Relapsed acute megakaryoblastic leukemia in Down syndrome (AMKL-DS) may be cured with chemotherapy alone, without stem cell transplantation (HSCT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17543-17543
Author(s):  
S. Jayabose ◽  
C. Sandoval ◽  
O. Levendoglu-Tugal ◽  
M. F. Ozkaynak
Keyword(s):  
Down Syndrome ◽  
Good Health ◽  
Lung Lesion ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
Megakaryoblastic Leukemia ◽  
Transient Leukemia ◽  
High Dose Cytarabine ◽  
Disease Free

17543 Background: Children with recurrent AMKL -DS have an extremely poor prognosis without HSCT. Methods: We report a case of a relapsed AMKL-DS cured with intensive chemotherapy alone, without HSCT. Results: A 19 month old boy with Down syndrome, who had transient leukemia as a newborn, developed AMKL-DS (GATA1 positive) and was treated with four cycles of CI-TAD: continuous infusion of cytarabine and daunorubicin, and oral thioguanine for four days, and intrathecal cytarabine; followed by two cycles of high dose cytarabine plus L-Asparaginase; and three weekly doses of intrathecal cytarabine. Although he achieved remission at the completion of first cycle of the induction chemotherapy, he relapsed within 6 weeks after the completion of therapy. He then received the following chemotherapy over the next six months: Cycle 1 and 2. High dose Ara-C ( 33. 3 mg/kg q 12 hours x 8 doses) on days 0 to 3 plus mitoxantrone 0. 4 mg/kg/day x 4 on days 3 to 6 Cycle 3. High dose Ara-C 33. 3 mg/kg q 12 hours x 8 doses Cycle 4 and 5 (FLAG): Fludarabine 0. 8 mg/kg/day x 4 plus Ara-C 67 mg/kg/d x 4 and G-CSF 10 mcg/kg/day x 4 all on days 0 to 3. He achieved complete remission after the 1st cycle of chemotherapy, and underwent further cycles of chemotherapy while waiting for HSCT from an unrelated donor. But after the 5th cycle of chemotherapy, he developed a pulmonary lesion of fungal etiology for which he received three months of therapy with liposomal amphotericin. Because of a persistent lung lesion on imaging, he was considered ineligible for HSCT, and no further therapy was given. His bone marrow aspirate after the 3rd cycle of therapy was negative for GATA1. He has been disease-free for 59 months after the completion of his last cycle of chemotherapy, and he is currently in good health without any evidence of pulmonary or cardiac dysfunction. Conclusions: Intensive chemotherapy alone, without HSCT, may be curative for relapsed AMKL- DS. No significant financial relationships to disclose.

Philadelphia Chromosome Negative (Ph-) Very High Risk (VHR) Acute Lymphoblastic Leukemia (ALL) in Children and Adolescents: The Impact of Intensified Chemotherapy on Early Event Free Survival (EFS) in Children’s Oncology Group (COG) Study AALL0031.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 911-911 ◽  
Author(s):  
Kirk R. Schultz ◽  
William Paul Bowman ◽  
William Slayton ◽  
Alexander Aledo ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Chemotherapy Regimen ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
High Dose Cytarabine ◽  
Induction Failure ◽  
The Impact ◽  
Very High

