Allogeneic Stem Cell Transplantation (SCT) with Non Myeloablative Conditioning Regimen (NST) Following Intensive Consolidation May Be Equivalent to Conventional alloSCT and Superior to autoSCT for Patients over 50 with Acute Myeloid Leukemia (AML) in 1stCR: First Results of the AML 2001 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 319-319 ◽  
Author(s):  
B. Lioure ◽  
J. Delaunay ◽  
D. Blaise ◽  
N. Milpied ◽  
P. Guardiola ◽  
...  
Keyword(s):  
Conditioning Regimen ◽  
Phase Iii ◽  
Late Relapse ◽  
Marrow Graft ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Significant Difference ◽  
First Results ◽  
Alternative Sources

Abstract From 11/01 until 04/05, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were included in prospective phase III AML 2001 trial. After achieving CR, research to identify an HLA-identical sibling was performed for all patients as they received low dose consolidation (Daunorubicin (D): 60 mg/m2 × 2d OR Idarubicin (I): 12 mg/m2 × 2d plus SC ARAC 100 mg/m2 ×7d). 33 % patients had a donor then could proceed to a T-replete alloSCT: either conventional if age ≤ 50 (bone marrow graft; conditioning regimen: TBI (12 Gy 6 fractions over 3d) - cyclophosphamide (60 mg/kg × 2d); GvHD prophylaxis: ciclosporin-methotrexate d1+3+6) = arm M; or NST if age 51–60 (peripheral blood; Busulfan (oral Bu 4–8 mg/kg over 2d) - Fludarabin (30 mg/m2 × 4d) – Thymoglobulin® (2,5 mg/kg × 2d); ciclosporin alone), AFTER intensive consolidation (D: 60 mg/m2 × 2d OR I: 12 mg/m2 × 2d plus ARAC 3 g/m2 × 8 doses over 4d) = arm m. A small group of patients with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction = 3% CR1 patients) didn’t receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered at relapse = arm C. Patients without donor proceed to intensive consolidation then 1 or 2 autoSCT (1st after HDM 200 mg/m2 according to randomization, then Bu 16 mg/kg over 4d + HDM 140 mg/m2 for all patients) = arms A + B; they were combined for analysis as no difference was observed for DFS and OS. Actual results concern 532 patients with 15 months follow-up (A + B = 367; M = 111; m = 54). Median age was different between 3 groups (A + B = 46; M = 40; m = 54) as no difference was observed regarding leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: A + B = 15%; M = 11%; m = 11%), intermediate (A + B = 72%; M = 78%; m = 67%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; A + B = 13%; M = 11%; m = 22%). Conventional alloSCT results in better 2y DFS than autoSCT arms (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06) as toxic death rate is higher (36% all deaths in arm M vs 14 % in arms A + B). No significant difference was observed between conventional alloSCT and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50: 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). After NST, toxicity accounts for 25% deaths, as relapse rate is 40% at 2y with no late relapse thereafter (vs 48 % at 2y and 61 % at 4y in arms A + B). In conclusion: 1) conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1 despite higher toxicity; 2) NST after intensive consolidation seems promising: for older patients as toxicity is lower than conventional alloSCT, as few late relapse are observed in comparison with chemotherapy or autoSCT approaches; 3) NST may extend use of alternative sources of allogeneic hematopoietic stem cells to propose alloSCT approach for the majority of patients ≤ 60 with AML in CR1. Data with more than 2 years follow-up will be presented.

No Benefit of Adding High-Dose Melphalan (HDM) Suppported by Autologous Stem Cell Transplantation (SCT) over Treatment with Conventional Induction, HD ARAC Consolidation, and Auto SCT (Busulfan + HDM) for Acute Myelogenous Leukemia (AML) under 60: First Results of the Randomized AML 2001 Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 608-608 ◽  
Author(s):  
B. Lioure ◽  
A. Pigneux ◽  
C. Recher ◽  
F. Witz ◽  
T. Lamy ◽  
...  
Keyword(s):  
Early Death ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Marrow Graft ◽  
Prognostic Features ◽  
Frequent Use ◽  
Significant Difference ◽  
First Results ◽  
High Dose Melphalan

