Clofarabine Salvage Therapy Prior To Allogeneic Hematopoietic Stem Cell Transplantation In Patients With Relapsed Or Refractory AML – Results Of The Bridge Trial –

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 304-304
Author(s):  
Jan Moritz Middeke ◽  
Regina Herbst ◽  
Stefani Parmentier ◽  
Gesine Bug ◽  
Mathias Hänel ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Disease Free Survival ◽  
High Rate ◽  
Unrelated Donor ◽  
Free Survival ◽  
Unrelated Donors ◽  
Disease Free ◽  
Refractory Aml

Abstract Background In relapsed or refractory acute myeloid leukemia (AML) long-term disease-free survival may only be achieved with allogeneic stem cell transplantation (HSCT). However, only about 40% of patients (pts) with relapsed AML receive HSCT. A number of factors contribute to this low rate, among them, a moderate activity of currently available salvage regimens and accumulating toxicity of chemotherapy. Clofarabine is considered to have a favorable risk-benefit ratio in this indication and has been successfully used in conditioning regimens. Our goal was to study the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT. Here, we report the results of the BRIDGE trial (NCT 01295307), a phase II, multicenter, intent-to-transplant study. Patients and Methods Between March 2011 and May 2013, 84 pts with relapsed or refractory AML older than 40 years were enrolled. Pts were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2 days 1-5). Pts with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2 day -6 to -3 and melphalan 140 mg/m2 on day -2. In pts with partially matched unrelated donors ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil. Results Median age was 61 years (range 40 – 75). Forty-four pts suffered from relapsed AML and 40 pts had refractory disease. According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as interm. I, 17% as interm. II and 20% as adverse risk. Complex and monosomal karyotypes were present in only 12% and 10% of pts, respectively. FLT3, NPM1 and CEPBA mutations were found in 16%, 24%, and 4% of the pts. The mean value of the HCT-CI score was 1.6 (range 0 - 7) at the time of study enrollment and 2.3 (range 0 - 7) at the time of conditioning. The overall response rate assessed at day 15 after start of CLARA was 80% (46% good response defined as less than 10% blast in the bone marrow (BM) and 33% moderate response with at least a marked reduction in BM blasts or BM cellularity and absence of blast in the peripheral blood). Seventeen pts did not respond to CLARA and were subsequently treated off study. Due to early death, three pts were not evaluable for treatment response. Overall, 66% of the pts received HSCT within the trial. Donors were HLA-identical siblings in eight pts (14%), HLA-compatible unrelated donors in 30 pts (55%) and unrelated donors with one mismatch in 17 pts (31%). Treatment success defined as complete remission, CR with incomplete recovery or >95% BM donor chimerism and an absolute neutrophil count >0.5 /nL on day 35 after HSCT was achieved in 62% of the pts. Disease-free survival (DFS) is shown in Figure 1. With a median follow up of 16 months the OS for all enrolled patients at one year is 51% (95% CI, 39% to 63%). At the time of enrollment, 14% had a related donor and 33% had an unrelated donor. In 46% of the pts donor search was initiated at the time of enrollment. For 7% of pts donor search was not successful. Time from study entry to HSCT was remarkably low with a median of 33 days (range 19 – 116 days). Of note, time interval did not differ between related and unrelated donors (Figure 2). Day 30 and day 100 mortality, which covered salvage therapy and HSCT, was 9% and 27%, respectively. Six out of seven pts who died within the first 30 days hat refractory AML and thus entered the trial already with a history of long-lasting neutropenia. Liver toxicity was the most frequent adverse event. Fifty percent of the pts had transiently elevated liver enzymes CTCAE grade III considered to be related to clofarabine. Twenty-one patients developed CTCAE grade III – IV sepsis throughout the study treatment. GvHD grade II – IV and III-IV until day 100 after HSCT occurred in 36% and 21% of the pts, respectively. Conclusions This intent-to transplant study allows for a realistic estimate for the outcome of elderly pts with relapsed or refractory AML. We demonstrate a high rate of leukemia-control by CLARA. Fast unrelated donor search and work up and conditioning with clofarabine and melphalan in aplasia allowed for a high rate of successful HSCTs. While the long-term results require longer follow-up the overall results are promising. Disclosures: Middeke: Genzyme: Speakers Bureau. Schetelig:Genzyme: Research Funding. Off Label Use: Clofarabine, not approved for AML.