Abstract Background: VHR patients eligible for COG AALL0031 had an expected 5-year EFS ≤ 40% and consisted of those with Ph+ ALL, severe hypodiploidy (<44 chromosomes), and induction failure (IF) with >25% blasts at the end of standard induction therapy. Patients with hypodiploidy and IF are the subject of this report. Ph+ patients were reported previously (Blood Schultz KR, et. al. Blood2006; 108:87a.). Methods: Between 10/14/02 and 10/20/06, 63 evaluable patients (41 hypodiploidy and 22 IF) were enrolled in AALL0031 after completion of a 3- or 4-drug induction, and begun on an intensive chemotherapy regimen. Induction failure patients not entering complete remission (CR) after the first two chemotherapy cycles, ifosfamide and etoposide (cycle 1) and IV cyclophosphamide, IV etoposide) followed by high dose methotrexate and high dose cytarabine (cycle 2), were removed from study. Remission patients were assigned to 8 cycles of standard maintenance. All patients received triple intrathecal chemotherapy followed by cranial irradiation. An HLA-identical blood and marrow transplantation (BMT), by donor availability or to an intensive ~2.2 year chemotherapy regimen. The intensive chemotherapy regimen included a reinduction block (daunomycin, cyclophosphamide, vincristine, L-asparaginase, dexamethasone), intensification block [IV methotrexate (Mtx), etoposide, cyclophosphamide, high dose cytarabine, L-asparaginase], with each block repeated followed by 4 cycles of intensive maintenance (high dose Mtx, PO Mtx, IV vincristine, PO 6-MP). Unrelated donor BMT was not an option on AALL0031. Results: Twenty-one of 22 (95%) IF patients achieved CR after two cycles of therapy. Of these, 12 continued chemotherapy, 2 underwent BMT, and 7 were taken off protocol for an unrelated donor BMT. At 2-years, the EFS for IF patients was chemotherapy (46±17%) or related/unrelated donor BMT (67±17%; p = 0.50). Twenty-eight hypodiploidy patients continued chemotherapy, 12 underwent related donor BMT and 1 was taken off protocol for an unrelated donor BMT. For hypodiploid patients, the 2 year EFS was 57±10% for those receiving chemotherapy compared to related/unrelated donor BMT (67±14%, p=0.74). These outcomes compared favorably with COG historical controls (n=16, 44±12%; p=0.30). We lack a COG historical control for a comparison with IF patients. We examined minimal residual disease (MRD) at the end of cycle 2 in patients undergoing related/unrelated BMT and those receiving chemotherapy. With MRD > 0.01% (n=9) and < 0.01% (n=6), 2-year EFS was 56±19% and 83±15% (p=0.27), respectively. Chemotherapy groups showed a 2 year EFS for > 0.01% of 57±22% (N = 7) compared to 53±12% for ≤ 0.01% (N=19; p =0.83). Conclusions: The AALL0031 regimen attained a very high CR (95%) for IF patients. Small number severely limited statistical power. We found better outcomes for AALL0031 versus historical data, for allogeneic BMT versus chemotherapy, and MRD negativity versus positivity in BMT patients, although none were statistically significant. Future strategies focused on inducing lower MRD early in therapy may improve outcomes for both chemotherapy and BMT. International collaborations to allow for higher patient accrual should be considered.

Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission.

1992 ◽  
Vol 10 (1) ◽  
pp. 41-46 ◽  
Author(s):  
G J Schiller ◽  
S D Nimer ◽  
M C Territo ◽  
W G Ho ◽  
R E Champlin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Disease Free Survival ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
High Dose Cytarabine ◽  
First Remission ◽  
Disease Free

PURPOSE Despite substantial progress in the treatment of acute myeloid leukemia (AML), fewer than 25% of patients survive free of leukemia for more than 5 years without allogeneic bone marrow transplantation (BMT). In this study we analyzed the results of one or more cycles of high-dose cytarabine-based consolidation chemotherapy as compared with allogeneic BMT in first remission. PATIENTS AND METHODS The results in 28 adult patients, aged 16 to 45 years, who underwent a closely HLA-matched BMT for AML in first remission were compared with those in 54 consecutive, age-matched, adult patients treated with one or more cycles of high-dose, cytarabine-based consolidation chemotherapy. RESULTS After a median follow-up of 4 years, the actuarial risk of leukemic relapse was considerably lower in the transplant group than in the group treated with consolidation chemotherapy (32% +/- 26% v 60% +/- 14%; P = .05). Treatment-related mortality, however, was much higher in the group treated with BMT (32% v 6%, P = .002). The actuarial disease-free survival at 5 years was not significantly different for the two groups (45% +/- 24% v 38% +/- 14%). CONCLUSIONS Our results show that BMT in first remission AML did not offer a disease-free survival advantage over intensive postremission consolidation chemotherapy. Larger studies are needed to identify patients who might benefit most from BMT.