Abstract From 11/2001 until 04/2005, 832 patients (median age 46, 18–60) with AML (previous diagnosis of myelodysplasia or myeloproliferative disorder, and M3 excluded) were 1st randomized to received induction with continuous IV ARAC (200 mg/m2, x 7d) and Daunorubicin (D: 60 mg/m2 x 3d) OR Idarubicin (I: 8 mg/m2 x 5d). If marrow blasts > 5% on D15, 2nd induction course was applied (D: 35 mg/m2 x 2d OR I: 8 mg/m2 x 2d plus ARAC 1 g/m2 x 4 doses over 2d). After achieving CR, all patients received low dose consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus SC ARAC 100 mg/m2 x 7d). Patients with HLA-identical sibling receive a T-replete alloSCT: either conventional (bone marrow graft, TBI-cyclophosphamide, ciclosporin-methotrexate) if age ≤ 50 = arm M; or non myeloablative (NST: peripheral blood, Busulfan (Bu)-Fludarabin-Thymoglobulin®, ciclosporin alone), AFTER intensive consolidation (idem below) if age 51–60 = arm m. A small subgroup of patients (3 % patients in CR) with a donor but low-risk prognostic features (favorable cytogenetics, no hyperleucocytosis, CR after 1 induction) did not receive 1st line alloSCT but intensive consolidation then a 2nd HD ARAC course; alloSCT was therefore considered for relapse = arm C. Other patients proceed to 2nd randomization: intensive consolidation (D: 60 mg/m2 x 2d OR I: 12 mg/m2 x 2d plus ARAC 3 g/m2 x 8 doses over 4d) PLUS 1 autoSCT (Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm A; or intensive consolidation PLUS 2 autoSCT (HDM 200 mg/m2 THEN Bu 16 mg/kg over 4d + HDM 140 mg/m2) = arm B. After 1st randomization (D vs I), no difference was observed between 2 arms regarding age, leukocytosis or cytogenetic subgroups: favorable (t8;21) or inv16: D = I 13%), intermediate (D 66%, I 59%), defavorable (5, 7, complex, 11q23 except t(9;11) or 3q; D 21%, I 28%). Use of both anthracyclins results in same CR rate (D 83% vs I 85%); early death (3%); projected EFS (D 46% vs I 50%, p = 0,28) and OS (D 61% vs I 64%) at 2 years. Noteworthy was the more frequent use of 2nd induction course to obtain CR with D (30%) as compared with I (22%). 78% of all patients in CR proceeded to 2nd randomization or were assigned to alloSCT arms (33 % of them). Actual results concern 550 patients with 15 months follow-up. No benefit was observed with addition of HDM 200 for 2y projected DFS (A 53% vs B 49%) or OS (A = B 68%). Toxic death rate was higher in arm B, accounting for 18% total deaths vs 6% in arm A. Conventional alloSCT results in better 2y DFS than combined arms A+B (M 71% vs A+B 52%, p=0,007) thought 2y OS advantage remains non significant (M 77% vs A+B 68%, p=0,06). No significant difference was observed between conventional and NST (2y DFS 62%, OS 68%). Advantage for NST over autoSCT arms was non significant for DFS (p=0,24) and OS. Same results are obtained if considering only patients aged > 50 : 2y EFS (m 62% vs A+B 50%, p=0,27) and OS (m 68% vs A+B 65%). In conclusion: conventional alloSCT remains the best consolidation treatment for patients ≤ 50 with AML in CR1; NST after intensive consolidation seems promising for older patients and may extend use of alternative sources of alloSCT; HDM course adds no benefit for these patients. Data with more than 2 years follow-up will be presented.

A Experimental Study and Clinical Result of Prophylaxis aGVHD with Humanized Anti-CD25 Monoclonal Antibody in Haploidentical BMT.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1251-1251
Author(s):  
Shu-Quan Ji ◽  
Hui-Ren Chen ◽  
Heng-Xiang Wang ◽  
Hong-Min Yan ◽  
Mei Xue ◽  
...  
Keyword(s):  
Median Time ◽  
Conditioning Regimen ◽  
Control Group ◽  
High Dose ◽  
Marrow Graft ◽  
Hla Antigen ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Significant Difference