scholarly journals – Updated Results from the Bridge Trial: Long-Term Survival and Impact of Donor Availability – Clofarabine Salvage Therapy Prior to Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed or Refractory AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1204-1204
Author(s):  
Jan Moritz Middeke ◽  
Regina Herbst ◽  
Stefani B Parmentier ◽  
Gesine Bug ◽  
Mathias Hänel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Salvage Therapy ◽  
Treatment Success ◽  
Unrelated Donor ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Unrelated Donors ◽  
Refractory Aml

Abstract Background: In relapsed or refractory acute myeloid leukemia (AML), long-term disease-free survival may only be achieved with allogeneic hematopoietic stem cell transplantation (HSCT). Within the BRIDGE Trial, the safety and efficacy of a clofarabine salvage therapy as a bridge to HSCT was studied. Here, we report long-term survival data and the impact of donor availability at the time of study enrollment. The BRIDGE trial (NCT 01295307) was a phase II, multicenter, intent-to-transplant study. Patients and Methods: Between March 2011 and May 2013, 84 patients with relapsed or refractory AML older than 40 years were enrolled. Patients were scheduled for at least one cycle of induction therapy with CLARA (clofarabine 30 mg/m2 and cytarabine 1 g/m2, days 1-5). Patients with a donor received HSCT in aplasia after first CLARA. In case of a prolonged donor search, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine 30 mg/m2, day -6 to -3, and melphalan 140 mg/m2 on day -2. In patients with partially matched unrelated donors, ATG (Genzyme) at a cumulative dose of 4.5 mg/kg was recommended. GvHD prophylaxis consisted of CsA and mycophenolate mofetil. Results: Forty-four patients suffered from relapsed AML and 40 patients had refractory disease. The median patient age was 61 years (range 40 – 75). According to the current ELN risk stratification 17% of pts were classified as favorable risk, 35% as intermediate I, 17% as intermediate II and 20% as adverse risk. The overall response rate assessed at day 15 after start of CLARA was 80% (defined as at least a marked reduction in BM blasts or BM cellularity and absence of blasts in the peripheral blood) with 31% of patients having less than 5% BM blasts at that time. Seventeen patients did not respond to CLARA, and were subsequently treated off-study. Due to early death, three patients were not evaluable for treatment response. Overall, 66% of the patients received HSCT within the trial. Donors were HLA-identical siblings in eight cases (14%), HLA-compatible unrelated donors in 30 cases (55%) and unrelated donors with one mismatch in 17 cases (31%). Treatment success was defined as complete remission (CR), CR with incomplete recovery (CRi) or CRchim (BM donor chimerism >95% and absolute neutrophil count >0.5/nL) on day 35 after HSCT. Treatment success was achieved in 61% of the patients. With a median follow up of 25 months, the OS for all enrolled patients at two years was 42% (95% CI, 32% to 54%). (Figure 1) The Leukemia-free survival at two years for those 51 patients who achieved the primary endpoint was 52% (95% CI, 40% to 69%). (Figure 2) At the time of enrollment, 14% of patients had a related donor and 33% had an unrelated donor available. In 46% of the patients, donor search was initiated at the time of enrollment. For 7% of patients, donor search was unsuccessful prior to enrollment and reinitiated. The OS at 2 years for patients with a related or an unrelated donor available was 75% (95% CI, 54% to 100%) and 47% (95% CI, 31% to 71%), respectively, while it was 29% (95% CI, 18% to 48%) for patients for whom donor search was initiated at time of enrollment (p = .09). Conclusions: Salvage therapy with CLARA, and subsequent conditioning with clofarabine and melphalan prior to allogeneic HSCT, provides good anti-leukemic activity in patients with relapsed or refractory AML. Fast unrelated donor search and work up, with conditioning in aplasia allowed a high rate of successful HSCTs. The leukemia-free survival for this group of elderly, high risk AML patients is very promising. Figure 1 Figure 1. Overall survival for all patients, n=84 Figure 2 Figure 2. Leukemia-free survival for all patients with primary treatment success, n=51 Disclosures Middeke: Genzyme: Speakers Bureau. Off Label Use: Clofarabine for AML. Schetelig:Genzyme: Research Funding; DKMS German Bone Marrow Donor Center: Employment.

