Allogeneic Stem Cell Transplantation Using a Reduced Intensity Conditioning (RIC) Regimen Has the Capacity To Produce Durable Remissions and Long Term Disease-Free Survival in Patients with High Risk Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1141-1141
Author(s):  
S. Tauro ◽  
S. Mackinnon ◽  
K. Peggs ◽  
G. Begum ◽  
P. Mahendra ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Abstract The toxicity of allogeneic stem cell transplantation (SCT) can be substantially reduced by the use of a reduced intensity conditioning (RIC) regimen and this has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with AML and MDS has not yet been defined and consequently their role in the management of these diseases remains conjectural. Seventy-six patients with high risk AML or MDS were allografted using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range 18–71 years). There were 46 males and 30 females; 41 patients received an allograft from an unrelated donor and 35 from a matched sibling donor. The 100 day transplant related mortality was 9% and no patient developed greater than Grade 2 graft-versus-host disease (GVHD). With a median follow-up of 36 months (range 13–70 months) 27 patients were alive and in remission with a 3y actuarial overall survival (OS) and disease-free survival (DFS) rate of 41% and 37% respectively. The 3y OS and DFS of patients with AML in complete remission (CR) at the time of transplantation was 48% and 42% respectively. In a multivariate setting, Cox regression analysis demonstrated prognostic significance of disease stage at the time of transplant with improved DFS in patients with AML in CR at the time of transplantation (HR=2.03, 95% CI=1.02–4.07). Disease relapse was the commonest cause of treatment failure occurring at a median time of 6 months post-transplant. Fourteen out of 27 (52%) patients relapsed within 6 months and 23/27 (85%) within twelve months defining a relatively narrow window for therapeutic intervention to prevent disease recurrence. The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts are capable of producing sustained disease free survival in a significant number of patients with AML who would be ineligible for allogeneic transplantation using a myeloablative conditioning regimen.

Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia

2005 ◽  
Vol 23 (36) ◽  
pp. 9387-9393 ◽  
Author(s):  
Sudhir Tauro ◽  
Charles Craddock ◽  
Karl Peggs ◽  
Gulnaz Begum ◽  
Premini Mahendra ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Disease Relapse ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Purpose The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural. Patients and Methods Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years). Results The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation. Conclusion The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning in Patients with Relapsed or Refractory Acute Myeloid Leukemia - Results of a Phase I/II Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1997-1997
Author(s):  
Martin Bornhaeuser ◽  
Thomas Illmer ◽  
Platzbecker Uwe ◽  
Ordemann Rainer ◽  
Schetelig Johannes ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Sinusoidal Obstruction Syndrome ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Conditioning Therapy ◽  
Disease Free ◽  
Reduced Intensity

Abstract Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within three months before or after allogeneic stem cell transplantation. In addition, excess of liver toxicity has been observed when GO was used directly before conventional intensive preparative regimens. We hypothesized that GO might be safe and effective as part of a fludarabine-based reduced-intensity conditioning regimen. 30 patients relapsing after conventional induction chemotherapy (n=17) or after previous transplantation (autologous n=3; allogeneic n=10) have been included in a prospective phase I/II trial. Per protocol the preparative regimen contained 6 mg/sqm and 3 mg/sqm GO on day-21 and day-14 followed by fludarabine 120 mg/sqm, 200 or 800 cGy total-body irradiation (TBI; depending on age and pretreatment) and stem cell infusion during GO-induced aplasia. Five patients who had previously undergone TBI received melphalan 140 mg/sqm. GvHD prophylaxis was performed with tacrolimus (starting day-1) and mycophenolate mofetil (1.5g BID from day 0). Four patients with progressive disease after GO did not proceed to conditioning therapy and went off study. A reduction of marrow blast counts after GO monotherapy was achieved in 15/30 patients (50%). In 11 cases without response to GO, an additional salvage regimen containing anthracyclines and high-dose cytarabine was administered before conditioning therapy and transplantation. 26 patients received G-CSF mobilized peripheral blood progenitor cells from matched-sibling (n=6) or unrelated donors (n=20). Primary engraftment was observed in all cases. With a median follow-up of 20 months (range 6–55) only one patient experienced sinusoidal obstruction syndrome which was reversible after treatment with defibrotide. Grade II-IV acute GvHD occurred in 15 patients (54%). Nine patients are alive in complete remission. Reasons for death in the other patients were relapse/progression (n=10) and GvHD/Infection (n=7). The probability of overall and disease-free survival at two years for patients having received a transplant is 38% and 32%, respectively. Blast reduction after GO was associated with a superior disease-free survival (48%, p=0.1). These data suggest that GO can be integrated into reduced-intensity conditioning therapy before allogeneic stem cell transplantation in patients with relapsed AML. Refractory patients with no response to GO monotherapy have a low chance of cure and should probably receive other combination therapies.

