Safety and Efficacy of Iron Chelation with Deferasirox in Adult Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5539-5539
Author(s):  
Young-Woo Jeon ◽  
Byung-Sik Cho ◽  
Hee-Je Kim ◽  
Jae-Ho Yoon ◽  
Seung-Hwan Shin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Serum Ferritin ◽  
Myeloid Leukemia ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Iron Chelation ◽  
Hematopoietic Stem ◽  
Safety And Efficacy ◽  
Acute Myeloid

Abstract Background The prognostic impact of serum ferritin level has been well established in patients with myelodysplastic syndrome and acute myeloid leukemia (AML) in the context of allogeneic hematopoietic stem cell transplantation (Allo-HSCT). However, the clinical safety and efficacy of iron-chelation therapy (ICT) for adult AML with hyperferritinemia post-Allo-SCT has not been evaluated. Materials and methods We retrospectively evaluated 320 consecutive patients with de novo AML who received Allo-HSCT at complete remission in a single institution between January 2007 and February 2012. Serum ferritin levels were monitored from initial diagnosis to the several time points during the post-transplantation period in both the ICT group (n=113) and the non-treated group (NT, n=191). In the ICT group, ICT was started at least a month after transplantation when serum ferritin levels over 1,000 ng/mL, and continued to the ferritin level lower than 500 ng/ml unless serious adverse effects and/or relapse. Sixteen patients treated less than one month with ICT due to early complications, such as infection(n= 10, 62.5%), liver toxicity (n=4, 25%), and poor compliance (n=2, 12.5%) were excluded in the ICT group. The baseline characteristics between two groups were not significantly different. Results The median treatment duration in ICT group was 6.4 months (range, 1.0-49.2) with dosage of 20-40 mg/kg/day. Deferasirox treatment was discontinued at least one time in 43 patients (38%) in ICT group due to toxicities and/or poor compliance, but almost patients (n=40, 93%) could be treated again with deferasirox without further toxicities. High serum ferritin level of pre-Allo-HSCT over 1,000 ng/ml was significantly associated with poor overall survival (OS, 52.2% vs. 75.4%, HR 0.78, P <0.001) and lower chronic graft-versus-host disease (GVHD, 53.3% vs. 74.6%, HR 0.83, P =0.001). With a median follow up of 40.2 months, OS, disease-free survival (DFS), and cumulative incidence of relapse (CIR), non-relapse mortality, acute (over grade II) and chronic GVHD were 62.7%, 63.7%, 11.6%, 5.9%, 24.4% and 42.8%, respectively. On multivariate analyses, ICT group had significantly lower CIR (25.9% vs. 37%, HR 0.65, P=0.011) and higher cumulative incidence of chronic GVHD (46% vs. 20.1%, HR 1.88 P<0.001), with a trend of superior survival (OS, 72.0% vs 63.4%, P=0.053; DFS, 70.3% vs 61.4 %, P=0.058), whereas no association with acute GVHD (P=0.473) Conclusion Our data demonstrate that ICT with deferasirox was well tolerable in AML with hyperferritinemia after Allo-SCT, and suggest the independent association of ICT with increased incidence of chronic GVHD and decreased relapse. Iron chelation may modulate of immunobiologic properties during the period of immune reconstitution (low level of Treg cells and higher CD16+ NK cells, 2014 ASH Abstract #2543) and/or induce direct anti-leukemia effect by iron depletion, which need to be further evaluated. Disclosures No relevant conflicts of interest to declare.

Hematologic Improvement with Iron Chelation using therapy Deferasirox in Patients with Aplastic Anemia: A Subgroup Analysis of KAMS0112 Prospective Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3424-3424
Author(s):  
Yoo-Hong Min ◽  
Sung-Soo Yoon ◽  
Hyeoung Joon Kim ◽  
Kyoo-Hyung Lee ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Platelet Count ◽  
Iron Overload ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Ferritin Level ◽  
Iron Chelation ◽  
Hemoglobin Level ◽  
Hematopoietic Stem ◽  
Wbc Count