scholarly journals Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial

2019 ◽  
Vol 37 (2) ◽  
pp. 105-114 ◽  
Author(s):  
Thomas Ruhstaller ◽  
Anita Giobbie-Hurder ◽  
Marco Colleoni ◽  
Maj-Britt Jensen ◽  
Bent Ejlertsen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Contralateral Breast Cancer ◽  
Disease Free Survival ◽  
Luminal Breast Cancer ◽  
Free Survival ◽  
Long Term Follow Up ◽  
Disease Free

Purpose Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. Patients and Methods BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. Results Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. Conclusion Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.

5-Year Results of Dose-Intensive Sequential Adjuvant Chemotherapy for Women With High-Risk Node-Positive Breast Cancer: A Phase II Study

1999 ◽  
Vol 17 (4) ◽  
pp. 1118-1118 ◽  
Author(s):  
C. Hudis ◽  
M. Fornier ◽  
L. Riccio ◽  
D. Lebwohl ◽  
J. Crown ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Pilot Study ◽  
Adjuvant Chemotherapy ◽  
Disease Free Survival ◽  
Free Survival ◽  
Dose Dense ◽  
Disease Free

PURPOSE: We conducted a phase II pilot study of dose-intensive adjuvant chemotherapy with doxorubicin followed sequentially by high-dose cyclophosphamide to determine the safety and feasibility of this dose-dense treatment and to estimate the disease-free and overall survival in breast cancer patients with four or more involved axillary lymph nodes. PATIENTS AND METHODS: Seventy-three patients received adjuvant treatment with four cycles of doxorubicin 75 mg/m2 as an intravenous bolus every 21 days, followed by three cycles of cyclophosphamide 3,000 mg/m2 every 14 days with granulocyte colony-stimulating factor support. RESULTS: Seventy-one patients were assessable, and all but two completed all planned chemotherapy. There was no treatment-related mortality. The most common toxicity was neutropenic fever, which occurred in 39% of patients. Median disease-free survival is 66 months (95% confidence interval, 34 to 98 months), and median overall survival has not yet been reached. At 5 years of follow-up, the disease-free survival is 51.7%, and overall survival is 60.0%. There is no long-term treatment-related toxicity, and no cases of acute myelogenous leukemia or myelodysplastic syndrome have been observed. CONCLUSION: Our pilot study of doxorubicin followed by cyclophosphamide demonstrates the safety and feasibility of the sequential dose-dense plan. Long-term follow-up, although noncomparative, is promising. However, this regimen is associated with a higher incidence of toxicity (and also higher costs) than the standard dose and schedule of doxorubicin and cyclophosphamide, and therefore it should not be used as conventional therapy in the absence of demonstrated improvement of outcome. Randomized trials testing the dose-dense approach have been completed but not yet reported. Because the sequential plan can decrease overlapping toxicities, it is an appropriate platform for the addition of newer active agents, such as taxanes or monoclonal antibodies.

Nonmyeloablative Conditioning and Hematopoietic Cell Transplantation (HCT) from HLA-Matched Related or Unrelated Donors for Chemotherapy-Refractory Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2323-2323
Author(s):  
Mohamed Sorror ◽  
Michael Maris ◽  
Barry Storer ◽  
Brenda Sandmaier ◽  
Monic Stuart ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Gvhd ◽  
Disease Free Survival ◽  
Cerebral Stroke ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Increased Risk ◽  
Unrelated Donors ◽  
Disease Free

