scholarly journals Consolidation of first-line therapy with busulphan and melphalan, and autologous stem cell rescue in children with Ewing’s sarcoma

2012 ◽  
Vol 47 (12) ◽  
pp. 1530-1534 ◽  
Author(s):  
K Drabko ◽  
A Raciborska ◽  
K Bilska ◽  
J Styczynski ◽  
M Ussowicz ◽  
...  
1997 ◽  
Vol 20 (10) ◽  
pp. 843-846 ◽  
Author(s):  
A Atra ◽  
JS Whelan ◽  
V Calvagna ◽  
AG Shankar ◽  
S Ashley ◽  
...  

2019 ◽  
Vol 70 (7) ◽  
pp. 1429-1437 ◽  
Author(s):  
Xiang-Yu Zhao ◽  
Xu-Ying Pei ◽  
Ying-Jun Chang ◽  
Xing-Xing Yu ◽  
Lan-Ping Xu ◽  
...  

Abstract Background Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the first-line therapy but are limited by side effects and acquired resistance. Methods We evaluated the safety and efficacy of donor-derived HCMV-specific cytotoxic T cells (CTLs) as a first-line therapy for HCMV infection after allo-SCT and investigated the underlying mechanisms. Results In humanized HCMV-infected mice, first-line therapy with CTLs effectively combated systemic HCMV infection by promoting the restoration of graft-derived endogenous HCMV-specific immunity in vivo. In a clinical trial, compared with the pair-matched, high-risk control cohort, first-line therapy with CTLs significantly reduced the rate of persistent (2.9% vs 20.0%, P = .018) and late (5.7% vs 20.0%, P = .01) HCMV infection and cumulative incidence of persistent HCMV infection (hazard ratio [HR], 0.13; 95% confidence interval [CI], 0.10–0.82; P = .02), lowered 1-year treatment-related mortality (HR, 0.15. 95% CI, 0.11–0.90. P = .03), and improved 1-year overall survival (HR, 6.35; 95% CI, 1.05–9.00; P = .04). Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance. Conclusions We provide robust support for the benefits of CTLs combined with antiviral drugs as a first-line therapy for treating HCMV infection and suggest that adoptively infused CTLs may stimulate the recovery of endogenous HCMV-specific immunity. Clinical trials registration NCT02985775.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 727-727
Author(s):  
Xiangyu Zhao ◽  
Xuying Pei ◽  
Xiaojun Huang ◽  
Ying-Jun Chang ◽  
Lanping Xu ◽  
...  

Abstract Background: Human cytomegalovirus (HCMV) infection, especially persistent HCMV infection, is an important cause of morbidity and mortality after allogenic stem cell transplantation (allo-SCT). Antiviral agents remain the mainstay of treatment and are recommend as the first-line therapy for HCMV. However, drugs are associated with significant toxicity, and their efficacy is limited in the absence of cell-mediated immunity. In recent years, adoptive immunotherapy with HCMV-specific T cells (CTLs) has been developed as an alternative option for HCMV, and data from previous studies have indicated that infusion of CTLs at early-stage of HCMV infection may have better benefits compared to salavage therapy. However, because CTLs remains time consuming and cost-intensive, so far there have no reports of first-line therapy with CTLs for HCMV infection, and the mechanisms driving the sustained antiviral immunity induced by adoptive T cells transfer remain undetermined. Our previous study had demonstrated that patients with acute graft-versus-host disease (aGVHD) were at high risk to develop persistent HCMV infection. Therefore, in the current study, we selected patients who developed aGVHD before HCMV reactivated and started CTLs generation in advance. This risk-stratified measure successfully selected patients who had high risk resisting to conventional anti-HCMV therapy , and spared low risk patients as well, making it feasible and financially viable to use CTLs as a first-line therapy. Aims: To provide robust support for the safety and efficacy of CTLs given as a first-line therapy for HCMV infection after allo-SCT, and gain some insight into the underlying mechanisms. Methods: Firstly, using humanized HCMV infected mice model, we explored where the adoptive transferred CTLs cells trafficked, evaluated the antiviral efficacy of CTLs and investigated the recovery of HCMV-specific immunity after T cell transfer. Secondly, we conducted a prospective clinical trial enrolled 35 allo-SCT patients who diagnosed with acute GVHD and had high risk developing persistent HCMV infection, intervened with antiviral agents combined with CTLs as first-line therapy and evaluated the long-term safety and durability of antiviral responses. As controls, we selected a cohort of 70 high-risk patients as well as another cohort of 70 low-risk patients who only received antiviral agents as first-line therapy without CTLs. We also evaluated the immune response after infusion and analyzed the association between immune recovery and HCMV clearance. Results: i) In humanized HCMV infection mice, adoptive infused CTLs had the ability to homing to organs, and effectively combated systemic HCMV infection by promoting the restoring of stem cell derived endogenous HCMV-specific immunity. ii) In clinical trial, first-line therapy with CTLs significantly reduced the rate (2.86% vs. 20.00%, P=0.018) and the cumulative incidence (HR=7.60, 95%CI=1.22-10.15, P=0.020) of persistent HCMV infection, and showed a lower one-year treatment related mortality (TRM) (HR=6.83, 95%CI=1.16-8.90, P=0.030) and a better one-year overall survival (OS) (HR=6.35, 95%CI=1.05-9.00, P=0.040) compared to high-risk control cohort. The cumulative incidence of persistent HCMV infection, one-year TRM and OS in CTL cohort were comparable to those in low-risk control cohort. Moreover, first-line therapy with CTLs promoted the quantitative and functional recovery of CTLs in patients, which was associated with HCMV clearance. Conclusion: In this study, we firstly demonstrated the safety and efficacy of CTLs administration as a first-line therapy for HCMV infection in humanized HCMV infection mice, and in a large clinical cohort study. The data provided robust support for the benefits of donor derived CTLs in treating HCMV infection as a first-line therapy, and suggested that infused CTLs might probably stimulate the recovery of donor derived HCMV-specific immunity. This trial was registered at www.clinicaltrials.gov as #NCT02985775. Figure. Figure. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5207-5207
Author(s):  
Sadao Aoki ◽  
Jun Takizawa ◽  
Masutaka Higashimura ◽  
Akihito Momoi ◽  
Nobuhiro Tsukada ◽  
...  