Abstract Between February 1999 and March 2004, eighty-seven patients with high risk leukemia, age 3–50 (median 19 year), who needed urgent transplant but no HLA-matched or single HLA-antigen mismatched donors available, received unmanipulated HLA haploidentical BMT. The 87 patients were classified as follows AML 27 (CR1 in 7, CR2 in 15 and 5 in relapse), All 38 (CR1 in 4, CR2 in 30 and 4 in relapse) , CML 22 ( 4 in CP, 12 in AP and 6 in BP). All donors were HLA-haploidentical relatives who had at least two major histocompatibility complex antigen mismatched with the recipients. 87 patients underwent haplo-BMT with G-CSF primed BM as stem cells. All patients received a same conditioning regimen including high dose Ara-C, Cyclophosphamide, antithymocyte globulin and total body irradiation to provide both immunosuppression and myeloablation. GVHD prophylaxis consisted of anti-thymocyte globulin, cyclosporin A, methotrexate and mycofenolate mofitel. 72 patients underwent the transplants with the addition of CD25 mAb (Basiliximab Novartis) for GVHD prophylaxis designated as CD25 mAb group. Basiliximab 20mg each by 30min intravenous infusion on 2 hours before transplantion and day 4 after transplantaion. The other 15 patients without Basiliximab for GVHD prophylaxis were as the control group. The two group of patients were comparable in disease status, HLA-disparity and median age of patients. Immunophenotyping, limited dilution assay and colony forming assays were used to measure the effect of Basiliximab on the subsets of lymphocytes, cytotoxic T lymphocyte precursors (CTLp) and hematopoietic cells. All donors were primed with G-CSF at 3-5ug/kg/d for 7 days and the marrow cells were harvested on the eighth day. G-CSF donor priming significantly increased CD34+ and colony forming progenitors in the marrow grafts. More importantly, it significantly reduced lymphocytes and reversed CD4+/CD8+ lymphocyte ratio in the grafts. Both of group who were treated with and without Basiliximab had similar marrow graft contents. All patients established trilineage engraftments.The median time to achieve an absolute neutrophil count 0.5x109/L was 19 days (range, 13 to 24 days). The median time to achieve platelets above 20x109/L was 22 days (range, 16 to 32 days). Between the two groups were no differences in engraftment. Incidence of grades II–IV acute GVHD were 13.9% with GVHD-related deaths 6.9% in Basiliximab group and 33.3% with 20% GVHD-related deaths in control group. There were a significant difference between the anti-CD25 mAb treated Vs non-treated group.Forty-nine patients who survived over 12 months were eligible for the evaluation of cGVHD. 12 patients developed extensive cGVHD, one in control group and eleven in Basiliximab group. 49 were alive in CR during a median follow-up of 30 months (range3–64 months), 42 in Basiliximab group and 7 in control group. Basiliximab significantly decreased alloreactive CTLp by 10–100 fold in limiting dilution assays. It had no effect on hematopoietic stem and progenitor cells as determined by in vitro colony-forming assays.The addition of basiliximab as aGVHD prophylaxis effectively reduced severe lethal aGVHD in haplo-BMT. It is possible to selectively eliminate or reduce the number of alloreactive T cells with anti CD25 antibody, which results in prevention of or a reduction in the severity of GVHD.

Long-Term Follow-Up of a Randomized Phase III Multicenter Study Comparing a Standard Versus an Intensified Conditioning Regimen for High-Dose Chemotherapy in Patients with Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 945-945
Author(s):  
Roland Fenk ◽  
Peter Schneider ◽  
Martin Kropff ◽  
Ali-Nuri Huenerlituerkoglu ◽  
Ulrich Steidl ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
High Dose Chemotherapy ◽  
Phase Iii ◽  
Study Endpoint ◽  
Primary Study ◽  
High Dose ◽  
Significant Difference

Abstract High-dose chemotherapy (HDT) improves the outcome of patients with multiple myeloma (MM) in comparison to conventional chemotherapy. Dose-escalating strategies including tandem HDT are currently evaluated to further improve remission rates and survival of patients. Therefore we conducted a randomized multicenter trial to compare an intensified conditioning regimen with the current standard high-dose melphalan. The primary study endpoint was response rate, with overall survival (OS), event-free survival (EFS) and toxicity analysed as secondary endpoints. Between 1997 and 1999 a total of 56 patients with stage II and III disease, who were matched for age (median 56 years), number of previous therapies (median time from diagnosis to transplant 7 months) and different risk factors (beta2-microglobulin, LDH, CRP, cytogentic abnormalities, chemoresistant disease, IgA-subtype, renal impairment), were randomized. All patients received 2 courses of oral idarubicine/dexamethasone and 2 courses of intravenous cyclophosphamide/adriamycine in combination with G-CSF followed by peripheral stem cell collection. Thirty patients were treated with melphalan 200mg/m2 (HD-M) whereas 26 patients received idarubicine 42mg/m2, melphalan 200mg/m2 and cyclophosphamide 120mg/kg (HD-IMC) followed by autologous blood stem cell transplantation. Acute toxicity was higher with HD-IMC, including 5 (20%) treatment-related deaths due to infections versus none (0%) in the HD-M group. This lead to early termination of the study. Severity of mucositis (grade III-IV 19 vs. 8 pts., p=0.001), CRP (20 vs. 7 mg/dl, p<0.001), days of fever (11 vs. 3, p<0.001), days with iv-antibiotics (13 vs. 4, p<0.001), number of erythrocyte-transfusions (6 vs. 2, p<0.001), number of platelet-transfusions (16 vs. 4, p<0.001) and days to granulocyte engraftment (18 vs. 11, p=0.007) were significantly higher after HD-IMC. After a follow-up of 5 years analysis restricted to patients surviving the first 30 days after HDT showed a trend to higher response rates (CR+vgPR: 47% (95%CI 24–72%) vs. 35% (95%CI 18–56%), PR 37% (95%CI 17–63%) vs. 48% (95%CI 29–68%) and time-to-progression (median 31 vs. 15 months, p=0.1) in the HD-IMC treatment arm in comparison to HD-M, but there was no significant difference in EFS and OS (median 22 vs. 30, p= 0.31 and 66 vs. 66 months, p=0.8, respectively). Univariate analysis demonstrated that LDH levels > 200 U/L (p=0.04) and chemoresistant disease (p=0.05) were a bad prognostic factor for EFS. Beta2-Microglobulin levels > 5mg/dl (p=0.01), abnormal conventional cytogenetics (p=0.02) and LDH levels > 200 U/L (p=0.03) were predictive for an inferior OS. In conclusion intensified conditioning for HDT had an intolerable high treatment-related mortality and did not improve EFS and OS in patients with multiple myeloma.