An Intergroup Randomised Trial of Standard Intensity Versus Reduced Intensity TBI-Based Conditioning In Patients with Acute Myeloid Leukemia in First Complete Remission

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 157-157 ◽  
Author(s):  
Martin Bornhauser ◽  
Joachim Kienast ◽  
Rudolf Trenschel ◽  
Andreas Burchert ◽  
Ute Hegenbart ◽  
...  
Keyword(s):  
High Risk ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Standard Intensity ◽  
Disease Free ◽  
First Complete Remission ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Abstract 157 Allogeneic hematopoietic cell transplantation (HCT) remains the treatment approach with the lowest risk of relapse in patients with intermediate or high-risk acute myeloid leukemia (AML). The lower incidence of relapse achieved with allogeneic HCT is sometimes offset by the higher rate of transplant-related deaths mainly occurring during the first 12–24 months after the procedure. With the advent of reduced-intensity conditioning regimens, older and less fit patients have become eligible for allogeneic HCT. But still, there is some debate as to the optimum level of conditioning intensity in order to reduce non-relapse mortality without jeopardizing overall cytoreductive efficacy. Stimulated by the promising results of a phase II trial exploring the efficacy and toxicity of a regimen combining Fludarabine 30 mg/m2 for four days combined with 800 cGy fractionated total-body irradiation (TBI), we designed this study to compare the mentioned regimen with standard-intensity conditioning. Adult patients with AML in first complete remission (CR1) with standard or high-risk cytogenetics were randomly assigned with a ratio 1:1 to standard intensity conditioning (6 × 200 cGy TBI (1200cGy) over 3 days and Cyclophosphamide 60 mg/kg per day over 2 days (Arm A)) or TBI 4 × 200 cGy (800 cGy) combined with Fludarabine 30 mg/m2 daily over 4 days (Arm B). Antithymocyte globuline was infused at a cumulative dose of 60 mg/kg (3 × 20 mg/kg from day -3 to -1) in recipients of grafts from unrelated donors (UD). Pharmacologic prophylaxis of graft-versus-host disease (GvHD) was performed with CsA starting day -1 and Mtx on days 1, 3, 6 and 11. The primary endpoint was transplant-related mortality (TRM) within the first 12 months after transplantation Secondary end-points included overall as well as disease-free survival and acute and chronic GvHD. Between November 2004 and December 2009, 198 patients were registered in the trial. Three patients had to be excluded for the violation of inclusion criteria. The intent-to-treat (ITT) population, thus, consisted of 195 subjects (96 Arm A, 99 Arm B). Eleven patients did not receive the study treatment. Therefore, the per protocol analyses involved 184 patients (90 Arm A, 94 Arm B). Median age was 45 years (range 18–60). 46% were female. Intermediate risk and high risk karyotypes were present in 62% and 38% of the patients, respectively. 60% of the patients received grafts from matched sibling donors. Grafts from UD with at least 9 out of 10 HLA alleles (HLA-A, B, C, DRB1, DQB1) were infused in 40%. The majority of patients (89%) received G-CSF mobilised peripheral blood stem cells. Donor type, cytogenetic risk, type of induction regimen and age (18–40 vs. > 40) had been strata for randomisation and were therefore well balanced between both groups. Most patients had received double induction therapy using 3+7 combinations of anthracyclines and cytarabine. The evaluation of the primary endpoint in the per protocol population showed a lower incidence of TRM after 12 months in Arm B (8%, 95% Confidence interval (CI) 3–14% versus 17%, CI 9–24% in Arm A, p=0.048; ITT p=0.06). The difference in TRM at 12 months was even more pronounced in the subgroup of patients > 40 years (5% Arm B versus 20% Arm A, p=0.01). With a median follow-up of 27 (range 4–81) months for patients alive, the probability of overall survival three years after randomisation was 62 % in the reduced-intensity Arm B versus 59% in Arm A (p=0.28). Probabilities of disease-free survival were 60% and 56% for Arm B and Arm A (p=0.44), respectively. The cumulative incidence of grade II-IV acute GvHD until day 100 was 16% in Arm B versus 23% in Arm A (p=0.15). Cumulative incidences of relapse three years after transplantation were not different between both treatment arms albeit a different kinetic of relapse could be documented. This trial shows for the first time in a prospectively randomized design in patients with AML in CR1 that reduced-intensity conditioning can result in significantly lower early TRM without increasing relapse risk. Fludarabine combined with 800cGy fractionated TBI can be regarded as a valid alternative to standard intensity conditioning even in younger patients with AML transplanted in first remission. Disclosures: No relevant conflicts of interest to declare.