A Study of the Toxicity of Gemtuzumab Ozogamicin in Primary and Relapsed AML, Administered Alone or Simultaneously with Intensive Chemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4512-4512
Author(s):  
Thomas Stauffer Larsen ◽  
Kai G. Schmidt
Keyword(s):  
Response Pattern ◽  
Gemtuzumab Ozogamicin ◽  
Infectious Complications ◽  
Late Relapse ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hepatic Toxicity ◽  
Allogeneic Transplant ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Introduction: Gemtuzumab Ozogamicin (Mylotarg®) is a humanized anti CD33 antibody linked to the cytotoxic drug calicheamicin, which has shown considerable antileukaemic effect in the treatment of relapsed AML. With special regard to its toxicity, we present our preliminary results of Mylotarg treatment when administered on compassionate basis as consolidating monotherapy, or combined with intensive chemotherapy. Patients and methods: A total of 86 doses, corresponding to 65 courses were administered to 49 patients. Indications for Mylotarg treatment ( mono ~ monotherapy; comb ~ combination therapy. No.of courses are shown in parentheses): Primary AML: Reinduction ( mono:1; comb:3). Cytogenetic reinduction ( mono:3; comb:1). Consolidation ( mono:24; comb:2). Relapsed AML: Induction ( mono:4; comb:11). Reinduction ( mono:1; comb:2). Cytogenetic reinduction ( mono:1). Consolidation ( mono:10; comb:2). Results: Up-front consolidation with Mylotarg as monotherapy ( 30 doses; 24 patients; mean Mylotarg dose 5.7 mg/m2). Fever: 51% of doses. Focal infections: 17%. Bacteremia 7%. Biochemical findings: Platelet nadir at day 10 ( < 20 bill./l: 25% doses). Neutrophil nadir at day 11 ( mean count = 0.12 bill./l). Hepatic toxicity ( grade 1; % of doses): Alkaline phosphatase 7%; ALAT: 13%; Bilirubin 0. A similar pattern was seen in the 10 relapsed patients consolidated with Mylotarg as monotherapy. One patient receiving an allogeneic transplant 3 months after Mylotarg treatment developed fatal VOD. Three other patients who undervent allogeneic stem cell transplantation 2, 2 and 3 months, respectively, after the administration of Mylotarg did not experience severe hepatic complications. We compared twelve courses of Mylotarg combined with DaunoXome and high dose cytarabine with ( n=10) or without ( n=2) added fludarabine and etoposide, administered to10 patients in 1st relapse with 8 similar courses but without Mylotarg, administered to 7 patients with similar characteristics regarding age, CR1 duration and cytogenetics ( mean Mylotarg dose 4.4 mg/m2). More cases of grade 3 diarrhea ( 33% vs 13%) and bacteremia ( 67% vs 38%) were seen in the Mylotarg group, in which three patients suffered hypoplastic deaths. One of these patients developed intestinal perforation following postremission treatment. The two other patients, with an early refractory relapse, and a late relapse with high risk chromosomal aberation, respectively, died from infectious complications following 20 and 36 days of profound neutropenia. These 3 patients recieved 5.9, 8.3 and 5.0 mg/m2 respectively, compared to the average Mylotarg dose of 4.4 mg/m2. Conclusion: Mylotarg seems to increase toxicity when added to intensive chemotherapy in relapsed AML. The feasibility of this approach must await further studies evaluating toxicity, appropriate dosing and response pattern. When administered as consolidating monotherapy toxicity is modest.

Does High Dose Cytosine Arabinoside Improves Disease Free Survival for Down Syndrome Acute Myelocytic Leukemia Patients?.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4612-4612
Author(s):  
Mahasen Saleh ◽  
Ashraf Khairy ◽  
Mohammed Al-Mahr ◽  
Hassan El-Solh ◽  
AbdulRahman Al-Musa ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Disease Free Survival ◽  
High Dose ◽  
Acute Myelocytic Leukemia ◽  
Free Survival ◽  
Post Induction ◽  
Myelocytic Leukemia ◽  
Group A ◽  
Group B ◽  
Disease Free