scholarly journals Comparison of Fixed Vs ALC-Based Doses of Thymoglobulin® (ATG) in Pediatric Patients with Acute Leukemia Given αβhaplo-HSCT: Impact on Immune Reconstitution at Day 90

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 16-16
Author(s):  
Giulia Barbarito ◽  
David C Shyr ◽  
Gopin Saini ◽  
Linda Oppizzi ◽  
Y. Lucy Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Pediatric Patients ◽  
Conditioning Regimen ◽  
Optimal Dose ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Αβ T Cells

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for pediatric patients with high risk or refractory leukemia. In the absence of related or unrelated HLA-matched donors, alternative approaches such as HLA-haploidentical HSCT have been implemented. Our group has developed one such approach, αβ T-cell/CD19 B-cell depletion (αβhaplo-HSCT), and demonstrated its clinical efficacy (Bertaina A, Blood 2018). In αβhaplo-HSCT, anti-thymocyte globulin (ATG) is used for preventing graft rejection and graft-versus-host disease (GvHD). However, the optimal dose still needs to be elucidated. Here, we present the first analysis comparing 2 different Thymoglobulin® ATG doses: one fixed at 3.75 mg/Kg, as established in previous European studies with the closely related ATG Grafalon®, and one based on a newly developed algorithm that also integrates absolute lymphocyte count (ALC). METHODS: Between March 2017 and April 2020, 27 pediatric patients (median age 12 years) with hematological malignancies were transplanted at Stanford University's Lucile Packard Children's Hospital. Importantly, 60% of these patients were in CR2 or greater and 2/27 had active disease at the time of HSCT. All children received a fully myeloablative conditioning regimen. On days -9/-8/-7 before αβhaplo-HSCT, patients were given a regimen of Thymoglobulin® ATG. No patient received post-HSCT pharmacological GvHD prophylaxis. The fixed dosage was given to 14 patients in cohort 1 (ATG: 3.75 mg/Kg) and the novel ALC-based dosage to 13 in cohort 2 (ATG ranging between 3-6 mg/Kg). All patients enrolled in this study (BMT Protocol 179 and 351 approved from our IRB) had a minimum follow-up of 100 days, evaluated at Day 30 and 90. Following Admiraal R (Lancet Hematology 2015), we defined CD4 immune reconstitution (IR) as more than 50 CD4 T-cells/ul twice within the first 100 days after HSCT. PBMC were enriched by Ficoll-Hypaque (Sigma Aldrich) density gradient centrifugation. Flow analyses were performed on fresh cells resuspended in PBS 2% FBS on Cytek DxP 10 flow-cytometer. At least 5x104 events of total cells were acquired and analyzed using FloJo software. RESULTS: With a median follow-up of 555 and 124 days for cohort 1 and 2 respectively, 12 patients (85.7%) in cohort 1 and 7 patients (54%) in cohort 2 achieved CD4 immune reconstitution. In cohort 2, CD3 αβ T cells were significantly lower at both Day 30 and Day 90 (P=0.0003, Figure 1A). At Day 90, both the CD4 and CD8 subpopulations were significantly depressed (P=0.01 and P=0.056, respectively, Figure 1C). In both subpopulations, the memory compartment was the most reduced (Figure 1D). The absolute numbers of CD3 γδ T cells did not differ between the cohorts at either Day 30 or 90 (Figure 1B). Viral reactivations were higher in cohort 1 (10/14, 71%) than in cohort 2 (6/13, 46%, P=NS). Half of the reactivations were CMV reactivations, but no patient developed organ disease. There was no statistically significant difference in overall survival and the incidence of relapse in the two cohorts. Three patients developed grade III-IV aGvHD: 2 in cohort 1 (14%) and 1 in cohort 2 (8%, P=NS). Remarkably, the only patient, who developed grade IV aGvHD in cohort 2, did not experience symptoms until Adenovirus reactivation 138 days after HSCT. CONCLUSION: Our analysis confirms that the optimal dose of ATG Thymoglobulin® before αβhaplo-HSCT remains elusive. There were no significant clinical differences between the 2 ATG regimens. However, the ALC-based regimen resulted in the more pronounced reduction of donor-derived memory T cells. Our analysis suggests two intriguing explanations for the observed pattern of results. First, the selective depletion of the memory compartment in both CD4 and CD8 T cells may well be due to a priming effect of ATG Thymoglobulin® on the few αβ T cells left over in the graft. Second, the equivalent reconstitution of naive T cells in the 2 cohorts is likely because the ATG has no impact on the thymus-dependent IR. Remarkably, in our overall cohort, 70% of the patients achieved CD4 IR by 90 days after αβhaplo-HSCT. This result is superior to the best results from other ex vivo T-cell depleted approaches 54%, recently reported by Van Roessel (Cytotherapy 2020). In vivo studies of the pharmacokinetics of ATG in αβhaplo-HSCT recipients and a comparison with the use of Grafalon® are required to shed more light on this crucial topic. Disclosures No relevant conflicts of interest to declare.

