003-2013 (P2). We retrospectively analyzed 188 patients in P1 and 201 patients in P2. The most significant protocol changes during P2 compared with P1 were a decrease in MAC protocols, particularly those containing TBI, an increase in RIC protocols, and altered GvHD prophylaxis. In addition, P2 had more patients with nonmalignant diagnoses (p = 0.002), more mismatched (MM) donors (p = 0.01), and more umbilical CB grafts (p = 0.03). Mesenchymal or DSCs were used for severe acute GvHD during P2. Three-yr OS in P1 was 58%, and in P2, it was 78% (p < 0.001). Improved OS was seen in both malignant disorders (51% vs. 68%; p = 0.05) and nonmalignant disorders (77% vs. 87%; p = 0.04). Multivariate analysis showed that SCT during P2 was associated with reduced mortality (HR = 0.57; p = 0.005), reduced TRM (HR = 0.57; p = 0.03), unchanged relapse rate, similar rate of GF, less chronic GvHD (HR = 0.49; p = 0.01), and more acute GvHD (HR = 1.77, p = 0.007). During recent years, OS has improved at our center, possibly reflecting the introduction of less toxic conditioning regimens and a number of other methodological developments in SCT.
|
|
| 5. |
- Svenberg, Petter
(författare)
-
Outcome after allogeneic stem cell transplantation with special reference to non-malignant disorders, chimerism and graft cell composition
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The outcome for patients undergoing allogeneic stem cell transplantation (HSCT), a treatment for several severe malignant and non-malignant disorders with hematopoietic origin, is a balancing act between beneficiary effects and risk factors. Treatment success is still limited by excessive immune response, such as graft-versus-host–disease (GVHD) and graft failure (GF), or the lack thereof as in malignancy relapse or severe infections. The main focus of this thesis is to evaluate treatment outcome of different patient groups and evaluate the effect of routine testing for these patients. In 2004, the decision to use an unrelated donor (URD) rather than a HLA-identical sibling for patients with a non-malignant disorder was, due to a higher risk for complications, more debatable than today. In Paper 1, we retrospectively analysed the outcome for 25 patients with non-malignant disorders who underwent HSCT with a unrelated HLA-A,B DRβ1- matched donor. All patients received anti-thymocyte globulin (ATG). Only 2 patients rejected their graft and the cumulative incidence of acute (only grade I and II were diagnosed) and chronic GVHD was 24%, and 21%, respectively. Also, the overall survival (OS) was 84% indicating that the results were comparable to patients undergoing a HSCT with a HLAidentical donor. Chimerism is a PCR-based technique used to determine the genotypic cell origin of post transplantation hematopoiesis for the detection of graft failure (GF) and relapse. Post HSCT, we can find either a mix of donor and recipient, i.e. mixed chimerism (MC) or only cells of donor origin i.e. donor chimerism (DC). In Paper 2, we retrospectively evaluated 58 patients (64 transplants) with non-malignant disorders and studied the outcome in relation to chimerism status and, in addition, how high MC was clinically managed (to avoid GF). We found MC in 64% of the transplants. Donor chimeric (DC) was more common after myeloablative conditioning (MAC) than after reduced conditioning (p=0.04), and patients with DC had a higher incidence of acute GVHD grade II–III (p=0.002) compared to patients with MC. Owing to high MC, no conclusive treatment was established, but patients with GF who underwent a re-HSCT did well. Outcome for adult patients after HSCT have improved. In Paper 3, we compared outcome after HSCT for pediatric patients between time periods 1992-2002 (P1) and 2003 to 2013 (P2). The most significant changes during P2 compared with P1 were a decrease in MAC protocols, altered GVHD prophylaxis and more eligible patients had a non-malignant diagnoses (p=0.002). Results showed more acute GVHD, less transplanted mortality (TRM) but relapse rate was unchanged. In all, 3-year overall survival (OS) improved from 58% in P1 to 78% in P2 (p<0.001). Lastly, pursuing the quest for relevant factors influencing patient outcome, its known that donor grafts entail not only stem cells (CD34+) but also potentially active lymphocytes whos numbers can differ depending on the donor and donor site. In Paper 4, we hypothesized that these donor graft lymphocyte sub-sets could influence patient outcome. We collected and evaluated routine flow cytometry donor graft data (i.e. CD34+, CD3+, CD19+, CD4+, CD8+, CD3-CD56+CD16+, CD4+CD127lowCD25high) for 299 patients with malignant diseases who underwent HSCT between 2006 and 2013 with peripheral blood stem cell grafts (we analysed unrelated separated from sibling donors). The multivariate analysis showed in the unrelated-group an association between a high CD8+ graft dose and decreased risk for relapse (p=0.006) and in the sibling group a high CD19+ graft dose was associated with increased risk for transplanted related mortality (p=0.036) and acute GVHD (p=0.003).
|
|
| 6. |
- Svenberg, Petter, et al.
(författare)
-
The importance of graft cell composition in outcome after allogeneic stem cell transplantation in patients with malignant disease
- 2019
-
Ingår i: Clinical Transplantation. - : Wiley. - 0902-0063 .- 1399-0012. ; 33:6
-
Tidskriftsartikel (refereegranskat)abstract
- Background Graft-versus-host disease (GVHD) and relapse remain majobstacles ftreatment success in allogeneic hematopoietic stem cell transplantation (HSCT). In the present study, we evaluated the immune cell profile of the graft to outcome after HSCT.Study design and method Flow cytometry data of graft cell subsets [CD34+, CD3+, CD19+, CD4+, CD8+, CD3-CD56+CD16+, CD4+CD127lowCD25high] from G-CSF primed peripheral blood stem cell (PBSC) donors was collected retrospectively from 299 patients with hematological malignancies undergoing HSCT between 2006 and 2013. The association to overall survival, transplant-related mortality (TRM), GVHD and probability of relapse was analyzed. Patients outcome from HLA-identical sibling (Sib) (n = 97) and unrelated donors (URD) (n = 202) were analyzed separately as all URD patients received anti-thymocyte globulin (ATG).Results Five-year overall survival was similar in the two cohorts (68% (Sib) vs 65% (URD)). The relapse incidence was significantly lower in the Sib cohort (24% vs 35%, P = 0.04). Multivariate analysis in the URD group revealed an association between a higher CD8+ dose and less relapse (HR, 0.94; 95%CI, 0.90-0.98; P = 0.006) as well as an association between higher CD34+ dose and both higher TRM (HR, 1.09; 95%CI, 1.02-1.20; P = 0.02) and relapse (HR, 1.09; 95%CI, 1.01-1.17; P = 0.025). The Sib analysis showed an association between a higher graft CD19+ dose and more severe acute GVHD (HR, 1,09; 95%CI, 1.03-1.15; P = 0.003) and TRM (HR, 1.09; 95%CI, 1.01-1.17; P = 0.036). In addition, a higher CD4+ graft content was associated to an increased risk for chronic GVHD (HR, 1.02; 95%CI 1.00-1.04; P = 0.06).Conclusion These data indicate an importance of PBSC dongraft composition in patients with a hematological malignancy.
|
|