Allogeneic Stem Cell Transplantation With Reduced Intensity Conditioning Regimen In Patients With Relapsed Hodgkin´s Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5511-5511
Author(s):  
Maria Marta Rivas ◽  
Mariano Berro ◽  
Sebastian Yantorno ◽  
Maria Virginia Prates ◽  
Jorge H Milone ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

Abstract Introduction Hodgkin´s Lymphoma (HL) is a highly curable disease. However, there are still patients with primary refractory disease or who relapse after first-line treatment, or even after high-dose chemotherapy with hematopoietic cell rescue. Allogeneic stem cell transplant (ASCT) is therapeutic for this patients. Objective To analyze the experience with relapsed HL patients that received ASCT with reduced intensity conditioning (RIC)regimen in 8 Argentine Medical Centers. Design and Population We performed a retrospective multicenter analysis from data obtained from medical records. Fifty-four patients with relapsed HL who received ASCT had a median age of 26years. The relationship between male / female was 1/1. Only 3 patients (5.5%) at the time of transplant had a performance status> 1 according to ECOG. Ninety-six percent of the patients had received previously autologous transplant. Most patients 43 (80%) received an identical sibling donor transplant. All patients receiving unrelated donor transplants had in vivo lymphocyte depletion as prophylaxis of graft versus host disease. Forty-three patients (79.6%) received as a conditioning regimen Fludarabine + Melphalan. The disease status at transplant was: complete remission (CR) 33%, partial remission (PR) 54%, stable disease / progressed (SD / PD) 13%. Results With a median follow up of 2.7 years, actuarial overall survival (OS) at 1 and 5 years was 65% and 20% respectively and disease free survival (DFS) at 1 and 5 years was 35 % and 18% respectively. The incidence of acute GVHD grade II-IV was 31%. Patients in CR at the time of transplant showed significant differences compared with those who were not in CR in DFS (1-5 years 52-27% vs 19-14%, p=0.01), OS (1-5 years 76-38% vs 59-13%, p=0.02) and non relapsed mortality (NRM) (1-5 years 6-12% vs 34-39%, p=0.04). Age, PS, the use Fludarabine + Melphalan as conditioning regimen, unrelated donor, aGVHD, were not variables that modified the overall survival and disease-free survival. Conclusion The ASCT with RIC regimen is a feasible therapeutic option in patients with HL, especially in patients who can achieve CR. The low rate of DFS is still an issue in this setting, may be new drugs may help in optimizing pretransplant response status to improve patients’ outcome. Disclosures: No relevant conflicts of interest to declare.