scholarly journals Symptom Burden of Busulfan and Melphalan Versus Melphalan Alone for Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 681-681
Author(s):  
Loretta A. Williams ◽  
Muzaffar H. Qazilbash ◽  
Qiuling Shi ◽  
Qaiser Bashir ◽  
Huei K. Lin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Muscle Weakness ◽  
Symptom Severity ◽  
Conditioning Regimen ◽  
Symptom Burden ◽  
Phase Iii ◽  
Dry Mouth ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Background: High-dose melphalan 200 mg/m2 (Mel) is the standard for autologous hematopoietic stem cell transplantation (autoHSCT) for multiple myeloma. Retrospective analyses suggested that a combination of busulfan and melphalan (Bu-Mel) may be associated with a longer progression-free survival (PFS). A secondary aim of a randomized, phase III trial that compared the safety and efficacy of Bu-Mel vs Mel was to compare the symptom burden of the two regimens. Symptom burden is the combined impact of disease- and therapy-related symptoms on patient functional ability. Methods: Patients were randomized to Bu-Mel (Bu 130 mg/m2 daily for 4 days, either as a fixed dose or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel 70 mg/m)2or Mel (Mel 100 mg/m2 daily for 2 days). A subset of patients completed the 20 symptom severity and 6 interference items of MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM) prior to the start of the treatment regimen and weekly for 4 weeks post autoHSCT. Symptoms and interference are rated on 0-10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Differences in individual symptom severity and interference between the two arms were assessed by t-tests and mixed modeling. Results: As previously reported, 204 (Bu-Mel: 104, Mel: 100) were enrolled between October 2011 and March 2017. At last evaluation, 52 (51%) and 49 (49%) patients achieved a CR (p=0.88), and 69 (68%) and 67 (67%) patients achieved a CR+nCR (p=0.88) in Bu-Mel and Mel arms, respectively. Median PFS was 64.7 months and 34.4 months (p=0.013) in Bu-Mel and Mel arms, respectively. There was no difference in OS between the two arms. One hundred sixty-five of the patients (Bu-Mel: 81, Mel: 84) completed at least one MDASI-MM assessment. Median ages at autoHSCT were 57.2 and 57.0 years in Bu-Mel and Mel groups, respectively (p=0.86). At baseline, t-tests showed significantly higher mean severity of constipation (1.80, standard deviation [SD] = 2.87 vs 0.98, SD = 1.94; p=0.036), muscle weakness (2.38, SD=2.49 vs 1.44, SD=1.87; p=0.034), diarrhea (1.45, SD=2.43 vs 0.60, SD=1.10; p=0.005), and global symptom interference (2.96, SD=2.81 vs 1.77, SD=2.00; p=0.003) in the Bu-Mel arm than the Mel arm. The Bu-Mel patients had a significantly higher mean severity of pain (5.67, SD=2.65 vs 3.17, SD=3.07; p=0.0043) and mouth sores (7.35, SD=2.41 vs 1.25, SD=2.22; p &lt;0.0001) than the Mel patients 7 days post autoHSCT. Longitudinal analysis using mixed modeling showed that the Bu-Mel arm had a significantly higher mean severity of pain (ED = 1.102, p=0.003), drowsiness (ED = 0.674, p=0.040), dry mouth (ED = 0.904, p=0.009), constipation (ED = 0.695, p=0.006), muscle weakness (ED = 0.815, p=0.006), mouth sores (ED = 1.683, p &lt;0.0001), rash (ED = 0.362, p=0.019), and interference with physical functions (general activity: ED = 1.015, p=0.010; working: ED=1.229, p=0.006; walking: ED=0.920, p=0.009) than the Mel arm during the 4 weeks following autoHSCT. Conclusions: Patients receiving Bu-Mel vs Mel prior to autoHSCT report some differences in symptom severity, with Bu-Mel patients experiencing more severe sore mouth, pain, and symptom interference with daily functioning. The greater intensity of the double-alkylating agent conditioning regimen of Bu-Mel likely led to these differences. The increased severity of drowsiness, dry mouth, constipation, and muscle weakness may be due to an increased need for opioids to control severe pain and mouth sores. The effect of significant differences in symptom severity and interference at baseline between these two groups, despite randomization, is not clear. However, the longer time to progression of myeloma with the Bu-Mel regimen may offset the greater symptom burden early post autoHSCT. Systematic measurement of symptom burden during clinical trials can provide useful information for clinicians and patients in evaluating the full impact of different treatment regimens and enhance treatment decision making and discussion between clinicians and patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Blastic plasmacytoid dendritic cell neoplasms: results of an international survey on 398 adult patients