Abstract Sixty-four patients (pts) with chemotherapy-refractory CLL who were ineligible for ablative allogeneic HCT due to age and/or comorbidities were given nonablative-HCT from related (n=44) or unrelated donors (n=20) between 1997-2003 (Table). Median pt age was 56 (range 44–69) years, interval from diagnosis to HCT was 4.4 (3–25) years, and number of prior regimens was 4 (range 1–12). Sixty-one pts were refractory to at least 1 regimen, 56 to fludarabine (FLU), 19 to alkylating agents, 14 to rituxumab and 4 to CAMPATH, and 2 had failed autologous HCT. Twenty-three pts (36%) had disease responsive to last chemotherapy [28% partial (PR) and 8% complete remission (CR)] while 34 were nonresponsive and 7 had untested relapse. Conditioning for HCT consisted of 2 Gy TBI alone (n=11) or combined with FLU (n=53), 90 mg/m2. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Pts received G-CSF mobilized peripheral blood mononuclear cells. After HCT, pts became neutropenic for a median of 11 days. Forty-four percent of pts had thrombocytopenia (<20,000 cells/ul). Three pts had graft rejection; 1 died with aplasia and 2 are alive with disease relapse. Incidences of grades II, III, and IV acute GVHD were 39%, 14%, and 2% respectively, and chronic GVHD was 50% at 2-years. With median follow up of 24 (range 2.8–62.8) months, the overall response rate was 67% (50% in CR). URD-pts had significantly higher CR rate than MRD-pts. All 11 responding patients tested had molecular eradication of their disease. Overall, 39 patients are alive; 25 in CR, 5 in PR, 2 with stable disease, and 7 with relapse/progression. Twenty-five pts died, 10 from progression, 10 from infections ± GVHD, 2 from cardiac causes, 1 from metastatic lung cancer, 1 from cerebral stroke and 1 from rejection and aplasia. Estimated 2-year rates of non-relapse mortality, disease free survival, and overall survival were 22%, 52%, and 60% respectively. In multivariate analysis, high pretransplant comorbidity scores predicted higher non-relapse mortality and worse survival while bulky lymphadenopathy predicted increased risk of progression. CLL appears susceptible to graft-versus-leukemia effects particularly after URD grafts and nonablative-HCT should be explored in phase II trials in pts with FLU-refractory CLL. Table: Results Related (n = 44) Unrelated (n = 20) P Acute GVHD grade II, III, and IV 39%, 11%, and 2% 40%, 20%, and 0% 0.41 2-year chronic extensive GVHD 44% 69% 0.56 Median follow up (range) 31 (3–63) months 12 (3–39) months CR at 2-years 42% 78% 0.005 Relapse/progression at 2 years 34% 5% 0.08 Surviving pts 13 CR, 3 PR, 2 stable, 5 progression, 1 relapse 12 CR, 2 PR, 1 relapse 2-year non-relapse mortality 22% 20% 0.75 2-year disease free survival 44% 75% 0.15 2-year overall survival 56% 74% 0.33

Age and Response after Autologous Stem Cell Transplantation (ASCT) Define a Group of Long-Term Event-Free Survivors among Patients (Pts) with Low-Grade Follicular Lymphoma (FL): A Single Institution Experience.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1883-1883
Author(s):  
Charalambos Andreadis ◽  
Elise A. Chong ◽  
Edward A. Stadtmauer ◽  
Selina M. Luger ◽  
David L. Porter ◽  
...  
Keyword(s):  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Autologous Bone Marrow ◽  
Large Cell ◽  
High Dose ◽  
Low Grade ◽  
Free Survival ◽  
Disease Free