Abstract Acute myelocytic leukemia (AML) in Down Syndrome (DS) children is characterized by a young age of onset (< 2 years), a low white blood cell count and high frequency of Megakaryocytic leukemia. DS children with AML have higher disease free survival (DFS) rates as compared to non DS AML patients. Previous studies have suggested that intensification chemotherapy may not be necessary for the treatment of DS children with AML. The objective of this study was to clarify the effectiveness and toxicities of using high dose Cytosine Arabinoside (HD AraC) intensification in the treatment of DS AML. Clinical data for children (<14 years) with DS AML, diagnosed between September 2000 to May 2005, were retrieved from the hospital data base. Patients were divided into two groups; Group A patients received chemotherapy containing HD AraC, while Group B patients did not. A total of 15 patients were included, eight in Group A and seven in group B. The median age at diagnosis was 22 months (A=23 months, B=22 months). The two groups were matched regarding their clinical and laboratory parameters. There was no significant difference in DFS between groups A and B, 75% and 85% respectively (P = 0.82) at a mean observation period of 42.9 months for group A and 23.12 months for group B. The median time to relapse was 6 months for group A and 8 months for group B. The overall treatment related toxicity was higher in Group A patients but achieved only borderline significance (P = 0.06). However, when toxicity was assessed separately for induction and post induction phases of chemotherapy there were significantly more infectious events (17 v. 2; p=0.0006) in the post induction phase which includes HD AraC intensification in Group A. Even when only serious infections (bacteremia, fungal infection, sepsis) were included in the evaluation this difference persisted (7 v. 1; p=0.0339), with less toxicity for Group B patients. No such difference was noted between the two groups during induction chemotherapy. In conclusion the use of HD AraC in post-induction intensification phases for DS AML children does not improve DFS and is associated with more treatment related toxicity.

Autologous Transplantation in De Novo Non-Promyelocytic Acute Myeloid Leukemia (AML) Patients in First Complete Remission (CR1) with Peripheral Blood Stem Cell (PBSC) Collection Following Consolidation with High-Dose Cytarabine and Etoposide: A Single Institution Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4461-4461
Author(s):  
Eugene Choi ◽  
Lingyi Chen ◽  
Srikanth Nagalla ◽  
Vamshi Kaveti ◽  
Regina Mullaney ◽  
...  
Keyword(s):  
De Novo ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Kaplan Meier ◽  
Cd34 Cells ◽  
High Dose Cytarabine ◽  
Lost To Follow Up ◽  
Disease Free

Abstract INTRODUCTION: Autologous PBSC transplant is an important yet evolving treatment modality for patients with AML. However, the ideal mobilization regimen from which to collect PBSC remains in question. Previous reports have indicated that highdose cytarabine with etoposide is both safe and effective in terms of successful PBSC procurement, subsequent engraftment, and disease outcome. METHODS: At our institution from 1994 to 2007, 38 consecutive patients with de novo non-promyelocytic AML in first complete remission following conventional induction chemotherapy were consolidated with high-dose cytarabine (2000mg/m2 IV q12h × 8 doses, days 1–4) and etoposide (40mg/kg IV over 96h) followed by G-CSF 5 mg/kg subcutaneously starting d14 until completion of PBSC collection. Patients underwent myeloablative therapy with busulfan (1mg/kg po q6h × 16 doses, days –7 to -4) and etoposide (60 mg/kg IV over 10h, day -3) with PBSC infusion occurring on day 0 with daily G-CSF 5 mg/kg. Data regarding stem cell yield, engraftment and patient outcome was collected retrospectively. RESULTS: The average patient age was 44 years (range 19–70). Following consolidation, at least 2×106 CD34 cells/kg were isolated from all 38 patients with a median of 9.4×106 (range 2.2–43) CD34 cells/kg over a mean of 4 collections (range 1–11). Overall, 36 of 38 (95%) remained in CR and went onto PBSC transplant (one died from infectious complications during consolidation, one relapsed before transplant). The median number of stem cells infused was 8.8×106 CD 34 cells/kg (range 2.2–47). All 36 patients engrafted with the mean number of days to neutrophil recovery (ANC&gt;500) being 11 (range 8–17) and the mean number of days to platelet recovery (&gt;20,000) being 12 (range 8–19). Disease-free outcomes in patients undergoing PBSC transplant while in CR1 are presented in Figure 1. The 3y overall survival in all pts was 66%, and 56% at 5y. For good-risk cytogenetic patients, 3y OS was 78% and the 5y OS was 75%. For intermediate-risk cytogenetic patients, OS was 47% and 36% at 3y and 5y respectively. Three patients with poor cytogenetics were autulogously transplanted. One patient relapsed at day 111 and expired at day 450. The second patient remains in CR at day 246. The third patient relapsed at day 104 and expired at day 322. CONCLUSION: In patients with de novo non-promyelocytic AML in CR1, consolidation with high-dose cytarabine plus etoposide is safe and provides excellent yield of PBSCs upon growth factor accelerated hematological recovery. Subsequent engraftment after autologous transplanation is rapid. Our outcomes support the viability of this regimen in patients with good and intermediate-risk cytogenetics. Figure 1: Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up. Figure 1:. Kaplan-Meier analysis of disease-free survival following autologous PBSC transplant. Cytogenetic analysis was unavailable in 5 patients, and 1 patient was lost to follow-up.

