Comparison Of Intravenous With Oral Busulfan In Allogeneic Hematopoietic Stem Cell Transplantation With Myeloablative Conditioning Regimens For Pediatric Acute Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3397-3397
Author(s):  
Motohiro Kato ◽  
Yoshiyuki Takahashi ◽  
Daisuke Tomizawa ◽  
Yasuhiro Okamoto ◽  
Jiro Inagaki ◽  
...  
Keyword(s):  
Stem Cell ◽  
Clinical Outcome ◽  
Acute Leukemia ◽  
Pediatric Patients ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Significant Survival ◽  
The Difference

Abstract Recently, intravenous busulfan (iv-BU) has replaced oral-BU, which can suppress variety of bioavailability. Also, iv-BU showed less hepatic toxicity by avoiding the hepatic first-pass effect of oral-BU. Previous reports showed that the use of iv-BU reduced early complications and decreased early non-relapse mortality (NRM). Some reports demonstrated that iv-BU may provide better overall survival (OS) in adult with malignant diseases. Although several reports have been published on pediatric patients using iv-BU, the number of patients included was small, and the reports mainly focused on acute toxicity or early clinical outcome because of a short follow-up period. Thus, the role of iv-BU in HSCT for pediatric patients with acute leukemia is yet to be determined. In this study, to compare clinical outcome of HSCT with iv-BU and oral-BU, we retrospectively analyzed HSCT based on data reported to the Japan Society for Hematopoietic Cell Transplantation (JSHCT) registry. The patients were selected according to the following criteria: (1) patients diagnosed with either acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) aged 15 years or younger when receiving HSCT, (3) BU-based myeloablative (more than 8 mg/kg) preconditioning regimens, and (4) HSCT performed between 2000 and 2010. Therefore, we analyzed 460 children with iv-BU (n = 198) or oral busulfan (BU) (n = 262) receiving hematopoietic stem cell conditioning transplantation (HSCT) with BU-based myeloablative conditioning for acute leukemia. The median age at HSCT was 4 years (range, 0–15 years). The median follow-up period was 1,828 days (range, 85–4,619 days) after HSCT in all the surviving patients, and 1,185 days (range, 100–3,759 days) after HSCT in the iv-BU patients. Although OS with iv-BU and oral-BU at day 100 after HSCT was 72.5 ± 3.2% and 66.9 ± 2.9%, respectively, OS at 3 years after HSCT was similar (iv-BU, 53.4 ± 3.7%; oral-BU, 55.1 ± 3.1% ), and the log-rank test for OS did not show statistically significant difference (p = 0.77) (Figure 1a). The result was concordant even when an analysis was limited to patients with ALL or AML. OS at 3 years for patients with ALL using iv-BU (n = 90) and oral-BU (n = 151) was 56.4 ± 5.5% and 54.6 ± 4.1, respectively (p = 0.51) (Figure 1b). OS at 3 years for patients with AML using iv-BU (n = 108) and oral-BU (n = 111) was 51.0 ± 5.0% and 55.8 ± 4.8%, respectively (p = 0.83) (Figure 1c). The similarity of OS was reproduced even with the limited cohort of 247 patients who received HSCT after 1st CR or 2nd CR without prior HSCT. OS at 3 years was 78.3 ± 4.2% for iv-BU patients (n = 98) and 78.7 ± 3.4% for oral-BU patients (n = 149) and the difference was not statistically significant (p = 0.66). Multivariate analysis also showed no significant survival advantage with iv-BU. Cumulative incidence of relapse at 3 years with iv-BU was similar with that of oral-BU (39.0 ± 3.6% and 36.4 ± 3.1%, respectively) (p = 0.67). Cumulative incidence of NRM at 3 years was 16.6 ± 2.7% with iv-BU and 18.3 ± 2.5% with oral-BU (p = 0.51). The iv-BU group showed a tendency toward higher engraftment probability at day 60 (96.0 ± 1.5%) compared with the oral-BU group (89.3 ± 2.0%), but the difference was not statistically significant (p = 0.22) This study was a retrospective study using registry data, and there are some limitations of our data. For example, as selection of iv-BU or oral-BU was strongly associated with the transplantation period, which may have introduced bias. Further prospective studies are required to establish an optimal allogeneic HSCT treatment strategy for pediatric patients with acute leukemia. In conclusion, our study provides valuable information on the role of iv-BU in myeloablative HSCT for pediatric acute leukemia. In children, iv-BU could not show significant survival improvement in outcome of acute leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting Bcl-2 and CD38 As Part of Personalized HSCT Conditioning Regimen in Chemorefractory Pediatric Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2084-2084
Author(s):  
Maria Alyabeva ◽  
Larisa Shelikhova ◽  
Larisa Shelikhova ◽  
Daria Shasheleva ◽  
Rimma Khismatullina ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Pediatric Patients ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
The Moment ◽  
Median Expression