Clonal Gammopathies Following Reduced Intensity Conditioning Transplantation with Fludarabine, Busulphan and Alemtuzumab for Myeloid Malignancies Predict Improved Overall Survival.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1410-1410
Author(s):  
ZiYi Lim ◽  
Antonio Pagliuca ◽  
Wendy Ingram ◽  
Dragana Milojkovic ◽  
Mojtaba Akthari ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Disease Free Survival ◽  
Autoimmune Disorders ◽  
Disease Stage ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Myeloid Malignancies ◽  
Disease Free

Abstract Clonal gammopathies and autoimmune disease following standard conditioning haematopoietic stem cell transplantation (HSCT) are thought to reflect immune dysregulation post HSCT. Serial serum protein electrophoresis was performed on 124 patients with myeloid malignancies undergoing Alemtuzumab based reduced intensity conditioning (RIC) HSCT. The median age of patients was 53 years (range 22–72), with a median follow-up of 521 days (range 82–2096). The median follow-up for survivors was 720 days (range 82–2096). The majority of patients were treated for myeloid malignancies: MDS 84, AML 28, CML 10, others 2. There were 45 sibling and 79 VUD allografts. All patients received the same RIC protocol with FBC (30mg/m2 fludarabine iv day −9 to −5, 4 mg/kg busulphan oral from day −3 to −2; and 20 mg alemtuzumab iv from day −8 to −4) conditioning with cycloporine A for GvHD prophylaxis. Patients with autoimmune disorders or clonal gammopathies prior to transplant were excluded from the study. We observed the presence of clonal gammopathies in 49 patients (40%). On analysis of immunoglobulin sub-classes, the M component was identified as monoclonal in 21 (43%), biclonal in 16 (33%) and oligoclonal in 12 (24%). The predominant Ig isotype was IgG (84%), and gammopathies were present for a median time of 138.5 days (range: 27–462). The kappa:lambda ratio between samples was 1.6:1. The median level of gammopathies was 2.6 g/l (range 1.0–16.5). There was no evidence of plasma cell dyscrasia on bone marrow assessment in any of the patients. We compared the characteristics of patients with and without gammopathies. There were no significant differences in donor or recipient age, sex, disease type, stem cell source, stem cell dose. The incidence of viral infections, acute GvHD, donor lymphocyte infusion (DLI) was similar between the groups. However, patients with gammopathies were more likely to have chronic graft versus host disease (GvHD) (p=0.006). Bone marrow chimerism was available for analysis on 45 patients. At time of detection of gammopathy, 34 patients (76%) had achieved full donor chimerism, and 11 patients (24%) were mixed donor chimerism. Of the entire group of 124 patients, 11 patients (9%) developed autoimmune disorders. There was however no association between the presence of autoimmune disorders and clonal gammopathies (p=0.50). When patients with gammopathies were compared with those without, there was a significant difference in both disease free survival (54% vs 24%, p=0.012), and overall survival (69% vs 45%, p=0.007). On univariate analysis, early disease stage and presence of gammopathy were significant predictive variables for improved disease free survival and overall survival. On multivariate analysis, disease stage was the only independent variable for disease free survival (p<0.01, HR 2.345, 95% CI 1.282–4.288), and both disease stage (p=0.05, HR 1.901, 95% CI 1.000–3.615) and presence of gammopathy (p=0.01, HR 0.421, 95% CI 0.217–0.815) were independent predictors of overall survival. The role of humoral responses following transplantation is still undefined, and it is possible that the gammopathies seen in our cohort are a surrogate response to a heterogenous group of stimuli. Clonal gammopathies are a frequent and benign occurrence following RIC HSCT, and its appearance may define a subgroup of patients with a favourable overall outcome.

Radioimmunotherapy-based conditioning for hematopoietic cell transplantation in children with malignant and nonmalignant diseases

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4642-4650 ◽  
Author(s):  
Ansgar S. Schulz ◽  
Gerhard Glatting ◽  
Manfred Hoenig ◽  
Catharina Schuetz ◽  
Susanne A. Gatz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pilot Study ◽  
Confidence Interval ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Disease Free Survival ◽  
Reduced Intensity Conditioning ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity

AbstractTargeted irradiation of the bone marrow with radiolabeled monoclonal antibodies (radioimmunotherapy) represents a novel therapeutic approach with both myeloablative and antileukemic potential. In an open-label, single-center pilot study, 30 pediatric and adolescent patients undergoing hematopoietic cell transplantation for malignant (n = 16) and nonmalignant (n = 14) disorders received treatment with a 90Y-labeled anti-CD66 monoclonal antibody. Patients with a high risk of relapse (n = 7) received additional treatment with standard conditioning based on either total body irradiation or busulfan to intensify the antileukemic effect. In patients with comorbidities (n = 23), radioimmunotherapy was combined with a reduced-intensity conditioning regimen to reduce systemic toxicity. Preferential irradiation of the bone marrow was achieved in all patients. Nonrelapse mortality was 4 (13%) of 30 patients. In patients with malignant diseases, the probabilities of overall and disease-free survival at 2 years were 0.69 (95% confidence interval 0.37-0.87) and 0.46 (95% confidence interval 0.19-0.70), respectively. In patients with nonmalignant diseases, the probability of both overall and disease-free survival at 2 years was 0.94 (95% confidence interval 0.63-0.99). This pilot study demonstrates that radioimmunotherapy is effective in achieving myeloablation with low additional toxicity when used in combination with standard or reduced-intensity conditioning in young patients.

Improved Outcomes for Peripheral Blood Stem Cell Transplantation in Advanced Myelodysplastic Syndrome.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2304-2304
Author(s):  
Scott R. Solomon ◽  
Richard Childs ◽  
Aldemar Montero ◽  
Elaine Sloand ◽  
Laura Wisch ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood Stem Cell ◽  
Advanced Disease ◽  
Disease Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Blood Stem Cell Transplantation ◽  
Reduced Intensity ◽  
Risk Of Relapse ◽  
Related Mortality

Abstract Allogeneic marrow or peripheral blood stem cell transplantation (PBSCT) is the only curative treatment for myelodysplastic syndrome (MDS). Historically, transplantation for MDS has produced long-term disease-free survival rates of 30–40%, partially due to high procedural mortality (~40%) in this patient population. Although transplant outcomes in younger patients with low-risk disease have been favorable, inferior results are seen in older patients and those with more advanced disease. Evidence suggests that the lower transplant-related mortality (TRM) and improved graft-versus-leukemia seen with PBSCT may translate into improved clinical outcomes for MDS patients. Forty-four patients, aged 12–73 years (median 50) received a PBSCT from a matched related sibling donor (MRD). Patients aged <55 years, without prohibitive comorbidity, received myeloablative conditioning consisting of total body irradiation and cyclophosphamide, followed by a T cell depleted allograft and scheduled post-transplant donor lymphocyte infusions (MST, n=23). Patients ineligible for an ablative transplant due to age or poor health received reduced intensity conditioning (fludarabine and cyclophosphamide, melphalan, or busulfan) followed by a T cell replete allograft (n=21). Six patients had low-risk MDS (RA/RARS), while the majority of patients (86%) had advanced disease (RAEB [9], RAEBT [6], AML [13], therapy-related MDS [10]). Median follow-up is 15.3 (range 2–82) months. Patients with therapy-related MDS had a significantly lower survival rate due to a very high risk of relapse (figure). The actuarial probabilities of overall survival (OS), disease-free survival (DFS), relapse, and TRM were 64%, 59%, 26%, and 23% for primary MDS patients, and 51%, 47%, 40%, and 25% for the whole cohort. Transplant-related mortality in patients under 50 years of age was 11% vs. 45% in patients ≥50 years (p=0.03). OS and DFS were significantly better in recipients of MST (64%, 57%) than in patients receiving reduced-intensity PBSCT (33%, 34%), due to a higher risk of relapse in the latter group (55% vs. 29%, p=0.10). In nineteen patients <50 years receiving MST, actuarial probability of OS, DFS, relapse, and TRM were 81%, 72%, 23%, and 7%, respectively. In summary, PBSCT yields superior outcomes for patients with primary MDS, even in patients in transformation to AML. The inferior outcomes seen in therapy-related MDS suggest alternative therapies are required for this patient population. Reduced intensity transplantation permits curative therapy for MDS patients not amenable to MST, but at the price of increased TRM and relapse in this older cohort. Figure Figure