Abstract Abstract 3424 Patients with aplastic anemia (AA) are suffered from various complications related to bone marrow failure and peripheral cytopenia. Although immunosuppressive therapy or hematopoietic stem cell transplantation has been performed for curative purpose, the majority of patients have been treated only by supportive cares including repeated transfusion. However, because continued transfusion eventually induces iron overload in many tissues and organs, transfusional iron overload and its consequences are another life-threatening problems for AA patients. Previous reports about iron chelation therapy (ICT) have mainly shown its efficiency for decreasing tissue iron and safety. However, improvement in hematopoiesis after iron chelation therapy has been limitedly reported as case reports or trials involving small number of patients without objective tools for measuring tissue iron content. In the KAMS0112 study (a multi-center, open label, prospective study evaluating the efficacy of ICT with deferasirox in transfusional iron overload with myelodysplastic syndrome or AA using quantitative R2-MRI, Ferriscan), a total of 54 patients with AA showing serum ferritin level over 1,000 ng/ml were enrolled from 19 institutes, and further analyzed for the changes in hemogram during ICT as well as efficacy and safely of deferasirox. During the study, the specific treatments for AA, such as immunosuppressive therapy or hematopoietic stem cells transplantation, were not undertaken. During 1 year prior to study, patients received 23.7±16.9 units of red blood cell (RBC) product, and the baseline serum ferritin level and liver iron content (LIC) were 4,164±447 ng/ml and 20.1±12.0 mg Fe/g DW, respectively. Deferasirox was given orally at a dose of 20 mg/kg/day for at least 6 months to all patients. If the serum ferritin level falls below 500 ng/ml, treatment was withheld. In spite of continued transfusional support during the study, serum ferritin level and LIC were significantly decreased after 1 year of ICT with deferasirox (Ds-ferritin=−3,076.7±489.9 ng/ml, p=0.0003; DLIC=−7.73 mg/Fe/g DW, p=0.001). To evaluate the improvement of each parameter in hemogram by ICT, patients with baseline hemoglobin level less than 8.0 g/dl (n=28), with baseline WBC count less than 4/ml (n=43), and with baseline platelet count less than 20/ml (n=31) were selected separately. At the end of study, hemoglobin level and platelet count (8.2±3.0 g/dl and 22.2±31.4/ml, respectively) was significantly increased from the baseline value (6.1±1.1 g/dl, p=0.001; 12.5±12.4/ml, p=0.05, respectively). WBC count was also slightly increased (from 2.1±0.9/ml to 2.3±0.9/ml, p=0.457). Considering the relatively uniform criteria of transfusion, the finding that hemoglobin level and platelet count could increase above 8 g/dl and 20/ml, respectively, after 1 year of deferasirox treatment is clinically significantly. Due to gradual improvement of anemia, requirement of RBC transfusion had continuously decreased during the study period (R2=0.31). This subanalysis of KAMS0112 study demonstrates that ICT using deferasirox can be effective in improving anemia and thrombocytopenia in the transfusional iron overload patients with AA, as well as reducing serum ferritin level and LIC. Further studies might be required to elucidate the mechanism involved in the improvement of hematopoiesis associated with correction of deranged intracellular iron homeostasis. Disclosures: Min: Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Lee:Novartis: Research Funding. Won:Novartis: Research Funding. Shim:Novartis: Research Funding. Kim:Novartis: Research Funding. Seung:Novartis: Research Funding. Kim:Novartis: Research Funding. Lee:Novartis: Research Funding. Chung:Novartis: Research Funding. Hyun:Novartis: Research Funding. Jo:Novartis: Research Funding. Jung:Novartis: Research Funding. Sohn:Novartis: Research Funding. Yoon:Novartis: Research Funding. Kim:Novartis: Research Funding. Joo:Novartis: Research Funding. Cheong:Novartis: Research Funding.