Abstract Introduction The outcome hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory leukemia is poor. The incidence of relapse exceeds 50% and survival varies from 10 to 40%. Additional attempts at remission induction with various combinations of chemotherapy are unlikely to improve the outcome and will contribute to toxicity. We hypothesized that personalized targeted therapy combined with high-dose chemotherapy may improve the outcome of allogeneic hematopoietic stem cell transplantation in a cohort of pediatric patients with refractory leukemia. Bcl-2 and CD38 were chosen as potential targets due to frequent expression in pediatric acute leukemias, availability of marketed targeted therapies, venetoclax and daratumumab, and expected non-overlapping toxicity profile of these agents and the conditioning regimen. Materials and methods A total of 16 pts with chemorefractory disease (T-ALL - 2, AML - 8, JMML - 6, 12 male, 4 female, median age 5,7 years), underwent HSCT between November 2017 and June 2018, median follow-up - 3 months (1,6-7). All pts were transplanted from haploidentical donors, had active disease (AD) at the moment of SCT, for 12 (75%) pts it was the first allogenic HSCT, for 4 pts it was the second HSCT. Median bone marrow leukemia burden before cytoreduction was 22% (3-75). Bcl-2 expression on the tumor cells was detected in all pts (100%) with the median expression of 69% (0,7-100), CD38 expression was detected in 10 pts (AML=7, ALL=2, JMML-1) with the median expression of 96% (71-100). Ten pts received treosulfan-based conditioning, 3 - busulfan-based and 3 -TBI-based. GVHD prophylaxis included tocilizumab at 8 mg/kg on day -1, post-transplant bortezomib and abatacept at 10 mg/kg on day -1, +7, +14, +28. Three pts received thymoglobulin 5mg\kg. According to the expression of Bcl-2 and CD38 on tumor cells, 9 patients (56%) received Daratumumab (anti-CD38 monoclonal antibody) on day -6, 15 patients (94%) received venetoclax at 300 mg/m2/day on days -7 to -2. TCRαβ+/CD19+ depletion of PBSC with CliniMACS technology was implemented in all cases. The median dose of CD34+ cells in transplant was 11 x106/kg (range 7-18), α/β T cells - 40x103/kg (range 11- 139). Modified (CD45RA-depleted) donor lymphocyte infusions (DLI) were administered to 15 pts, 9 pts received modified DLI on day 0. Result Primary engraftment was achieved in 13 (81%) of 16 pts. The median time to ANC and platelets recovery was 14 days (11-22). Engraftment was 100% (10 of 10) among patients with acute leukemia and 50% (3 of 6) among patients with JMML. Three patients with JMML had early disease progression. There were no significant toxic effects after HSCT and no cases of transplant-related mortality. The median NK- cells count by the day +30 was 0,185 x 106/ml (range 0,019- 0,472), the median levels of αβ T cells and gd T cells were 0,045 x 106 /ml (range 0 - 0,364) and 0,07 x 106 /ml (range 0 - 0,349, respectively. Acute GVHD grade 1-2 was developed in 2 pts (15%), none of them required systemic immunosuppressive therapy. There were no cases of chronic GVHD. One (7,6%) patient with AML relapsed on day +61. Three pts (1 with AML and 2 with JMML) died from disease progression, 1 patient with JMML died from complications after the second HSCT. At the moment of reporting 12 pts (9 of 10 with acute leukemia and 3 of 6 with JMML) are alive, in complete remission with a median follow up of 3 months (1,5-7m). Conclusion We suggest that addition of venetoclax and datatumumab to the backbone of myeloablative haploidentical HSCT with αβ T cell depletion is not associated with increased toxicity and may lead to improved early outcomes in a cohort of pediatric patients with chemorefractory acute leukemia. This approach can be further tested in a prospective trial with the goal to increase the anti-leukemic efficacy of HSCT. Disclosures No relevant conflicts of interest to declare.

scholarly journals Second Allogeneic Hematopoietic Stem Cell Transplantation for Post-Transplant Relapsed Acute Leukemia in Children - an EBMT PDWP Retrospective Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 912-912
Author(s):  
Isaac Yaniv ◽  
Aviva C. Krauss ◽  
Eric Beohou ◽  
Arnaud Dalissier ◽  
Selim Corbacioglu ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Prognostic Factor ◽  
Acute Leukemia ◽  
Pediatric Patients ◽  
Multivariate Analyses ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Entire Cohort