Abstract Introduction: Most patients with advanced-stage follicular lymphoma(FL) cannot be cured by conventional chemotherapy and have median survival of 7 to 10 years. High-dose chemotherapy (HDT) supported by autologous stem cell transplantation(ASCT) gives a survival benefit for patients with aggressive lymphoma. Recent several multicenter studies have shown that clinical and molecular remissions can be attained in patients with FL receiving intensified high-dose sequential chemotherapy and autografting. We have reported the efficacy and safety of high-dose bi-weekly THP-COP with G-CSF support (HDBW-TCOPG) for non-Hodgkin’s lymphoma. Therefore, we performed a pilot clinical trial to evaluate the efficacy and toxicity of HDBW-TCOPG followed by HDT with ASCT as first-line therapy in patients with advanced-stage FL. Patients and methods: Between August 1998 and December 2003, 10 Japanese patients with previously untreated FL from whom informed consent was obtained were included in this single-center pilot study. Median age was 48 years. All patients had stage 3 or 4 disease, aaIPI LI 8 and HI 2. Histological subtypes of FL included grade 1 4; grade 2 4; grade 3a 2. HDBW-TCOPG consisted of pirarubicin 70 mg/m2 on day 1; cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; predonisolone 50 mg/m2 from day 1 to 5; lenograstim 2.0 mg/kg/day from day 3. Five patients who enrolled after rituximab was approved for indolent B-cell lymphoma in Japan received induction therapy combined HDBW-TCOPG with rituximab 375mg/m2 on day -2 (R-HDBW-TCOPG). Six cycles were administered at intervals of two weeks. PBSC were collected during the later cycles of HDBW-TCOPG or on the recovery of high-dose etoposide regimen (500mg/m2 for 3 days) administered after the completion of HDBW-TCOPG. Leukaphereses were performed until a minimum of 2.0x106/kg CD34+ cells had been collected. The conditioning regimen consisted of ranimustine 200mg/m2 on day-7 and -2; paraplatin 300mg/m2 on day -6, -5, -4, -3; etoposide 500mg/m2 on day −5, −4, −3; cytarabine 2.5 g/m2 every 12 hours on day −2, −1 (MCE-CA regimen) in 2 patients or cyclophosphamide 50mg/kg on day −2, −1 (MCEC regimen) in 8 patients. Results: Sufficient numbers of PBSC were collected in 5 of 7 patients mobilized with HDBW-TCOPG and in all 5 patients with high-dose etoposide. The median time to reach total number of leukocytes of 1.0 x109/l was nine days (range 8–11). All 10 patients who were in PR at the end of HDBW-TCOP(G) achieved CR post APBSCT. After a median follow up of 36.6 months (range 7–66 months) PFS and OS are 90% and 90%, respectively, for all patients. One patient developed secondary myeloid leukemia with t(3;21) and died at 35 months after APBSCT without signs of recurrence of lymphoma. Another patient who relapsed at 35 months after transplantation. IgH or BCL2 rearrangement was detected by PCR analysis prior to therapy in three patients and one of them still showed detectable disease after HDBW-TCOPG induction. However, all three patients demonstrated MRD negativity after HDT with ASCT. Conclusion: HDBW-TCOPG as induction therapy followed by HDT with ASCT is feasible for advanced-stage FL with acceptable toxicity, and this short term highly intensified therapy may induce cure of the disease by minimizing MRD, but longer follow up is needed to evaluate the impact on survival.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1097-1097
Author(s):  
Nicholas Heaney ◽  
Mhairi Copland ◽  
Karen Stewart ◽  
Judith Godden ◽  
Anne Parker ◽  
...  