2020 ◽  
Vol 4 (19) ◽  
pp. 4838-4848
Author(s):  
Kamel Laribi ◽  
Alix Baugier de Materre ◽  
Mohamad Sobh ◽  
Lorenzo Cerroni ◽  
Caterina Giovanna Valentini ◽  
...  
Keyword(s):  
Palliative Care ◽  
Dendritic Cell ◽  
Plasmacytoid Dendritic Cell ◽  
Therapeutic Approaches ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Prognostic Features ◽  
Non Hodgkin Lymphoma ◽  
Autologous Hsct

Abstract The purpose of this study is to describe the clinical and prognostic features and to evaluate the outcome of different therapeutic approaches among patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) who have been diagnosed and treated in different institutions. A total of 398 patients from 75 centers were included in the study. Treatment consisted of non-Hodgkin lymphoma (NHL)–like regimens in 129 (32.8%) patients and acute leukemia (AL)–like regimens in 113 (23.5%) patients. In 61 (15.5%) and 16 (4.1%) patients, chemotherapy was followed by allogeneic and autologous hematopoietic stem cell transplantation (HSCT), respectively. Twenty-seven (6.9%) patients received radiotherapy, 6 (1.5%) received new agents, and 62 (15.7%) received palliative care. After a median follow-up of 12 months, median overall survival (OS) was 18 months. Patients who received NHL/AL-like regimens, followed by allogeneic HSCT, had the best outcome; median OS was not reached. OS was 65 months for patients who underwent autologous HSCT; 18 months and 14 months, respectively, for those treated with AL-like and NHL-like regimens without consolidation; and 4 months for those receiving palliative care (P &lt; .001). In BPDCN, chemotherapy with lymphoma- or AL-like regimens, followed by transplantation, represents the therapeutic strategy associated with the best outcome. Consolidation with allogeneic HSCT, when feasible, appears superior to autologous HSCT.

Involvement of Donor T-Cell Cytotoxic Effector Mechanisms in Preventing Allogeneic Marrow Graft Rejection

Blood ◽  
1998 ◽  
Vol 92 (6) ◽  
pp. 2177-2181 ◽  
Author(s):  
Paul J. Martin ◽  
Yoshiki Akatsuka ◽  
Michael Hahne ◽  
George Sale
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Rejection ◽  
Fas Ligand ◽  
Conditioning Regimen ◽  
Marrow Graft ◽  
Hematopoietic Stem ◽  
Cd8 Cells ◽  
Allogeneic Marrow ◽  
Cytotoxic Effector

Abstract Donor CD8 cells play a pivotal role in preventing allogeneic marrow graft rejection, possibly by generating cytotoxic effectors needed to eliminate recipient T cells remaining after the pretransplant conditioning regimen or by producing cytokines needed to support the growth and differentiation of hematopoietic stem cells. In the present study, we assessed the role of donor T-cell cytotoxic effector function as a mechanism for eliminating recipient CD8 cells that cause marrow graft rejection in mice. The ability to prevent rejection was minimally affected by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin. Doubly mutant perforin-deficient, Fas ligand-defective CD8 cells were completely unable to prevent rejection. Our results indicate first that recipient CD8 effectors responsible for causing marrow graft rejection are sensitive to cytotoxicity mediated by both perforin- and Fas-ligand-dependent mechanisms, and second that donor T cells must have at least one functional cytotoxic mechanism to prevent allogeneic marrow graft rejection. © 1998 by The American Society of Hematology.