Treatment of Therapy-Related Myeloid Neoplasms with High-Dose Cytarabine/Mitoxantrone Followed by Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1030-1030
Author(s):  
Lucy A Godley ◽  
Uchenna O. Njiaju ◽  
Margaret Green ◽  
Howard Weiner ◽  
Shang Lin ◽  
...  
Keyword(s):  
Induction Chemotherapy ◽  
Disease Free Survival ◽  
High Dose ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Myeloid Neoplasms ◽  
High Dose Cytarabine ◽  
Autologous Hct ◽  
Disease Free

Abstract Abstract 1030 Poster Board I-52 Few clinical protocols have focused exclusively on the care of patients with therapy-related myeloid neoplasms (t-MN), and typically the disease confers a poor prognosis. We conducted a clinical trial exclusively for these patients. Between February 2003 and February 2009, we enrolled 32 adult patients with untreated t-MN. The median age was 56 years old (range, 23-83), and 38% were >60 years old. Eight patients (25%) had a total combined Charlson comorbidity index of >4, indicating that they were at high-risk for toxicity from the treatment, either due to older age or medical co-morbidities. T-MN developed following cytotoxic therapy for a malignant disease in 28 patients (88%), following cytotoxic therapy for rheumatologic disease in 2 patients (6%), and with immunosuppressive therapy after solid organ transplants in 2 patients (6%). The latency interval was highly variable, but the greatest fraction of patients (28%) experienced a latency of 4 - 9 years between their primary cytotoxic treatment and development of t-MN (median latency, 3.6 years; range 0.9-23 years). In 8 patients (25%), the latency was 2 years or less. 84% of patients had clonal cytogenetic abnormalities; 35% had a complex karyotype; 45% had abnormalities of chromosomes 5 or 7 or both.; 5 patients had t(9;11). All patients received induction chemotherapy with high-dose cytarabine (3,000mg/m2 over 4 hours) followed immediately by mitoxantrone (30mg/m2 over 1 hour), both given once on days 1 and 5 in a timed-sequential schedule. The complete remission (CR) rate after a single course was 66% and the partial remission (PR) rate was 16%, for an overall response rate of 82%. Grade 4 cardiac dysfunction occurred in 4 patients, resulting in the early death of one. Three of these patients had normal ejection fractions prior to beginning induction chemotherapy (including the patient who died), and one began therapy with an ejection fraction of 43%. Among the 21 patients who achieved a CR, 13 (62%) received consolidation therapy with allogeneic HCT, 4 (19%) received an autologous HCT, and 3 (14%) received only further chemotherapy. Three of the 5 patients who achieved a PR received an allogeneic HCT. Long-term disease-free survival (DFS) was observed in patients with each of the 3 modalities of consolidation therapy. The median overall survival (OS) was 399 days (range, 15-1972+), and OS at 1 year was 51%. Survival was significantly better among those patients who achieved a CR (median, 673 days) compared to those who had a PR (median, 126 days) to induction chemotherapy (P=0.003). OS at 1 year was 74% for patients who had achieved a CR compared with 20% for patients who had achieved a PR to induction. Median DFS was 415 days, with 59% of patients remaining disease-free at 1 year. OS was significantly longer in patients who underwent HCT compared to those who did not. The median survival for patients who received an allogeneic HCT was 673 days (range, 74-1798+) compared to 399 days for patients who received an autologous HCT (range, 353-917+), and 93 days for patients who received no transplant (range, 15-1972+) (P=0.002). OS at 1 year was 72% for patients who had undergone an allogeneic HCT, 75% for patients who had an autologous HCT, and 17% for patients who had not received a transplant. The DFS at 1 year was 67% for patients who underwent either an allogeneic or autologous stem cell transplant compared to 25% for those who did not have a transplant. To date, 9 patients (28%) remain alive and disease-free: 7 (22%) after allogeneic HCT; 1 after autologous HCT; and 1 after consolidation with only chemotherapy. Overall, remission induction therapy with high-dose cytarabine and mitoxantrone is an effective and tolerable regimen for patients with t-MN, allowing aggressive consolidation regimens, HCT, and long-term disease-free survival. Disclosures: Stock: Genzyme: Research Funding.