scholarly journals The 17-Gene Leukemic Stemess Score Can Predict Treatment Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3299-3299
Author(s):  
Dennis Dong Hwan Kim ◽  
Taehyung Kim ◽  
Tracy Murphy ◽  
Steven M Chan ◽  
Mark D. Minden ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Allogeneic Hct ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Introduction: A 17-gene stemness score (LSC17 score) had been reported to determine the risk of therapy resistance in acute myeloid leukemia (Nature 2016), and this was replicated successfully in 5 independent cohorts (n=908). When the patients were stratified according to the median value of the LSC17 score, allogeneic hematopoietic stem cell transplantation (HCT) did not affect overall survival (OS) from initial diagnosis for either high- or low-score patients (p=0.2 for high and p=0.06 for low LSC17 score groups). In the present study, we aimed to further perform a subgroup analysis confined to the patients receiving allogeneic HCT and determine whether the LSC17 score at leukemia diagnosis was associated with treatment outcomes including OS, leukemia-free survival (LFS), non-relapse mortality (NRM), relapse incidence (RI), and acute/chronic GVHD following allogeneic HCT. Methods and patients: Out of 452 patients with available LSC17 scores, 123 patients were included into the final analysis who received allogeneic HCT using matched (n=104, 84.6%) or mismatched/haploidentical donors (n=19, 15.4%). 80 patients were from the previous study (Nature 2016), while 43 patients were a prospectively accrued cohort during 2016-2018. Patients and transplant characteristics were: male/female (n=61/62); median age, 51 (17-73); CR status prior to HCT, CR1 (n=93, 75.6%), CR2 (n=30, 24.4%); Conditioning regimen, reduced intensity/myeloablative conditioning (n=59, 48.0% vs n=64, 52.0%); GVHD prophylaxis using post-transplant cyclophosphamide (PTCy; n=45, 36.6%) or T cell depletion (n=62, 50.4%); Cytogenetic risk, favorable (n=10, 8.1%), intermediate (n=70, 56.9%), adverse (n=26, 21.1%), inconclusive or not done (n=17, 13.8%). The LSC17 score for each patient was measured in a diagnostic sample using a NanoString assay and compared to the high/low threshold of a reference AML cohort (Ng et al, Nature 2016 and unpublished data). Transplant outcomes were compared according to the LSC17 risk group for OS, LFS, NRM and RI. Univariate and multivariate analyses were conducted for OS and LFS using Cox's proportional hazard model or for NRM and RI using Fine-Gray model, respectively. The following variables were included in the model: the LSC17 score group (high vs low LSC17 score), chronic GVHD, CR status (CR2 vs CR1), Cytogenetic risk (adverse vs favorable/intermediate/inconclusive), GVHD prophylaxis (PTCy vs others, T-cell depletion vs others), Age (above 60 vs others), donor type (mismatched/haploidentical vs matched donors). Results: With a median follow-up duration of 22 months among survivors after HCT, 23 patients experienced relapse (n=23, 18.7%) while 63 deaths (51.2%) were noted. Out of 123 patients, 58 (47.1%) had a low LSC17 score and 65 (52.9%) had a high LSC17 score. There was no difference in the distribution of LSC17 scores between the group who received HCT (n=123; 0.479±0.026) vs not (n=229; 0.456±0.019; p=0.491). LFS survival was significantly better in the low LSC17 score group (51.5 vs 32.4% for 2-year LFS rate, p=0.0219), and there was a trend to higher OS rate in the low LSC17 group (48.1%) compared to the high LSC17 group at 2 years (34.2%, p=0.09). Furthermore, patients with a low LSC17 score had a significantly lower RI (14.9% vs 27.3% for 2-year relapse incidence, p=0.028). There is no difference of NRM between the groups (37.2% vs 38.2% at 2 years, p=0.647). Multivariate analysis confirmed that the high LSC17 score group was associated with worse LFS (HR 1.874 [1.080-3.249], p=0.025). However, it was not confirmed with respect to OS or relapse incidence. As expected, it was not associated with NRM. Conclusion: A low 17-gene stemness score is associated with better leukemia-free survival and lower relapse incidence after allogeneic HCT, and is suggested to be associated with OS. The high LSC17 score group may be considered for novel therapeutic strategies to reduce the risk of relapse after allogeneic HCT. Figure Disclosures Chan: Celgene: Honoraria, Research Funding; AbbVie Pharmaceuticals: Research Funding; Agios: Honoraria. Minden:Trillium Therapetuics: Other: licensing agreement. Michelis:CSL Behring: Other: Financial Support. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Wang:Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; NanoString: Other: Travel and accommodation.

scholarly journals FLAMSA-RIC for Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes: A Systematic Review and Meta-Analysis