A Phase II Trial of Sequential Treatment with Cytoreductive Therapy and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation for Relapsed/Refractory Acute Myeloid Leukaemia, High-Risk MDS and Other High Risk Myeoid Malignancies: An Interim Report.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3480-3480
Author(s):  
Dimitris A Tsitsikas ◽  
Dana Warcel-Sibony ◽  
Heather E. Oakervee ◽  
Samir G Agrawal ◽  
Matthew Smith ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Sequential Treatment ◽  
Reduced Intensity Conditioning ◽  
Disease Free ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Abstract 3480 Background: Outcomes for patients with refractory or relapsed acute myeloid leukaemia (AML) are extremely poor and allogeneic haemopoietic stem cell transplantation (HSCT) provides the best hope for prolonged disease free survival. Ablative HSCT combines high dose, anti-leukaemic chemoradiotherapy and the graft versus leukaemia (GVL) effect, but is associated with significant toxicity and mortality and these risks rise exponentially with advancing age. Several factors mitigate against an attempt to transplant patients after relapsed disease, including a low probability of achieving second remission, high re-induction mortality, prolonged cytopenias and opportunistic infections and prolonged hospitalization. Based on promising results [1], we undertook a phase II study of sequential chemotherapy immediately followed by reduced intensity conditioning (RIC)-Allo with the aim of increasing the safety and applicability of AlloHSCT, while maintaining its antileukaemic efficacy. Patients/Methods: All eligible patients received treatment with Daunorubicin 45mg/m2 OD IV D-15 to D-13 and AraC 1.5g/m2 BD IV D-15 to D-10, a three day rest period, and conditioning with Fludarabine 25mg/m2 D-6 to D-2 and Cyclophosphamide 1g/m2 D-3 and -2 before receiving HSCT. Graft versus Host Disease (GVHD) prophylaxis was with Cyclosporine and Methotrexate. To date 33 patients were enrolled (table 1), of whom 31 patients underwent transplant. Results: 28/31 (90.3%) patients engrafted (neutrophils ≥0.5 and platelets ≥ 20) at a median of 33.5 days (15-49), while 3 died between d21-51 due to sepsis. The median d30, d60 and d100 whole blood chimerism was 96% (range 4–100), 80% (range 5–100), and 76% (range 0–100) respectively. 6/31 (19.4%) developed acute GVHD; 5 grade 1–2, 1 grade 4. Chronic GVHD was documented in 8 patients, extensive GVHD in 4/8. 7 patients had CMV re-activation (no CMV disease) and 1 non-specified pneumonitis. Median time of hospitalization was 37 days (30-61). No patient has required DLI to date. 18 pts (56.25%) achieved complete remission (CR) as assessed by day 30 bone marrow (BM). 2 had <5% blasts BM, 4 refractory disease, 4 died before evaluation, and 3 did not have a BM examination. 7 (6 previously documented CR in BM) of the 33 patients (21.2%) relapsed. Median time to relapse was 162 days (59–408). 18 /33 (54.5%) have died; 6 (33.4%) of sepsis, 5 (27.8%) of relapsed leukaemia, 4 (22.2%) of GVHD, and 3 (16.7%) of refractory leukaemia. D100 treatment related mortality (TRM) was 18.2% (n=6) and overall TRM is 30.3% (n=10). Median time of TRM was 84 days (range 21–519). 15 of the 33 patients (45.5 %) are alive, 12 of whom (36.4%) are disease free with a median follow up of 13 months (range 2–31 months). For these patients, the underlying diagnosis was relapsed AML in 7 (50 %), refractory AML in 5 (28.6 %), high risk MDS in 2 (14.3%) and other in 1 (7.1 %). 2 patients with relapsed and 1 with refractory AML subsequently relapsed after having achieved remission. Overall survival for the 31 patients is 45.2% with disease-free survival of 38.7%. Conclusions: Sequential treatment with cytoreductive therapy and immediate RIC Allo is associated with good engraftment rates with a TRM acceptable for this high risk group. Our preliminary data indicate a favourable survival outcome for these patients with a particularly poor prognosis. 1. Schmid C, Scheuning M, Schwerdtfeger et al. Long-term survival in refractory acute myeloid leukemia afetr sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood. 2006;108:1092-1099. Disclosures: Gribben: Roche: Consultancy; Celgene: Consultancy; GSK: Honoraria; Napp: Honoraria.

