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

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.

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.

scholarly journals Outcomes of AML Patients Undergoing Reduced Intensity Allogeneic Stem Cell Transplantation with Adverse Risk Disease By European Leukemianet Classification: A Single Center Retrospective Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5723-5723
Author(s):  
Zane Chiad ◽  
Clark Alsfeld ◽  
Robert Collins ◽  
Brion Randolph ◽  
Georges Nahhas ◽  
...  
Keyword(s):  
High Risk ◽  
Older Patients ◽  
Disease Free Survival ◽  
Single Center ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Disease Free ◽  
Reduced Intensity ◽  
Risk Of Relapse

Background: Acute myeloid leukemia (AML) is the most common acute leukemia in adults with a median age at diagnosis of close to 70 years. (Juliusson G, et al. Blood, 2011;119(17):3890-3899) The majority of patients with AML require allogeneic stem cell transplant (Allo-SCT) in order to achieve cure. European LeukemiaNET (ELN) published risk stratifications for AML patients according to cytogenetics in 2010 and then updated risk categories in 2017 to incorporate molecular abnormalities as well. The ELN adverse risk category predicts for a higher risk of relapse and worse overall survival (OS) compared to favorable and intermediate risk patients. (Döhner H, et al. Blood, 2017;129(4):424-447) Older patients are more likely than younger patients to have adverse risk disease. (Mrozek K, et al. JCO, 2012;30(36):4515-4523). In addition, older patients are typically not considered for myeloablative conditioning (MAC) regimens due to the high risk of non-relapse mortality (NRM). Thus, a significant proportion of AML patients who are candidates for Allo-SCT have adverse risk disease by ELN criteria and are only candidates for RIC Allo-SCT, both of which increase the risk of relapse. A recent randomized trial in AML and MDS patients noted a trend toward improved OS and statistically significant improvement in relapse free survival (RFS) favoring MAC over RIC (Scott BL, et al. JCO, 2017; 35(11): 1154-1161). Despite this, studies have shown durable remissions and long term disease free survival with RIC Allo-SCT in AML patients with high risk features. (Tauro S, et al. JCO, 2005; 23(36):9387-9393) However, to our knowledge no study has investigated the use of RIC Allo-SCT exclusively in patients who have adverse risk by 2017 ELN criteria. Thus, we reviewed AML patients with adverse risk disease by 2017 ELN criteria at diagnosis who underwent RIC Allo-SCT at our institution. Methods: We conducted a single center retrospective study of high risk adult AML patients by ELN criteria who underwent RIC Allo-SCT at MUSC from 3/20/2010 to 2/20/2018. Adverse risk disease was defined by the 2017 ELN criteria. Baseline demographic, clinical, laboratory, pathology, and outcomes data were collected by retrospective chart review. Kaplan Meier was utilized for time to event analysis. Results: A total of 42 patients with adverse risk AML received RIC Allo-SCT. The median follow up was 16.6 months. Clinical characteristics were collected for each patient and are included in table 1. The median age was 62 with 16 patients (38%) ≥ 65 years of age. Twenty-three patients had a HCT-CI score ≥ 3 (54%) with 9 patients (21%) having a HCT-CI score ≥ 5. Complete remission (CR) was defined as bone marrow blasts < 5% without known molecular evidence of persistent/relapsed AML. CR and CR with incomplete count recovery (CRi) was not able to be defined. Thirty-one patients (73%) were in CR1 at transplant, 7 patients (16%) were in CR2+ defined as CR necessitating ≥ 2 treatment regimens. Four patients (9%) never achieved a CR and were labelled as primary induction failure (PIF), and one patient (3%) received prior MAC Allo-SCT before receiving RIC Allo-SCT and was labeled as Relapse. Four of the five patients with disease status of PIF or relapse were deceased within 13 months of Allo-SCT. The non-relapse mortality (NRM) at 1 year was 26.2%. Relapse-free survival (RFS) at 1, 2, and 3 years was 57.1%, 45.2%, and 35.7% respectively. The overall survival (OS) at 1, 2, and 3 years was 66.7%, 50.0%, and 40.5% respectively. A subset analysis of the patients in CR1 or CR2+ prior to RIC-Allo SCT noted a NRM at 1 year of 27% along with a RFS at 1, 2, and 3 years of 59.5%, 48.7%, and 40.5% respectively. Cause of death included relapse (33%), infection (29%), acute GVHD (25%), and chronic GVHD (3%). Conclusion: This provides evidence that although adverse risk disease by ELN criteria and reduced intensity conditioning both increase the incidence of relapse in patients with AML, that RIC Allo-SCT for this high risk patient population can provide long term disease free survival. In addition, the favorable outcomes for patients in CR1 and CR2+ prior to RIC-Allo are promising. It would be interesting to investigate a larger multi-center series of patients with adverse risk disease by ELN in CR prior to RIC Allo-SCT. Minimal residual disease by myeloid molecular panel and/or flow in this patient population prior to transplant would be of great interest as well. Disclosures Edwards: Genzyme: Consultancy.