2019 ◽  
Vol 8 (9) ◽  
pp. 1437 ◽  
Author(s):  
Weerapat Owattanapanich ◽  
Patompong Ungprasert ◽  
Verena Wais ◽  
Smith Kungwankiattichai ◽  
Donald Bunjes ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Reduced-intensity conditioning (RIC) regimens are established options for hematopoietic stem cell transplantation (HSCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the efficacy of RIC regimens for patients with high-risk disease is limited. The addition of a fludarabine, amsacrine, and cytarabine (FLAMSA)-sequential conditioning regimen was introduced for patients with high-risk MDS and AML to combine a high anti-leukemic activity with the advantages of RIC. The current systematic literature review and meta-analysis was conducted with the aim of identifying all cohort studies of patients with AML and/or MDS who received FLAMSA-RIC to determine its efficacy and toxicity. Out of 3044 retrieved articles, 12 published studies with 2395 overall patients (18.1–76.0 years; 96.8% AML and 3.2% MDS; follow-up duration of 0.7–145 months; 50.3% had active AML disease before HSCT) met the eligibility criteria and were included in the meta-analysis. In the pooled analysis, the 1- and 3-year overall survival (OS) rates were 59.6% (95% confidence interval (CI), 47.9–70.2%) and 40.2% (95% CI, 28.0–53.7%), respectively. The pooled 3-year OS rate of the patients who achieved CR1 or CR2 prior to HSCT was 60.1% (95% CI, 55.1–64.8%) and the percentage of those with relapse or refractory disease was 27.8% (95% CI, 23.3–32.8%). The pooled 3-year leukemia-free survival (LFS) rate was 39.3% (95% CI, 26.4–53.9%). Approximately 29% of the patients suffered from grades 2–4 acute graft-versus-host disease (GVHD), while 35.6% had chronic GVHD. The pooled 1- and 3-year non-relapse mortality (NRM) rates were 17.9% (95% CI, 16.1–19.8%) and 21.1% (95% CI, 18.8–23.7%), respectively. Our data indicates that the FLAMSA-RIC regimen is an effective and well-tolerated regimen for HSCT in patients with high-risk AML and MDS.

Non Interventional Prospective Study On The Effect Of 48 Gene Variants On Different Endpoints After Allogeneic Stem Cell Transplantation For Patients With Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3287-3287
Author(s):  
Michael Koldehoff ◽  
Dietrich W. Beelen ◽  
Ahmet H. Elmaagacli
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Prospective Study ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Gene Variants ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Abstract Background Single-nucleotide polymorphisms (SNPs) are molecular markers that vary significantly among different populations. Our group has earlier reported about different genetic associations of SNPs with GvHD and/or outcome after allogeneic hematopoietic stem cell transplantation (HSCT) in different retrospective studies. Here we profiled SNPs in a non interventional prospective study (Trial No DRKS00004352) about the influence of different endpoints for patients (pts) with acute myeloid leukemia who underwent allogeneic HSCT between June 2011 and February 2013. Methods We analyzed simultaneously 48 different genes of every patient/donor pairs in whole blood by high-throughput LightCycler® 480 real-time PCR-system using high resolution melting optimization strategies. Results In this cohort 20 pts received grafts from HLA-identical siblings (23%), 42 pts from matched (48%) and 26 pts from mismatched (30%) unrelated donors. Transplant consisted of unmanipulated peripheral blood stem cells (n=79, 90%) or bone marrow (n=9, 10%). Of all pts (n=88, male 48 pts and female 40 pts), 18 (21%) had relapsed and 28 (32%) died of May 2013. In the cohort the occurrence of acute GvHD (aGvHD) grade 2-4 was influenced by gene variants on recipient side of CYP 2C9 (39% vs 72%, p<0.04), IL16 (53% vs 31%, p<0.01) and MTHFR 677, 1298 (31% vs. 52%, p<0.05). Furthermore, the occurrence of severe aGvHD ≥3 was influenced by GSTP1 A/G (3% vs 20%, p<0.04), LAT (6% vs 17%, p<0.02), MBL2 codon 550 (3% vs 22%, p<0.03), and VEGF 405 G/C (15% vs 7%, p<0.02). There was no significant correlation between different gene variants of pts and the estimate for 1-year overall survival (OS). We found that the rate of 1-year none-relapse mortality (NRM) was associated favorably with the detection of variants of NOD2 genes (0% vs 26%, p<0.04) and MBL codon 220 (7% vs 32%, p<0.05) and associated adversely with the detection of variants of LAT (16% vs 34%, p<0.03). The estimate 1-year relapse rate was associated adversely with the detection of variants of IL 10 592 C/A (15% vs 45%, p<0.05) and associated favorable with the detection of variants of TLR9 genes (40% vs. 10%, p<0.02) Conclusions These preliminary results suggest that different gene variants have influence on the transplant settings in pts with acute myeloid leukemia. Disclosures: Off Label Use: HCG will be discussed as new therapy for chronic GVHD.