Abstract Introduction: FL is generally responsive to conventional-dose chemotherapy but long term disease-free survival (DFS) is uncommon. High-dose chemo-radiotherapy followed by ASCT has the potential to induce remission in this disease but the long-term benefit of this modality remains to be determined. Methods: Between 1990 and 2003, we transplanted 52 pts originally diagnosed with low-grade FL (31 grade 1, 21 grade 2). Twenty-five (48%) had biopsy-proven large cell transformation (FL grade 3 or diffuse large cell lymphoma) before ASCT. The median number of prior therapies was 2 (range: 1 to 7). Prior to ASCT, 45 pts (87%) were responsive to salvage therapy with 20 pts (38%) in CR. Five pts (10%) had chemo-resistant disease at the time of ASCT. High-dose regimens included BCNU-cyclophosphamide-etoposide (31%), melphalan/TBI (27%), and cyclophosphamide/TBI (25%). Thirty-eight pts (73%) received peripheral stem cells (PSCT) and 14 pts (27%) received autologous bone marrow (BM) with 4-hydroxyperoxycyclophosphamide (4-hc) purging in 9 cases (17%). The median age was 49 yrs (range: 29–65). Results: There was 1 treatment-related death during the first 100 days. After ASCT, 36 pts (69%) achieved a CR, 2 (4%) had a PR, and 7 (13%) had stable disease. Among those in CR, 20 (56%) had a CR pre-ASCT, 14 (41%) had a lesser response, and 1 (3%) was chemo-resistant. Median follow-up (f/u) of survivors was 5.3 yrs (range: 1.7 months to 12.4 yrs). The median overall survival (OS) has not yet been reached. The median event-free survival (EFS) is 3.4 yrs (range: 1.7 months to 12.4 yrs). Among complete responders, more than 50% are disease free at last follow-up (range 1.7 months to 12.1 yrs). Variables favorably affecting EFS and OS are age < 60 yrs (p = 0.007, 0.015 respectively), achievement of a CR after ASCT (p = 0.002, 0.001), absence of transformation (p = 0.038, 0.017), BM vs. PSCT (p = 0.042, 0.086), and 4-hc BM purging (p = 0.044, 0.059). Number of prior regimens, response prior to ASCT, type of preparative regimen, and addition of TBI, were not significantly associated with EFS, DFS, or OS. In multivariable analysis, achievement of CR after ASCT and age < 60 yrs are the only significant predictors of EFS and OS. Adjusted for age, 53% of pts with a CR after ASCT are alive and event-free at last f/u (range: 2.4 months to 12.4 yrs) (Figure 1). In contrast, the median EFS among pts without a CR is 0.5 yrs (range: 1.7 months to 5.3 yrs). Conclusion: ASCT is a reasonable therapeutic approach to FL, resulting in long term EFS for some pts, even with relapsed, refractory and/or transformed disease. In our experience, significant predictors of EFS and OS after ASCT are complete response and age <60. The appropriate application and timing of ASCT in the management of pts with FL needs to be further evaluated in randomized, controlled clinical trials. Figure Figure

Second Allogeneic Bone Marrow Transplantation for Patients with Either Graft Failure or Relapsed Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1770-1770
Author(s):  
Stella Santarone ◽  
Erminia Di Bartolomeo ◽  
Pasqua Bavaro ◽  
Paolo Di Carlo ◽  
Paola Olioso ◽  
...  
Keyword(s):  
Graft Failure ◽  
Malignant Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Allogeneic Bone ◽  
Free Survival ◽  
Disease Free ◽  
Median Interval

Abstract Despite myeloablative and immunosuppressive conditioning therapy, allogeneic bone marrow transplantation (BMT) may fail because of either graft failure or relapse of the malignant disease. In this study we have evaluated the impact of second BMT on long-term disease-free survival (DFS) in 42 patients who were transplanted in our institution between January 1983 and March 2005. GRAFT FAILURE. Eleven patients (4 with aplastic anemia, 4 thalassemia major (TM), 3 chronic myeloid leukemia (CML), 2 acute myeloid leukemia (AML), 1 acute lymphoblastic leukemia (ALL), 1 myelodisplastic syndrome (MDS) received a second BMT for graft failure, either primary (n=8) or secondary (n=3). The median age at time of first BMT was 19 years (range, 3 to 42). The median interval between the first and second BMT was 35 days (range, 27 to 532). Donors were the same of the first BMT. They were HLA genotipically identical (n=8) or HLA phenotipically identical (n=1) or 1 antigen mismatched family members. Four patients died for BMT related causes (2 for acute GvHD, 1 for heart failure and 1 for CNS hemorrhage and rejection). Six patients are now living after a median follow-up of 169 months (range, 52 to 202). Five patients are cured and one had an autologous thalassemia reconstitution and is now living under transfusion treatment. RELAPSE. Thirty-one patients (11 with CML, 9 AML, 9 ALL, 1 MDS, 1 TM) were given a second BMT following relapse of the malignant disease. The median age at time of first BMT was 27 years (range, 1 to 43). The median interval between the first and second BMT was 528 days (range, 115 to 5584 ). Thirty patients received the second BMT from the same HLA genotipically identical family member used for the first transplant. One patient was given the first BMT from a matched unrelated donor and the second transplant from an haploidentical brother. The 6 months transplant related mortality (TRM) was 19%. Six patients died for BMT related causes (4 for acute GvHD, 1 for heart failure and 1 for infection and multiorgan failure). Eight patients had leukaemia relapse following second BMT. Five of them died of chemotherapy complications. One of them, who was reinducted into complete remission and received a third BMT from an unrelated donor, died because encephalopathy. Nineteen patients are living after a median follow-up of 72 months (range, 4 to 236). The 5-years probabilities of overall survival and disease free survival (DFS) were 59% and 52% respectively. The 5-years DFS for AML, CML and ALL patients was 72%, 54% and 12% respectively (p=0.03). The 5-years DFS for 17 patients conditioned with TBI and for 13 patients conditioned with busulphan (BU) was 62% and 31% respectively (p=0.09). This study show that many patients may benefit from a second BMT either following graft failure or leukemia relapse with an acceptable TRM. In particular, patients with AML or CML are the best candidates to be cured from second BMT. TBI conditioning regimen gives better results as compared to BU regimen.