Secondary Chromosomal Abnormalities Appear to Be Less Prognostic for Children with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL) Treated with Intensified Imatinib and Chemotherapy: Results of the Children's Oncology Group (COG) Study AALL0031.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2606-2606
Author(s):  
Andrew J. Carroll ◽  
Nyla A. Heerema ◽  
Meenakshi Devidas ◽  
W. Paul Bowman ◽  
Chenguang Wang ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Board Of Directors ◽  
Chromosomal Abnormalities ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
Advisory Committees ◽  
The Impact

Abstract Abstract 2606 Poster Board II-582 Background: Secondary chromosomal aberrations at diagnosis occur frequently in both pediatric and adult patients with Ph+ ALL. Several studies have shown that the presence of additional cytogenetic abnormalities is a major negative prognostic factor among children and adults with Ph+ ALL. A Japanese study in adults with Ph+ ALL indicated that the adverse prognostic significance of secondary rearrangements was seen even in patients treated with imatinib-combined chemotherapy including consolidation with blood and marrow transplantation (BMT) (Haematologica 92:287, 2008). Two-year EFS in that study was 48.5±5.7%, and the 50 patients with secondary chromosomal abnormalities had a 35% - 40% lower EFS than those with t(9;22) only (p=0.003). COG AALL0031 treated children with imatinib in combination with intensive chemotherapy. This study had an overall 3 year EFS of 80±11% for those receiving chemotherapy only, an outcome similar to those receiving allogeneic BMT. We evaluated the impact of secondary chromosomal abnormalities in children and adolescents receiving this regimen. Methods: Children and adolescents (age 1–21 years) with Ph+ ALL enrolled on AALL0031 after completing 3- or 4-drug induction therapy. Imatinib was given at 340mg/m2/day for an increasing number of days in combination with an intense chemotherapy backbone. Cohort 4 received imatinib for 126 (N=12) and cohort 5 for 280 continuous days (N=50) prior to maintenance therapy. The first two cycles of the intensive chemotherapy included ifosfamide and etoposide (cycle 1) and high dose (HD) methotrexate and HD cytarabine (cycle 2). Patients were non-randomly assigned to an HLA-identical related donor BMT, if a donor was available, or to an intensive chemotherapy regimen that continued for approximately 2.2 years. Unrelated donor BMT was not allowed; these patients were taken off protocol but included in survival evaluation by an intent-to-treat evaluation. Results: Satisfactory cytogenetic results were available for 71 (76%) of 93 enrolled children. Secondary aberrations were present in 46 (65%) patients. The most frequent secondary aberrations were +der(22) (N=21), =50 chromosomes (N=14), −7/del(7p) (N=11), abnormal (9p) (N=7), and +8 (N=5). The overall 3 year CCR was 79±6% for patients in cohorts 4/5, including those with non evaluable cytogenetics (N=55). When outcome analyses were limited to Ph+ ALL patients in cohorts 4/5 (N=43), three-year CCR for patients with Ph+ alone (N=14) was 86±10% versus 71±9% for those with Ph+ and secondary abnormalities (N=29) (p=0.19). Conclusions: In this study, the lower 3 year CCR seen in patients with Ph+ ALL with secondary chromosomal abnormalities was not significantly different than for children with Ph+ alone possibly reflecting small patient numbers. The lower 3 year CCR for Ph+ ALL with secondary chromosomal abnormalities in those treated on AALL0031 (∼15% lower) appeared to be less than that seen in the previous adult trial (∼35%). This may be the result of the addition of imatinib to intensified chemotherapy reducing the poor prognostic significance of additional chromosome abnormalities seen in previous studies. Larger patient numbers and longer follow-up will be necessary to answer this question. Disclosures: Schultz: DOR Biopharma: Membership on an entity's Board of Directors or advisory committees; Genzyme Canada: Membership on an entity's Board of Directors or advisory committees.