Abstract Introduction Using the EBMT registry, we retrospectively analyzed outcomes for 373 pediatric patients who underwent second allogeneic transplant for relapsed acute leukemia at 120 centers in 32 countries, between the years 2004 and 2013, in an attempt to assess relapse, survival, GVHD and other outcomes, as well as identify factors correlating with prognosis in this cohort of patients. To our knowledge, this is the largest analysis of pediatric patients undergoing second allogeneic HSCT for relapsed acute leukemia to date. This allowed for an independent analysis of each disease, including 214 patients with ALL and 159 with AML. Patients and Methods Centers received a questionnaire completing data already available in the ProMISe database on patients between 0-18 years of age treated between 2004 and 2013. Results A total of 387 patients received a second SCT after relapse. 373 have been included in the analysis, 214 for ALL and 159 for AML. Detailed data were available for 201 patients from 48 centers; for the remainder, analysis was based on the registry. For the entire cohort overall survival (OS) at 2 and 5 years were 38% and 29%, and leukemia free survival (LFS) 30% and 25% respectively. ALL: With a median follow up from 2nd SCT of 36.4 months, OS at 1 and 5 years were 47% and 28% respectively. LFS was 39% and 28% respectively. NRM at 2 years was 22%. In multivariate analyses favorable prognostic factors for both OS and LFS were: CR prior to 2nd SCT (p=0.0001), interval > 12 months between transplants (p=0.0007), use of myeloablative conditioning (p=0.039) and the presence of cGvHD after the first SCT (p=0.0001). Good prognostic factor for low NRM was interval of more than 12 months between transplants (p=0.0002). AML: With a median follow up from 2nd SCT of 50 months, OS at 1 and 5 years were 44% and 15% respectively. LFS was 28% and 15% respectively. NRM at 2 years was 18%. In multivariate analyses, favorable prognostic factors for OS as well as LFS were: CR prior to 2nd SCT (p=0.031;0.044 respectively), interval > 6 months between transplants (p=0.0003;0.0001 respectively), and having cGvHD after the first SCT (p=0.0001). Most patients experience disease relapse or NRM within the first year after their second transplant. This observation seems to be more consistent in patients transplanted for ALL, with more changes over time in patients with AML. For ALL in particular, the 2-year incidences of relapse, NRM and LFS were not different from those at 5-years. Even in the relapse setting, survival rates for patients with ALL remain superior to patients with AML, consistent with the prognostic differences at diagnosis. Our findings, consistent for the AML and ALL subgroups, suggest that cGHVD prior to second HSCT is associated with better outcome. The identification of cGHVD prior to second transplant has not been heretofore described as a favorable prognostic factor. This strong correlation merits further study, specifically as to the underlying biology for this association. Conclusion Children with relapsed acute leukemias have a substantial chance to become long term survivors following a second SCT. CR prior to second SCT, longer interval between transplants and the presence of cGvHD after the first transplant, are favorable prognostic factors for ALL and AML. Our findings may help physicians in discussing the risk-benefit of a second transplant. These results are particularly relevant in an era where an explosion of new therapies, specifically targeted therapies and those that modulate the immune response, behoove us to carefully identify subpopulations of patients for whom specific therapies are appropriate. Novel approaches are needed to minimize relapse risk as well as short and long term morbidity in these pediatric patients while considering a second SCT for relapsed acute leukemia. Disclosures Corbacioglu: Jazz Pharmaceuticals: Consultancy, Honoraria. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding.

Pregnancy after Allogeneic Hematopoietic Stem Cell Transplantation in Fanconi Anemia Patients: Multi-Institution Cases Report of Female Fertility Recovery

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 456-456
Author(s):  
Samir Kanaan Nabhan ◽  
Marco Bittencourt ◽  
Michel Duval ◽  
Manuel Abecasis ◽  
Carlo Dufour ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Fanconi Anemia ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Fertility Recovery

Abstract Introduction. Fanconi anemia (FA) is a rare autosomal recessive syndrome characterized by chromosome instability. Main clinical features include progressive bone marrow failure, skeletal defects, increased susceptibility to malignancy and reduced fertility. Moreover, most recipients of allogeneic hematopoietic stem cell transplantation (HSCT) suffer from secondary infertility owing to gonadal damage from myeloablative conditioning. We report a rare clinical situation of FA patients pregnancy after allogeneic HSCT. Methods. Retrospective analysis of transplanted FA female patients from 1982 to 2008. Five centers participated in this study on behalf of Aplastic Anaemia Working Party-EBMT. Medical records were reviewed and data collected on a standard case report form including detailed information on diagnosis, transplant procedure, gynecological and obstetrics follow-up. Results. Among 387 transplanted FA patients we identified 202 females who performed a HSCT with a median age of 10,5 years. Five patients became pregnant after the procedure and one of them, twice. They all had their FA diagnosis confirmed by chromosomal breakage test and a bone marrow aspirate with severe hypoplasia/aplasia. Median age at transplantation was 12 years (range 5–17 years). All patients received myeloablative conditioning regimens (cyclophosphamide with or without thoraco-abdominal irradiation) before a bone marrow transplantation, 4 patients from HLA matched sibling donors and 1 from unrelated donor. During follow-up, 4 patients presented signs of ovarian failure (amenorrhea, low levels of FSH/LH and high levels of estradiol). Apart from 1 patient who spontaneously recovered regular menses, the other three received hormonal replacement therapy (HRT) for this purpose. Pregnancy occurred from 3,5 to 17 years after transplant. One patient had an early interruption with a caesarian section at 27 weeks because of an imminent HELLP syndrome. Other pregnancies were uneventful. Among the newborns, there were no FA positive tests, no congenital anomalies and all of them had normal growth and development. Patients remain alive with a median follow-up of 12 years after transplantation with normal hematological status. Conclusion. Fertility recovery after HSCT can result from incomplete depletion of the ovarian follicle reserve. HRT should begin promptly to prevent the early and late unwanted effects related to oestrogen deficiency after HSCT. Recovery of normal ovarian function and a viable pregnancy, is a realistic possibility even in Fanconi anemia patients following allogeneic SCT.