Impact of Molecular Markers and Cytogenetic Abnormalities on Long-Term Overall Survival and Disease-Free Survival after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Acute Myeloid Leukemia (AML) patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4476-4476
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Xavier Thomas ◽  
Carole Charlot ◽  
Fiorenza Barraco ◽  
...  
Keyword(s):  
Molecular Markers ◽  
Myeloid Leukemia ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Cytogenetic Abnormalities ◽  
Allogeneic Hsct ◽  
Disease Free

Abstract We performed a retrospective analysis from our transplant registry on first allogeneic hematopoietic stem cell transplantations (HSCT) for acute myeloid leukemia (AML) patients (pts) between 1996 and 2007. Our principal objective was to analyze the impact of molecular markers on the long-term overall and disease-free survival (OS and DFS) after first allogeneic HSCT. We found 364 pts, only 63 pts had retrospectively available conserved cells at diagnosis. The expression levels of WT1, Evi1, Flt3 and Hoxa9 were performed by quantitative RT-RQPCR. The mutational status of MLL duplication, FLT3 (internal tandem duplication or nucleotide substitutions) (ITD), NPM1 and CEBPα were determined by PCR, RFLP and/or sequencing analysis. All pts except 1 had a karyotype analysis at diagnosis. Among these 63 pts, there were 27 (43%) males and 36 (57%) females, with a median age of 41 years (18-64). The FAB classification was M0: 6, M1: 10, M2: 13, M4: 6, M5: 21, M6: 3, M7: 1 and 3 unclassified. Concerning the karyotype analysis, 25 (40%) pts had a normal karyotype, 37 (60%) pts presented cytogenetic abnormalities classified as favourable prognosis in 5 cases (8%), intermediate in 13 cases (21%) and poor in 19 cases (31%). Regarding the molecular markers evaluated in all pts: 4(6%) pts had Flt3over-expressed (ov-ex), 19 (30%) FLT3 ITD+, 3 (5%) MLLdup, 10 (16%) Hoxa9 ov-ex, 7 (11%) Evi1 ov-ex, 15 (24%) NPM1mut+, 25 (40%) WT1 ov-ex and 1 CEBPαmut+ (this marker was evaluated only in 12 pts). Associations between these markers and the karyotype prognosis groups are shown in Figure1. Twenty three (36%) pts had no abnormal molecular markers and 40 (54%) pts had at least one abnormal marker: 10 (16%) 1 marker, 10 (16%) 2 markers, 12 (19%) 3 markers, 4 (6%) 4 markers and 4 (6%) 5 markers. Concerning the karyotype, among the 23 negative molecular pts, 22 have been evaluated and there were 9 (41%) normal, 11 (50%) poor and 2 (9%) favourable; and among the 40 positive pts, 16 (40%) were normal, 8 (20%) poor, 13 (32.5%) intermediate and 3 (7.5%) favourable. Concerning transplantation, 50% of HSCT were done after 2004 and the median interval between diagnosis and transplantation was 6 months (2.6–68.5). Before conditioning, 41 pts were in CR (26 CR1, 14 CR2 and 1 CR3), 8 in PR and 14 in relapse. Twenty five (40%) pts received a non-myelo-ablative conditioning and 38 (60%) a myelo-ablative one. There were 34 sex-mismatched (21 M→F and 13 F→M), 21 ABO incompatibility (6 minor and 15 major), 55 were HLA matched and 8 mismatched. Twenty three (36.5%) pts received PBSC, 37 (59%) bone marrow and 4 (6.5%) cord blood cells from 47 (75%) HLA siblings and 16 (25%) unrelated donors. After transplantation, 59 (94%) pts engrafted, 42 developed AGVHD (21gr1, 13 gr2 and 8 gr4), and among 51 evaluable pts, 13 developed cGVHD (7 limited and 6 extensive). At the last follow-up, 20 pts have relapsed, 29 pts are alive (28 CR and 1PR) and 34 died [18 (53%) from TRM and 16 (47%) from relapse]. At the median follow-up of 48 months, the OS and DFS for the whole population were 40% (33–47) and 40% (34–46) respectively with a maximum follow-up of 130 months and for the different subgroups according to karyotype and molecular markers the results are shown in Table 1. The univariate analysis showed a significant impact of FLT3 ITD and over-expression of FLT3RQ on long-term DFS, (p=0.03 and p=0.02 respectively), and a trend on long-term OS (p=0.08). Concerning the karyotype and some other markers (MLL, EVI1, NPM1 and Hoxa9), we did not observe any significant difference because of small number of pts in some subgroups. The known benefic impact of NPM1mut+, was erased because the majority of this group presented an associated FLT3 ITD+. In addition, we are performing a multivariate analysis that will be presented. In conclusion, allogeneic HSCT in this high risk population of AML pts, allowed a good probability of long-term OS and DFS, despite the presence of high number of bad molecular markers and cytogenetic abnormalities. Finally, AML pts with FLT3 ITD+ seem not benefit from allogeneic HSCT as well as patients with NPM1mut+ associated with FLT3ITD+. Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Figure 1. Frequencies and distribution of different molecular markers and karyotype subgroups Table 1. OS and DFS according to different molecular markers and karyotype subgroups