Prospective Evaluation of Azacitidine Maintenance Following Allogeneic Hematopoietic Stem Cell Transplantation in Patients with High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5476-5476 ◽  
Author(s):  
Harinder Gill ◽  
Albert Kwok Wai Lie ◽  
Yok Lam Kwong ◽  
Anskar Y.H. Leung
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Poor Risk ◽  
Acute Myeloid

Abstract Introduction and aim. Relapse following allogeneic hematopoietic stem cell transplantation (HSCT) is a major cause of treatment failure and is associated with a poor prognosis. Overall survivals are around 50% at 5 years following allogeneic HSCT in intermediate and high risk AML. Survivals remain less than 20% in poor-risk and very poor-risk patients based on the cytogenetic profile. Thus, prevention of relapse following allogeneic HSCT remains an unmet clinical need. Low-dose azacitidine maintenance post-HSCT has been shown to augment graft-versus-leukemia effect and may prolong survivals. We aim to prospectively evaluate the effect of azacitidine maintenance following allogeneic HSCT in high risk AML and MDS. Method. Consecutive patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in remission following first allogeneic HSCT or second allogeneic HSCT (from the original donor) were recruited. High risk AML in this study comprised patients with poor risk karyotype, secondary AML transformed from underlying MDS, presence of fms-like tyrosine kinase 3-internal tandem duplication (FLT3 -ITD) and non-remission before HSCT. Azacitidine was administered at 100mg daily for 3 days per cycle every 28 days until progression or a maximum of 8 cycles. The clinicopathologic and treatment characteristics were determined. The occurrence of graft-versus-host disease (GVHD) was determined. DNA chimerism was determined in the bone marrow before the initiation of azacitidine, after 4th and 8th cycles of azacitidine and at 1 year. DNA chimerism was determined by quantification of polymorphic short tandem repeat sequences. The progression-free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier analysis. Results. Thirty-four patients with high-risk AML (N=31) and MDS (N=3) were recruited. The median duration of follow-up was 14 months (range: 2 - 44 months). Twenty-two patients received azacitidine maintenance after first allogeneic HSCT, whereas 12 patients received azacitidine maintenance after a second allogeneic HSCT from the same donor following relapse from a first allogeneic HSCT For patients receiving azacitidine after first HSCT, at a median follow-up of 18.5 months (range: 5- 36 months), the median PFS was not reached, and the median OS was 32 months (95% confidence interval [C.I.]: 24.85-39.15). The 24-month PFS and OS were 66.1% and 73.2% respectively. Acute and chronic GVHD occurred in 7 (31.8%) and 17 patients (77%). For patients receiving azacitidine after second HSCT, at a median follow-up of 14 months (range: 9 - 46 months), the median PFS and OS were 9 months (95% C.I.:6.94-11.04) and 14 months (range: 11.77 - 16.23 months). The 24-month PFS and OS were 25% and 14% respectively. Acute and chronic GVHD occurred in 1 (8.3%) and 5 (41.7%) patients respectively. In both groups, 100% donor chimerism was achieved during azacitidine maintenance. Conclusion. Azacitidine maintenance following first allogeneic HSCT resulted in favorable 2-year survivals in selected patients with high-risk AML and MDS. Nevertheless, survivals were poor despite azacitidine maintenance after second allogeneic HSCT from the same donor. Full donor chimerism was maintained during azacitidine maintenance. Disclosures No relevant conflicts of interest to declare.

Maintenance Therapy With Decitabine After Allogeneic Hematopoietic Stem Cell Transplantation For Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4638-4638 ◽  
Author(s):  
Iskra Pusic ◽  
Jaebok Choi ◽  
Noel Bernabe ◽  
Camille N. Abboud ◽  
Peter Westervelt ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Maintenance Therapy ◽  
Myeloid Leukemia ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
To Receive ◽  
Acute Myeloid