Abstract Recommended first-line therapy for patients with chronic phase (CP) CML is imatinib mesylate (IM). Although IM induces complete cytogenetic responses (CCR) in the majority of patients, disease often remains detectable by Q-RT-PCR, likely reflecting stem cell persistence. Furthermore, primary and acquired resistance to IM have led to concerns about response durability. Allogeneic stem cell transplantation (SCT) remains the only curative option and with reduced intensity conditioning (RISCT) is less toxic and may be offered to a broader patient group. Our novel approach used IM to establish disease control (CCR) in patients with newly diagnosed CP CML prior to RISCT (fludarabine/melphalan/MabCampath). Prophylactic escalating DLI was given for residual disease. 18 patients (4 centres) were recruited between 2001 and 2006. Of these, 3 received myeloablative SCT, 2 for progression to blast crisis prior to SCT and the third for failing to reach a major cytogenetic response. 15 patients with a median age of 39y (21–56y) received sibling RISCT. Hasford scores were 38% low, 54% intermediate and 8% high risk. EBMT risk scores were 1–2 (13 patients) and 3–4 (2 patients). 5 patients required IM dose escalation to achieve CCR prior to RISCT. Follow-up data extends to a median of 31 (12–61) months (m) post RISCT. The RISCT procedure was well tolerated with rapid engraftment and short in-patient stays. 53% had infective episodes post RISCT, including CMV reactivation (86% patients at risk), EBV+ post transplant lymphoproliferative disease (2 patients) and PCP (1 patient). 1 patient developed aGvHD (grade III) and 8 cGvHD (6 limited, 2 extensive). DLI was given to 13 patients (87%), 6 for elevated Bcr-Abl, 4 for mixed chimerism and 2 for both. The median total dose was 0.65 × 107CD3+cells/kg (0.1–6.65 × 107cells/kg) in a median of 2 infusions. GvHD was seen in 6 of 12 patients receiving DLI (50%). IM was required in 4 patients with residual disease and all discontinued IM once disease control was re-established (4–13m of IM). 1 of 15 transplanted has died (at 12m with GvHD and infection). Of surviving patients median Bcr-Abl measurements fell as follow-up progressed. 8 patients currently have sustained undetectable Bcr-Abl. 7 of these 8 received DLI, the other had GvHD. The interval between last DLI and first proof of disease eradication was median 2m (range 1–28m). Only 2 of these 8 patients received IM post-transplant. In this study, the patients receiving RISCT were in early CP with a CCR to IM. It is likely that the majority would have maintained CCR if not offered transplantation. However the number of patients who achieved undetectable Bcr-Abl following RISCT and DLI compares favourably with the response expected with IM alone. The patients have tolerated the transplant procedure well and are currently off all treatment for CML. Regular monitoring remains necessary, however if relapse occurs it should be DLI responsive. Currently IM is the accepted first line therapy in the majority of patients however we would highlight the importance of RISCT in selected groups and believe our approach is effective and well tolerated.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3111-3111
Author(s):  
Margot Robles ◽  
Loic Ysebaert ◽  
Stephane Vigouroux ◽  
Anne Huynh ◽  
Marie Parrens ◽  
...  