Holmium-166 (166Ho)-DOTMP Skeletal Targeted Radiotherapy (STR™) with Melphalan and Autologous Peripheral Stem Cell Transplant (PBSCT) for Multiple Myeloma (MM).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 922-922 ◽  
Author(s):  
Mark Goodman ◽  
William I. Bensinger ◽  
Sergio Giralt ◽  
Donna Salzman ◽  
Katherine L. Ruffner ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hemorrhagic Cystitis ◽  
Conditioning Regimen ◽  
Complete Response ◽  
Phase Iii ◽  
High Dose ◽  
Cell Transplant ◽  
Red Marrow

Abstract Background: 166Ho-DOTMP is a beta-emitting radiophosphonate that localizes specifically to the bone surfaces and can deliver high dose radiation both to the bone and bone marrow. Follow-up data from 3 clinical trials with STR as conditioning for patients with MM undergoing autologous PBSCT are presented. Methods: In 2 Phase I/II dose-escalation trials, 83 patients received a dose of 166Ho-DOTMP STR calculated to deliver 20, 30, or 40 Gy to the red marrow; 82 pts received melphalan (140 or 200 mg/m2) ± 8 Gy TBI (n=25), followed by PBSCT. As of June, 2004, 77 subjects have been followed for at least 48 months. In a separate Phase II dosimetry trial, 12 patients received two 30 mCi tracer doses of 166Ho-DOTMP STR to determine the reproducibility of biodistribution and pharmacokinetics (PK). All pts received a 25 Gy therapy dose with concurrent IV hydration and continuous bladder irrigation, followed by 200 mg/m2 melphalan and PBSCT. These patients have been followed for at least 18 months. Results: Up to 2.3 Ci/m2, 166Ho-DOTMP STR was given in the Phase I/II trials; 29/83 (35%) patients achieved complete response (CR) and overall response rate (CR + PR) was 64% (7 pts not evaluable). The Kaplan-Meier estimate of median survival is 5.2 years for all 83 patients. In patients who are at least 4 years post transplant who achieved a CR, the survival is 74% (n=27). In patients who achieved less than a CR at least 4 years ago, the survival is 34% (n=44). Dose-related radiation-induced kidney toxicity presented in some patients more than 6 months post-therapy. The dose of 166Ho-DOTMP STR in the Phase II dosimetry trial was 550 to 860 mCi/m2, 166Ho-DOTMP. Currently, 18 months of follow-up reveals no occurrence of hemorrhagic cystitis or > Grade 2 elevated creatinine. A CR rate of 17% with an overall survival of 92%, was observed. In 10 patients who received 166Ho-DOTMP STR 750 mCi/m2 ± 10% in the Phase I/II trial, the CR rate was 40%, and the 4-year survival was 70%. Monitoring for safety and duration of response is ongoing in all 3 trials. Conclusion: Follow-up from the Phase I/II trials confirms that 166Ho-DOTMP STR provides favorable efficacy and safety as part of the conditioning regimen for patients with MM undergoing PBSCT. A Phase III, randomized multicenter study is now open to enrollment, comparing the safety and efficacy of 166Ho-DOTMP STR plus melphalan to melphalan alone as conditioning for PBSCT in subjects with primary refractory MM who have failed to respond to induction therapy, including high-dose dexamethasone, and are within 18 months of diagnosis.

The Utility of Consolidative Upfront High Dose Chemoradiotherapy and ASCT in Patients with Mantle Cell Lymphoma (MCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2072-2072
Author(s):  
Daniel Persky ◽  
Carol S. Portlock ◽  
Simone Lessac-Chenen ◽  
Alexia Iasonos ◽  
Andrew D. Zelenetz ◽  
...  
Keyword(s):  
Bone Marrow Involvement ◽  
Conditioning Regimen ◽  
Stage Iv ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Significant Difference ◽  
Dose Dense

Abstract Introduction: Two approaches to improve progression-free survival (PFS) in MCL are intensifying induction, as with hyperCVAD/M-A regimen, or intensifying consolidation with high dose chemoradiotherapy (HDT) and ASCT as in the prospective European MCL Network Trial. At MSKCC the strategy is to incorporate both approaches by administering an anthracycline-containing regimen in a dose dense fashion (CHOP- or R-CHOP-14) followed by consolidation with ICE (ifosfamide, carboplatin, etoposide) and HDT/ASCT. Patients: Forty six patients with newly diagnosed MCL underwent HDT/ASCT between 11/96 and 2/05. The median age was 55 years; 74% were male; 72% had bone marrow involvement, 39% had GI involvement, 7% were in leukemic phase, and 91% presented with stage IV disease. Splenomegaly was seen in 35%, B symptoms in 9%, KPS>70 in 93%, elevated LDH in 23%, and blastoid histology in 9%. Results: Induction was 4 to 6 cycles of CHOP-14 (43%), R-CHOP-14 (37%), or other doxorubicin-containing regimen (20%). Consolidation was performed with 2–3 cycles of ICE in 53% or R-ICE in 39%. Upfront treatment was well tolerated and permitted adequate stem cell collection and prompt transition to HDT/ASCT. Conditioning regimens were TBI/CY/VP-16 (59%) and BEAM (41%). Involved field radiation therapy was administered to 65%. Post-ASCT rituximab maintenance was given to 39%, with 57% of patients receiving rituximab as part of their treatment. Anthracycline-based induction led to CRu of 44% and ORR of 98%. Seventy two percent of patients were transplanted in CR, while the remaining 28% were in PR. At a median follow-up of 2.5 years (range 0.4–8.0 years) 17% of the patients have died and 24% have had progressive disease. The median OS and PFS have not been reached (lower 95% CI, 5.7 years and 4.4 years, respectively). The 5-year PFS and OS are 58% and 83%, respectively. The use of rituximab at any point during treatment prolonged PFS - only 1 of 26 patients receiving rituximab relapsed, as compared to 10 of 20 patients who were rituximab naive (p=0.03); thus far there is no significant difference in OS. There was no day 100 treatment related mortality. One patient developed bronchiolitis obliterans after ASCT and died of pulmonary fibrosis 6.5 years later; 3 patients have died of secondary cancers - one case each of MDS (1.6 years after ASCT), melanoma and lung cancer. Conclusion: These data provide evidence that dose-dense induction with CHOP-14 or R-CHOP-14 and consolidation with ICE/HDT/ASCT appears to be safe and effective, with minimal acute toxicity. Although the median follow-up is short, the use of rituximab appears to improve PFS. This contrasts with the findings of German LGLSG and may be a consequence of in vivo rituximab purging. Future therapy could incorporate all the successful elements of prior treatment programs, including R-CHOP-14, R-ICE, and radioimmunotherapy with high dose chemotherapy conditioning regimen, followed by ASCT and rituximab-based maintenance. PFS stratified by Rituximab PFS stratified by Rituximab