Outcome of Relapse After Allogeneic Stem Cell Transplantation (SCT) In Patients with acute Myeloid Leukaemia (AML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4514-4514
Author(s):  
Raynier Devillier ◽  
Roberto Crocchiolo ◽  
Anne Etienne ◽  
Thomas Prebet ◽  
Aude Charbonnier ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Disease Free Survival ◽  
Response Duration ◽  
Best Supportive Care ◽  
Salvage Treatment ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
Median Response

Abstract Abstract 4514 Introduction: Although allogeneic SCT is associated with the lowest rates of relapse, 20% to 30% relapse. For these patients there is no standard therapy. They may receive intensive salvage, donor lymphocyte infusion (DLI) or palliative chemotherapy. Recently, new agents such as lenalidomide showed promising activity (Vij et al. ASH 2009Abs#842). We retrospectively analyse the outcome of 46 patients from our Institution who relapsed from AML following allo SCT. Patients and methods: We selected patients with a diagnosis of AML according to WHO criteria who relapsed between Jan 2000 and Apr 2010 from our database. Primary endpoint was response rate and duration after salvage treatment. Secondary end points were the overall survival (OS) and disease free survival (DFS) for responsive patients. At relapse, patients received either curative (anthracycline and/or high dose cytarabine and/or gemtuzumab) or non curative salvage (low dose cytarabine and/or oral chemotherapy or best supportive care (BSC)). OS was calculated from the date of relapse. Results: Initial patients characteristics included: median age=46 years [range: 16–69], favourable-risk (n=1; 2%) intermediate-risk (n=25; 57%) or poor-risk cytogenetics (n=18; 41%). Thirty patients were transplanted in complete remission (28 [61%] in CR1 and 2 [4%] in CR2), and 16 (35%) with refractory disease. The conditioning regimen was myeloablative conditioning (MAC) and reduced intensity conditioning (RIC) for 9 (20%) and 37 (80%) patients respectively. 27 patients (59%)received an allograft from matched related donor (MRD) HLA sibling donor, 7 (15%) from unrelated donor (MUD), 11 (24%) from cord bloods and 1 (2%) from haplomismatch donor. Median time from SCT to relapse was 3.8 months, 28 patients (61%) relapsed <6 months after SCT. 19 patients (41%) received curative salvage treatment, 17 (37%) non intensive chemotherapy and 10 (22%) BSC. Among the 19 patients who received intensive salvage therapy, 13 achieved CR (68%) and 1 achieved PR. There were 2 (10%) toxic deaths. Median response duration was 6.8 [range: 0.7–17.9] months and 1-year DFS was 20%. The overall median survival (OS) was 3.6 months. Factors influencing survival were: treatment (curative vs non curative: OS= 7.7 vs 1.8 months, p=0.005), time between allo SCT and relapse (>6 months versus <6 months, OS= 7.7 months versus 1.9 respectively; p=0.032) and status at SCT (CR vs non CR, 5.1 vs 1.8 months, p= 0.02). Conclusions: Our results confirm that the prognosis of the patients who relapse after allo SCT is very poor with a median 3.6 months survival underlining the need for new therapies. Initial CR duration, status at transplant and salvage treatment significantly affect survival after relapse. In a selected group of 41% of patients who relapsed after allo SCT and received intensive chemotherapy, 68% achieved CR and survived significantly longer. Disclosures: No relevant conflicts of interest to declare.