Abstract Abstract 3111 Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of rare malignancies usually occurring in middle-aged to elderly patients (pts), with an advanced disease and unfavorable international prognostic index (IPI) scores. Excluding ALK-positive anaplastic large cell lymphomas (ALCL) and indolent mycosis fungoides, they are often characterized by a poor prognosis. There is no consensus about optimal therapy and the role of allogeneic stem-cell transplantation (allo-SCT) as first line therapy remains to be investigated. In an effort to explore this therapeutic option in younger pts, we undertook a retrospective analysis in 2 french centers. The records of all pts aged between 18 and 65 years diagnosed with PTCL in Bordeaux and Toulouse between January 2005 and April 2012 were reviewed. Cutaneous T-cell lymphomas and ALK-positive ALCL were excluded. Patients with an IPI score at diagnosis of 0/1 were excluded as well as those who never reached at least a 1st partial response according to the criteria reported by Cheson. Patients relapsing within 3 months after the 1st response and thus ineligible for allo-SCT were also excluded. The primary objective was to compare the outcome of allo-SCT (allo group) as compared to non-allogeneic SCT therapies (no-allo group) in these pts with high-risk PTCL in 1st response. Thirty-three patients were included (16 in the allo group, 17 in the no-allo group). Fifteen pts in the allo group were treated in Bordeaux where allo-SCT was always pursued during the study period in responding pts with an IPI score ≥ 2 at diagnosis. In Bordeaux, the absence of allo-SCT in 1st response was explained by the absence of a suitable donor or the refusal of the patient. The therapeutic strategy in Toulouse was different with 11 pts in the no-allo group, allowing us to undertake this retrospective comparison. In the allo group, conditioning regimes were of reduced intensity (n=12) or myeloablative (n=4). The sources of stem cells were PB (n=13), BM (n=2) or cord blood (n=1). Donors were matched related (n=7), matched unrelated (n=6), mismatched unrelated (n=2). In the whole cohort, the first chemotherapy regimes were CHOP or CHOP-like (n=31), DHAP (n=1), ICE (n=1). In the allo vs no-allo groups, the median ages at diagnosis were 54 years (20–65) vs 59 years (29–64), p = 0.5; the number of pts diagnosed before 2009 were 7 vs 9, p=0.6; the lymphoma subtypes were PTCL-NOS (4 vs 9, p=0.1), angioimmunoblastic (8 vs 6, p=0.4), others (4 vs 2, p=0.3); the IPI scores at diagnosis were 2 (5 vs 5, p=0.9), 3 (6 vs 3, p=0.2), 4/5 (5 vs 9, p=0.2); the number of pts in CR1 and PR1 were 13 vs 13, p = 0,7 and 3 vs 4, p=0.7; the number of chemotherapy lines to reach the 1st response were 1 (8 vs 15, p=0.02), 2 (4 vs 2, p=0.3) or 3 (4 vs 0, p=0.03). Five patients in the no-allo group were treated with an autologous SCT in 1st response. Three patients in the allo group were treated with autologous SCT to reach the 1st response. With a median follow-up of 34 months (8–74) after the 1st response, in the allo vs no-allo groups, the 2-year OS (figure 1) were 87% ± 8% vs 49% ± 13%, respectively (p= 0.06); the 2-year EFS (figure 2) were 81% ± 10% vs 33% ± 12%, respectively (p = 0.007). In the allo and no-allo groups, 3 and 12 pts respectively, have relapsed. In the allo and no-allo groups, 2 and 8 pts respectively, have died, all from disease progression. The modest size of our study and the potential biases inherent to such a restrospective design preclude the declaration of any firm conclusion. However, these preliminary data suggest that patients under 65 years of age with high-risk PTCL (IPI ≥2) might benefit from allo-SCT in 1st response, in comparison with non-allogeneic SCT therapies. Randomized studies are warranted to further delineate the optimal first line therapy in these patients. Our center is currently participating to such an ongoing european study comparing allo-SCT vs auto-SCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures: No relevant conflicts of interest to declare.


2012 ◽  
Vol 4 (1) ◽  
pp. e2012075 ◽  
Author(s):  
Giuseppe Visani ◽  
Paola Picardi ◽  
Patrizia Tosi ◽  
Alessandro Isidori

The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment armamentarium of aggressive B- and T-cell non-Hodgkin lymphoma (NHL) is still a matter of debate. In the pre-Rituximab era, the PARMA study demonstrated the superiority of HDT/ASCT over conventional salvage chemotherapy in chemosensitive, relapsed patients. Subsequently, HDT/ASCT has become a standard approach for relapsed NHL. With the advent of Rituximab in the landscape of NHL, transplantation as part of first-line therapy has been challenged. However, no benefit in terms of disease-free or overall survival of HDT/ASCT over standard therapy was shown when Rituximab was added to both arms. Moreover, the superiority of HDT/ASCT over conventional salvage therapy in patients relapsing from first-line therapy including Rituximab was not confirmed. From these disappointing results, novel strategies, which can enhance the anti-lymphoma effect, at the same time reducing toxicity have been developed, with the aim of improving the outcome of HDT/ASCT in aggressive NHL.In T-cell lymphoma, few publications demonstrated that consolidation of complete remission with HDT/ASCT is safe and feasible. However, up to one-third of patients may never receive transplant, mostly due to progressive disease, and relapse still remains a major concern even after transplant.


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