A Novel Sequential Treatment Utilizing CPX-351 As Salvage Chemotherapy Followed by a Reduced Intensity Conditioning Allogeneic Stem-Cell Transplantation for Patients with Refractory Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3030-3030
Author(s):  
Usama Gergis ◽  
Gail J. Roboz ◽  
Ellen Ritchie ◽  
Joseph M. Scandura ◽  
Karen-Sue B. Carlson ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Reduced Intensity Conditioning ◽  
Co Morbidity ◽  
Phase 1B ◽  
Morbidity Index ◽  
Reduced Intensity

Abstract Abstract 3030 Introduction: Allogeneic Hematopoeitic Stem cell Transplantation (HSCT) using standard ablative or reduced intensity conditioning regimens is often ineffective in patients with primary refractory and relapsed acute leukemia. Sequential administration of cytoreductive chemotherapy followed by a Reduced Intensity Conditioning (RIC) regimen may lead to improved results (Schmid et al Blood 2006). CPX-351 is a novel liposomal formulation that encapsulates the combination of cytarabine and daunorubicin in a fixed 5: 1 ratio. In vitro, it selectively concentrates in the marrow compared to other organs. Clinically, CPX-351 is well tolerated, with a favorable extramedullary toxicity profile, making it an appropriate cytoreductive agent prior to conditioning for HSCT. Patients and Methods: In a 3+3 phase I trial, patients with relapsed or primary refractory acute leukemia were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 28, -26 and -24 followed by RIC with IV busulfan 3.2 mg/kg/day on days -6 to -3 and fludarabine 30 mg /m2/day on days -6 to -3 (Bu/Flu). GVHD prophylaxis consisted of tacrolimus starting on day -3, at a starting dose of 0.03 mg/kg/24 hours as a continuous infusion and adjusted to achieve a trough level between 10 and 15 ng/ml. and methotrexate 10 mg/m2 IV on days 1, 3, 6 and 11 (Methotrexate dose was reduced to 5 mg/m2 after observing grade 3 mucositis in the first 3 patients). The protocol was amended to include a phase 1B in addition to the above mentioned phase 1A. In phase 1B, patients were treated with escalating doses of CPX-351 starting at 60 mg/m2 on days - 21, -19 and -17 followed by IV Bu/Flu conditioning. Thirty two patients (AML-27, ALL-2, CML in blast crisis-1, high risk MDS-2) have been enrolled to date. Nine patients are in-evaluable due to short follow up (2), sepsis resulting in aborted transplant plans (4), appendicitis (1), early death at day +12 due to sepsis prior to engraftment (1) and donor's unavailability after receiving one dose of CPX-351 (1). Twenty three patients who underwent HSCT are evaluable (AML-19, ALL-2, high risk MDS-2). We calculated the transplant co-morbidity index as well as the prognostic score identified by the CIBMTR in patients with refractory leukemia undergoing HSCT (Duval et al. JCO 2010). The twenty three evaluable patients have a median age of 58 (range 33–72), co- morbidity index 2 (range 0–6) and CIBMTR score 3 (range (2–5). All patients received HLA compatible grafts (MUD-15, MRD-8). Results: Nineteen patients achieved complete hematologic remission by day 30 post transplant. All nineteen patients had adequate donor's engraftment for neutrophils and platelets at a median time of 15 days (range 12–35) and 16.5 days (range 10–90) respectively. Four patients continued to have active disease by day 30. Five more patients had a disease relapse before or shortly after day 100 and one patient had a relapse 22 months post transplant for a total of 10 relapsed patients (43%). Three patients died of acute GI GVHD 2, 6 and 9 months after transplant (all were in remission). One patient died of a pre existing brain tumor progression and one patient died of liver cirrhosis due to iron overload one year after transplant for a total non relapse mortality of 21%. At a median follow up of 6 months, eight patients are alive without evidence of leukemia (35%). Acute GVHD grade II-IV occurred in 8 patients (35%) and was the cause of death in 3 patients. Chronic GVHD occurred in 3 patients (13%). Grade 2 mucosal injury as defined by Bearman toxicity criteria was the most common toxicity developing in 15 patients (65%). Conclusion: The maximum tolerated (MTD) dose of CPX-351 followed by RIC HSCT was not found after a series of 4 treatment cohorts on Arm A and 2 treatment cohorts on arm B. Further dose escalation to define MTD is ongoing in both arms. Remission status is not a prerequisite for a successful outcome in selected patients who otherwise are candidates for transplantation. Disclosures: Off Label Use: CPX is not FDA approved. Feldman:celator: Consultancy.