One Antigen HLA-Mismatched Related and 8/8 Allele Matched Unrelated Donors Are Associated with Similar Survival after Hematopoietic Cell Transplantation for Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 965-965
Author(s):  
David Valcarcel ◽  
Fangyu Kan ◽  
Tao Wang ◽  
Stephanie J. Lee ◽  
Stephen R Spellman ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Unrelated Donor ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Unrelated Donors ◽  
Related Donor ◽  
Disease Free

Abstract Patients in need of an allogenetic hematopoietic cell transplant but who lack an HLA genotypically identical sibling donor, are faced with the decision to consider a single HLA antigen mismatched related donor, or a search for a suitable 8/8 matched unrelated donor. We compared the outcomes of adult patients (≥18 years old) receiving a transplant for the treatment of AML or ALL in first or second remission from either a one-antigen mismatched related donor (MMRD group, N=89) reported to the CIBMTR or an 8/8 HLA-A, B, C and DRB1 allele matched unrelated donor (UD group, N=700) facilitated by the NMDP between 1995–2005. MMRD group was typed by serological or DNA-based methods for HLA-A, -B and –DR with all results verified by lab report review. The UD group was retrospectively typed for HLA-A, B, C and DRB1 by high resolution typing methods. Most received myeloablative conditioning regimens (77%), calcineurin inhibitor-based GVHD prophylaxis (100%) and T cell replete grafts (100%). 13% received ATG with the conditioning regimen. Median follow-up was 54 and 38 months in the MMRD and UD groups, respectively. The MMRD group was younger (median age 35 vs 43, p=0.002), had more ALL patients with low-risk cytogenetics (43% vs 18%, p=0.005), had older donors (median age: 38 vs 34, p=0.047), were more likely to receive methotrexate for GVHD prophylaxis (89% vs 77%, p=0.014) and were more likely to be transplanted prior to 2001 (62% vs 24%; p<0.001). There were no differences in patient or donor gender, diagnosis, disease-status, cytogenetic-risk of AML, time from diagnosis to transplant, stem cell source, conditioning regimen, use of ATG and Karnofsky index. Univariate comparisons (MMRD vs. UD) showed: 3-year OS (42% vs 44%, p=0.647), 3-year DFS (41% vs 41%, p=0.931), 3-year TRM (39% vs 31%, p=0.136), 3-year incidence of relapse (20% vs 28%, p=0.094), grade III–IV acute GVHD by 100 days (22% vs. 15%, p=0.147), chronic GVHD by 1 year (35% vs 47%, p=0.029). All multivariate analyses were adjusted for patient and transplant characteristics and are shown in the table below. In summary, transplants utilizing one-antigen mismatched related and 8/8 allele-matched unrelated donors did not significantly differ in overall survival or disease free survival, but chronic GVHD was more frequent after UD transplantation. Outcome RR (MMRD vs. UD) 95% CI p-value Survival 0.99 0.73–1.34 0.94 Disease-free survival 1.06 0.80–1.41 0.69 Treatment related mortality 1.14 0.77–1.69 0.52 Relapse 0.81 0.50–1.30 0.38 Acute GVHD III–IV 1.53 0.91–2.57 0.11 Chronic GVHD 0.58 0.39–0.85 0.006