Gemtuzumab Ozogamicin-Based Salvage, Followed by Allogeneic Hematopoietic Stem Cell Transplantation, Is Highly Effective in Young Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) in First Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2603-2603 ◽  
Author(s):  
Marie-Anne Hospital ◽  
Christian Recher ◽  
Xavier Thomas ◽  
Emmanuelle Tavernier ◽  
Bruno Lioure ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
High Dose Cytarabine ◽  
First Relapse

Abstract Abstract 2603 Purpose Although CBF-AML (i.e. with t(8;21) or inv(16)/t(16;16)) represents a favorable cytogenetic AML subgroup (Döhner, Blood 2010), 35–45% of these patients still relapse after standard intensive chemotherapy. The immunoconjugate gemtuzumab ozogamicin (GO) was shown to be effective in patients with relapsed AML in non randomized studies and has been recently demonstrated in a Phase 3 trial as associated with a significant benefit in younger adults with CBF-AML (Burnett, JCO 2011). In this study, we thus investigated the impact of GO-based salvage at first relapse in this specific subgroup of patients with CBF-AML. Patients and Methods We retrospectively analysed the medical records of 84 patients aged 60 years or less with CBF-AML in first relapse after intensive chemotherapy and treated in 18 French centers. None of these patients received allogeneic (alloSCT) or autologous (autoSCT) hematopoietic stem cell transplantation in first complete remission (CR). As salvage, 27 patients received GO, combined with high-dose cytarabine in most of them; 21 patients received high-dose cytarabine and anthracycline without GO; 36 patients received conventional chemotherapy based on standard-dose cytarabine and anthracycline. Post-remission therapy was alloSCT in 49 patients, autoSCT in 17 patients, and chemotherapy alone in 11 patients. Results Among 84 patients with a median age of 39 years [16–58], 36 patients had t(8;21) AML and 48 patients had inv(16)/t(16;16) AML. Median CR1 duration was 12.9 months [2.6–55.3]. Second complete remission (CR2) rate was 92% (77/84), and early death rate was 1% (1/84). The median follow up was 4.0 years. The 5-year overall survival (5y-OS) and relapse-free survival (5y-RFS) was 52% [39–64%] and 48% [36–60%] respectively. Patients receiving alloSCT in CR2 had a better outcome (5y-OS, 56% versus 43%; p=0.05). In patients not allografted in CR2, RFS was similar after autoSCT and chemotherapy alone (5y-RFS, 44% versus 47%, respectively). Patients treated with GO had similar CR rate but a lower risk of second relapse and a better survival than other patients (5y-RFS, 89% versus 55%; p=0.05 and 5y-OS, 90% versus 45%; p=0.03). In univariate analysis, other factors associated with a better OS were younger age, longer CR1 duration, but not CBF subtype (p=0.03, 0.01, and 0.20, respectively). In multivariate analysis adjusted on age, CR1 duration, and CBF subtype, GO salvage was still associated with a significant benefit in OS (HR=0.16 [0.04–0.69], p=0.01) and RFS (HR=0.19 [0.04–0.80], p=0.02). With a median post-relapse follow-up of 2.2 years, no relapse nor death were observed in the 19 patients who received GO salvage followed by alloSCT in CR2 (p=0.007 for RFS; p=0.008 for OS). Moreover, in patients who received alloSCT, previous GO therapy significantly improved post-transplantation outcome. Conclusion Younger patients with CBF-AML in first relapse had a high second complete remission rate regardless the intensive chemotherapy salvage. More interestingly, the outcome of these patients was significantly improved by the addition of GO-based salvage, especially when followed by alloSCT. Disclosures: Off Label Use: GO is available in Europe as a compassionate treatment for relapsed AML.

scholarly journals Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5409-5415 ◽  
Author(s):  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
Jean-Pierre Bourquin ◽  
Michael N. Dworzak ◽  
Christine von Neuhoff ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Independent Predictor ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Event Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Pediatric Aml

Abstract Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, plogrank0.047, EFS 84% ± 4% versus 59% ± 7%, plogrank0.001, and CIR 14% ± 4% versus 34% ± 7%, p(gray)0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

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