Hematopoietic Stem Cell Transplantation (HSCT) from Alternative Donors for Acute Leukemia at High-Risk of Relapse. The Haploidentical Option.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 441-441
Author(s):  
Franco Aversa ◽  
Antonio Tabilio ◽  
Adelmo Terenzi ◽  
Stelvio Ballanti ◽  
Alessandra Carotti ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Leukemia ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Prognostic Features ◽  
Post Transplant ◽  
Leukemia Relapse

Abstract Despite advances in chemotherapy for acute leukemia, survival is poor when patients have unfavourable prognostic features at diagnosis, when they do not achieve CR after the first induction cycle and when they are in second or later remission. In these circumstances an allogeneic HSCT is preferred. The chance of finding a matched unrelated donor depends on the HLA diversity and although molecular analysis achieves closer matches it reduces the probability of finding a donor. Furthermore, many patients relapse while waiting for transplant. Transplantation of HSCs from a one-haplotype mismatched family member offers an immediate source of HSCs to almost all leukemia patients who urgently need an allogeneic transplantation because of the high-risk of leukemia relapse and who do not have a matched, either related or unrelated, avaible donor. Over the past decade, our group has shown the two major obstacles to mismatched transplants, that is severe acute GVHD in T-cell-replete transplants and graft rejection in T-cell-depleted transplants, can be overcome by infusing a megadose of extensively T-cell-depleted HSCs after an immuno-myelo-ablative conditioning regimen. Since our first reports (Aversa et al. Blood 1994 and NEJM 1998), the main modifications to our original approach were: a) in October 1995, fludarabine was substituted for cyclophosphamide in our TBI-based conditioning regimen; b) peripheral blood cells were positively selected by using initially the Ceprate device and then, since January 1999, the Clinimacs instrument which ensures a 4.5 log T-cell depletion in a one-step procedure with no E-rosetting; c) in the 138 patients transplanted since January 1999 post-transplant G-CSF administration was stopped so as to improve immune recovery. The patient population included 90 AML and 48 ALL, median age 28 years (range 9–62), 40 (29%) in bad-risk CR I, 43 (31%) in second or later CR and 55 (40%) in relapse at transplant. Primary full-donor engraftment was achieved in 125/134 evaluable patients (93%); 8 patients engrafted after second transplants. Overall engraftment was achieved in 133 patients (96%). Without any post-transplant immunosuppressive prophylaxis, grade II-IV acute GvHD occurred in 7/133 evaluable patients and 5/106 developed chronic GvHD. Cumulative incidence (C.I. 95%) of non-leukemia mortality was 36% (19%–53%) and 40% (19%–66%) for patients who were respectively in CR or in relapse at transplant. 38/51 deaths were infection-related. Disease status was the major risk factor for relapse and EFS. Cumulative incidence of leukemia relapse was 27% (12%–45%) and 60% (30%–80%), p=0.006, for ALL patients in CR and relapse respectively; 17% (8%–29%) and 46% (29%–61%), p=0.0001, for AML in CR and relapse respectively. ALL and AML patients transplanted in relapse have, respectively, a 6% and 13% probability of surviving event-free. For those transplanted in remission, EFS is respectively 38% and 50% for ALL and AML patients in any CR at transplant. These results indicate the mismatched transplant should be offered to high-risk acute leukemia patients without a HLA-identical donor not as a last resort, but as a viable option in the early stages of the disease.

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