The Clinical Significance of Matching for Alleles at the Low Expression HLA Loci DP, DQ and DRB3/4/5 in Unrelated Hematopoietic Stem Cell Transplantation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 561-561 ◽  
Author(s):  
Marcelo Fernandez-Vina ◽  
John Klein ◽  
Michael D Haagenson ◽  
Stephen R Spellman ◽  
Stephanie J. Lee ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Hla Class I ◽  
Cell Types ◽  
Hematopoietic Stem ◽  
Minimal Impact ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Conditioning Regimens ◽  
The Difference

Abstract Single or multiple mismatches at HLA-A, B, C, and DRB1 have a detrimental effect on outcome of bone marrow transplantation using unrelated donors. Most of these loci encode for products that are expressed with high density on the surface of many cell types. In contrast, HLA-DRB3, DRB4, DRB5, DQ, DP encode for class II products that are expressed at low levels (LEL); some investigations suggest that mismatches in some of these loci have a minimal impact on outcome. We hypothesized that the influence of the LEL is weak and cumulative and only demonstrable in combination with mismatches (MM) in other loci. National Marrow Donor Program data from 3853 US transplants performed from 1988–2003 were analyzed to investigate this hypothesis. Patients had AML, ALL, CML or MDS and received myeloablative conditioning regimens. Most patients received calcineurin-based GvHD prophylaxis with T-replete grafts (79%). Nearly all received marrow grafts (94%). Median follow-up was 6 years. HLA loci were typed retrospectively by high resolution methods. MM was defined as the difference in the antigen recognition site of the HLA molecule of the patient and donor and computed in GvH and HvG vector, the highest vector mismatch was assigned as overall mismatch for a locus. Because multiple comparisons were made, only p-values <0.01 were considered significant. All analyses were adjusted for patient and transplant characteristics. Transplants were stratified according to match grade in the high expression loci (HEL) as 8/8, 7/8 and <7/8; the MM in LEL were computed as 0, 1, 2 and 3 or more MM. A greater degree of mismatch in the HEL was associated with a greater degree of MM in the LEL (p<0.0001); 3 or more MM in the LEL were found in 6, 11 and 21 percent of the patients receiving transplants matched in 8/8, 7/8 and <7/8 HEL groups, respectively. In the 7/8 group, multiple mismatches in the LEL loci were significantly more common in the patients presenting a mismatch in HLA-DRB1 than in the HLA class I loci (p <0.0001); 3 or more MM in the LEL loci were found in 33 percent of the patients presenting one mismatch in HLA-DRB1 while only 8 percent of the patients with one mismatch in either HLA-A, B or C loci presented 3 or more MM in the LEL loci. RESULTS: In the 8/8 HEL group, mismatches in LEL did not significantly associate with mortality. In the 7/8 HEL group, patients with 3 or more MM in LEL in the GvH vector had a significantly higher risk for mortality and treatment related mortality than the subgroups with 0MM (RR=1.44; 95% Confidence Interval (CI):1.07–1.94; p=0.015; and RR=1.63; CI:1.17–2.28; p=0.004) and 1MM (RR=1.46; CI:1.12–1.90; p=0.005; and RR=1.50; CI:1.12–2.01; p=0.006) in LEL, and a similar but not significant trend was observed when compared to the 2MM subgroup. No single LEL appeared to have a more pronounced effect on clinical outcome, when mismatched, versus the other LEL. CONCLUSION: The presence of 3 or more mismatches at LEL may adversely affect clinical outcome after 7/8 matched transplantation. Mismatches at HLA-DRB1 were associated with the occurrence of additional LEL mismatches. Prospective evaluation of matching for HLA-DRB3, 4, 5, DQ and DP loci may be warranted to reduce post-transplant risks in donor recipient pairs matched for 7/8 HEL.

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