Allogeneic and Matched Unrelated Donor Hematopoietic Stem Cell Transplantation (HSCT) for Hematologic Malignancies Using a Modified Reduced Intensity Conditioning Regimen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5324-5324
Author(s):  
Marion Raflores ◽  
James Rossetti ◽  
John Lister ◽  
Richard Shadduck ◽  
John Lech ◽  
...  
Keyword(s):  
Stem Cell ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Reduced Intensity Conditioning Regimen ◽  
Disease Free ◽  
Related Mortality

Abstract INTRODUCTION:Use of a reduced intensity conditioning regimen (RICR) in hematopoietic stem cell transplant may result in lower treatment related mortality (TRM), less acute graft versus host disease (aGVHD) and better survivability, utilizing the graft versus tumor effect from HSCT. METHODS: Our institution’s original RICR protocol conditioning regimen (Trial A) consists of fludarabine 30 mg/m2 (Day-5 to D-2), melphalan 140–180 mg/m2 (Day -3) and ethyol 910 mg/m2 (Day-3) in addition to mycophenolate mofetil 1 g q12H and tacrolimus(serum level 5–15 ng/ml) beginning Day -3 as immunosuppressive therapy. Transplantation was done using peripheral blood stem cells from the best HLA-antigen match sibling (allo) or matched unrelated donor (MUD). We retrospectively compared transplant data from this original protocol to a modified RICR protocol (Trial B) using a lower dose of melphalan 100mg/m2 and addition of thymoglobulin 2mg/kg/d (D-2 to D0). RESULTS: 46 patients were transplanted in Trial A with median age of 46 years. 25 patients had allogeneic and 21 had MUD transplant. 30 patients were transplanted in Trial B with median age of 44 years. 22 patients had an allogeneic and 8 had a MUD transplant. All patients were heavily pretreated with 13 patients in Trial A and 9 patients in Trial B have undergone at least one previous stem cell transplant. At D30, all patients in Trial B were alive while 11% of patients in Trial A died of treatment related cause. At D100, 51% of patients in Trial A and 70% of patients in Trial B were alive. D100 TRM was 40% in Trial A and 20% in Trial B. Table 1. Treatment Outcome OS(%) TRM (%) RM (%) Trial A Trial B Trial A Trial B Trial A Trial B OS:overall survival TRM:treatment related mortality RM: relapse mortality 30 Days MUD 81 100 19 0 0 0 Allo 96 100 4 0 0 0 Total 89 100 11 0 0 0 100 days MUD 40 63 60 38 0 0 Allo 60 73 24 14 16 14 Total 51 70 40 20 9 10 1 year overall survival was 30% in trial A and 20% in Trial B. 1 year disease free survival (DFS) was 18% in trial A and 13% in Trial B. Table 2. 1 year treatment outcome* Overall Survival(%) Disease Free Survival (DFS) % Trial A Trial B Trial A Trial B *for Trial B, 5 living patients have not yet reached 1 year follow-up MUD 21 13 14 0 Allo 37 23 21 18 Total 30 20 18 13 Incidence of aGVHD≥2 in patients not receiving DLI and alive for more than 30 days post transplant was 56% in Trial A (MUD 67%, Allo50%) and 25% in Trial B (MUD63%, Allo 6%). At D100, aGVHD was the most common cause of death in Trial A while overwhelming sepsis was leading cause of death in Trial B. WBC engraftment with ANC&gt;500 was achieved in 98% of patients in Trial A and 93% of patients in Trial B. Average day of engraftment was 13 days in Trial A and 15 days in Trial B. Platelet engraftment with platelet count at least 20,000 was achieved in 80% of patients in both protocols with average day of engraftment at 18 days in Trial A and 21 days in Trial B. 95% of patients in Trial A had achieved at least 80% donor marrow cells at D100 while only 81% achieved this level of chimerism in Trial B. CONCLUSION: The modified RICR protocol for HSCT is a tolerable regimen which results in a lower incidence of D100 TRM and aGVHD but overall and disease free survival are not improved. Marrow engraftment is achieved although slightly delayed compared to the original protocol.

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.

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