Disease-Free Survival Of Myelodysplastic Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation Is Not Associated With Disease Status and Donor Sources

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2158-2158
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Xing-Yu Cao ◽  
Yan-Li Zhao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Disease Free Survival ◽  
Disease Status ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Disease Free ◽  
Related Mortality

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is an only curative modality currently for myelodysplastic syndrome (MDS). High-risk MDS usually has lower complete remission (CR) rate and higher chemotherapy-related mortality compared with de novo acute myeloid leukemia (AML). To examine whether CR before HSCT has survival benefit for MDS treated by HSCT, we retrospectively analyzed the data during 11 years from our center. The clinical outcomes of MDS after HSCT from different donor sources have also been evaluated. Objective In present clinical study, the effects of disease status and donor sources on disease-free survival (DFS) of MDS after HSCT were studied. Methods From August 2001 to December 2012, total 122 patients with MDS that underwent HSCT in our center were enrolled. Male to Female was 76: 46. The median age was 35 (8 to 57) years old. The median blasts in bone marrow (BM) before conditioning were 9% (1% to 65%). According to 2008 WHO classification, the patients were diagnosed as refractory cytopenias with unilineage dysplasia (RCUD) in 12, refractory anemia with ring sideroblasts (RARS) in 2, 5q- in 1, refractory cytopenias with multilineage dysplasia (RCMD) in 15, refractory anemia with excess blasts (RAEB) -1/RAEB-2 in 36 and transformed AML in 56. For International Prognostic Scoring System (IPSS), 12 patients were in low-risk, 27 in intermediate-1, 24 in intermediate-2, and 59 in high-risk. Based on BM blast percentage pre-conditioning, 47 cases were less than 5%, 43 patients were between 5% to 20%, and 32 cases were more than 20%. The stem cells were from identical siblings (45) or unrelated donor (24) or haploidentical family members (53). Conditioning regimens were BUCY/BUFLU for identical sibling HSCT, and BUCY/BUFLU plus ATG (Thymoglobuline, 8-10mg/kg) for unrelated or haploidentical transplants. Graft-versus-host disease prophylaxis was employed by Cyclosporin A, Methotrexate and Mycophenolate mofetil as reported previously (DP Lu et al., Blood 2006; 107:3065). Results: With median follow-up 31 (1-144) months, DFS was 73.8%. Fourteen patients (11.4%) relapsed. Transplant-related mortality was 14.8%. No significant differences on DFS were found among RCUD/RARS/5q- (68.8%), RCMD (85.7%), RAEB-1/RAEB-2 (72.2%) and transformed AML (73.2%) (p=0.761). A similar DFS was seen in different risk categories (73.3% in low-risk, 79.2% in intermediate-1, 75.0% in intermediate-2 and 71.2% in high-risk; p=0.861). Moreover, CR or not before HSCT has no remarkable effect on DFS (blasts <5%, 78.7%; blasts 5% to 20%, 67.4%; blasts > 20%, 75.0%; p=0.342). Donor sources have also no significant effects on DFS (identical sibling 75.6%, unrelated donor 79.2%, haploidentical family member 69.8%; p=0.651). Conclusions Our clinical results have shown that under current protocol, DFS of MDS after allogeneic HSCT is quite encouraging no matter the disease status and stem cell donor sources. Therefore, it is not necessary that complete remission is achieved by chemotherapy before transplant. Haploidentical family member is an important alternative donor for patients with MDS when matched either identical sibling or unrelated donor is not available. Disclosures: No relevant conflicts of interest to declare.

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