The Role of Hematopoietic Cell Transplantation (HCT) for Burkitt Lymphoma: a Report From the Center for International Blood and Marrow Transplant Research (CIBMTR)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2390-2390
Author(s):  
James L. Gajewski ◽  
Jeanette Carreras ◽  
Hillard M. Lazarus ◽  
Ginna G. Laport ◽  
Silvia Montoto ◽  
...  
Keyword(s):  
Burkitt Lymphoma ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
B Cell Lymphoma ◽  
Unrelated Donor ◽  
Free Survival ◽  
Disease Free

Abstract Abstract 2390 Burkitt lymphoma (BL) is an aggressive B cell lymphoma primarily affecting children and young adults and is characterized by the highest doubling time of any tumor. Cyclical intensive chemotherapy and rituximab confer high complete remission (CR) rates and 80% long term disease free survival in chemotherapy sensitive disease. The role of autologous (autoHCT) or allogeneic (alloHCT) transplant is not well described in BL. We report the outcomes of 241 recipients of HCT for BL between 1985 and 2007 reported to the CIBMTR. Five patients (pts) received syngeneic twin grafts in addition to autoHCT in 113 pts, HLA identical sibling alloHCT (SIB) in 80 pts and mismatched related or unrelated donor (UNR/MM) alloHCT in 48 pts. Baseline patient and disease related risk factors varied significantly between cohorts (table1). The autoHCT cohort had a higher proportion of pts with chemotherapy sensitive disease (86%), peripheral blood grafts (73%) and HCT in first CR (42%). In the UNR/MM cohort, 25% pts were chemotherapy resistant and only 6% were in CR1. The use of autoHCT has declined in recent years with the majority (81%) performed before 2001. Conditioning regimen for alloHCT was myeloablative in 88% (86% and 92% in SIB and UNR/MM respectively). Treatment related mortality (TRM) was higher in alloHCT recipients (table1). Cumulative incidence of relapse/progression at 5 yrs (95% CI) was 44 (35-53)% for autoHCT, 42(31-53)% for SIB and 48 (34-62)% for UNR/MM. For autoHCT, 5-yr progression free survival (PFS) was 48(39-58)%, 78% for those in first CR versus 27% for disease beyond CR1 (p<0.001). For alloHCT, 5-yr PFS was 50% for those in first CR versus 19% for disease beyond CR1 (p=0.001) (figure 1). 5-yr PFS was 30 (20-41)% for SIB and 22 (12-35)% for UNR/MM. Progressive BL was the commonest cause of death. Conclusion: While autoHCT and alloHCT are both feasible in patients with BL, the use of autoHCT appears to be declining in recent years concomitant with the advent of modern chemotherapy. AlloHCT was performed in those with considerably higher risk disease. Approximately one fifth of advanced BL pts receiving alloHCT beyond CR1 had long term disease free survival. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document