Introduction Disease recurrence is the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (alloHSCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Graft-versus-host disease (GVHD) is the major cause of non-relapse morbidity and mortality after alloHSCT. Decitabine (DAC) is a hypomethylating agent that irreversibly binds to and inhibits DNA methyltransferase-1, leading to loss of DNA methylation. DAC maintenance may help eradicate minimal residual disease and facilitate a graft-versus-leukemia effect. Lower DAC doses are expected to be better tolerated after alloHSCT and equally effective in promoting hypomethylation. Additionally, DAC maintenance may have a favorable effect on the incidence of GVHD by enhancing the effect of T-regulatory lymphocytes (Choi et al, Blood, 2012). Methods Patients (pts) with AML/MDS in complete remission (CR) after alloHSCT, with ANC> 1,500/mm3, platelets> 50,000/mm3, and without grade III-IV acute GVHD were eligible to receive DAC, starting between day +50 and +100 after alloHSCT. We investigated 4 DAC doses: 5, 7.5, 10 and 15 mg/m2/day IV x 5 days of a 6-week cycle, for a total of 8 cycles. Each cohort contained 4-8 evaluable patients. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which< 20% of patients experience hematologic or non-hematologic dose limiting toxicities (DLT) during the 1st cycle of treatment. GVHD prophylaxis was at the physician discretion. Results 19 pts were enrolled to date; the median age was 60 y (22-66); 14 pts had AML and 5 MDS. All conditioning regimens were myeloablative; 14 donors were unrelated and 5 related. 3 cohorts have been completed and a final 4th cohort is currently enrolling. Median follow-up from alloHSCT is 24 mo (7-36). 8 pts (44%) completed all 8 cycles: 7 pts remain in CR with stable counts and full donor chimerism and 1 pt developed CNS-only relapse 26 mo after alloHSCT. 9 pts went off study before cycle 6: 1 pt for poor compliance after 6 cycles, 3 pts for relapsed disease (after 1, 2 and 5 cycles, respectively), 2 pts for sepsis, and 2 pts after physician decision. 6 pts have died: 3 from relapse, 2 from sepsis after 3 cycles of DAC (they were not neutropenic at a time), and 1 form sepsis >1 y after getting off study. 2 pts are still on study passed 3rd cycle. DAC maintenance was well tolerated. Associated hematological toxicities were mostly grade I/II leukopenia and thrombocytopenia. There was one occurrence of hematological DLT. No MTD has been reached. Non-hematological toxicities were grade I/II nausea, fatigue, neuropathy, and transaminase elevation. 2 pts had grade I-II acute GVHD prior to starting DAC and both resolved while on DAC; 1 pt developed grade IV gut GVHD coinciding with first cycle of DAC that completely resolved on DAC; 1 pt developed late acute GVHD of skin and liver around 6th cycle of DAC that resolved after few wks. 2/8 pts who completed 8 cycles of DAC developed very mild skin and oral chronic GVHD not requiring any systemic therapy, 1/8 pt developed late acute GVHD responding to therapy, and 1 pt developed overlap GVHD syndrome. 4/7 pts who went off study prior cycle 6, and did not have an early relapse, developed severe chronic GVHD requiring intensive immunosuppressive therapy. Conclusion To our knowledge this is the first report of DAC as maintenance therapy after alloHSCT. DAC at the dose of 15 mg/m2 for 5 days every 6 weeks is safe and can be administered in heavily pretreated pts in the post-alloHSCT setting. Approximately 43% of pts were able to receive all 8 cycles. The lack of toxicities and low incidence of GVHD indicate that a longer period of administration should be investigated. Although there is a trend of increased FOXP3 expression, results were not statistically significant. Further correlative studies, including genome-wide methylation studies, are ongoing. Disclosures: Off Label Use: Decitabine maintenance after alloHSCT.

scholarly journals High Post-Transplant Ferritin Level Associates with Adverse Survival and Higher Mortality Rate following Allogeneic Hematopoietic Stem Cell Transplant, whereas Pre-Transplant Ferritin Level Does Not

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3454-3454
Author(s):  
Warren Fingrut ◽  
Arjun Law ◽  
Wilson Lam ◽  
Fotios V. Michelis ◽  
Santhosh Thyagu ◽  
...  
Keyword(s):  
Prognostic Marker ◽  
Serum Ferritin ◽  
Research Funding ◽  
Serum Ferritin Level ◽  
Acute Gvhd ◽  
Ferritin Level ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Independent Prognostic Marker

Abstract Background: Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy for many hematologic and non-hematologic diseases; however, it is associated with significant morbidity and mortality. Many studies have shown that elevated pre-transplant ferritin levels are associated with increased risk of morbidity and mortality following HCT. Given ferritin's association with systemic inflammation, it is a plausible potential prognostic marker in the post-HCT period, including in patients with graft-versus-host disease (GVHD). The present study attempts to determine whether post-transplant serum ferritin level is an independent prognostic marker for outcomes post-HCT, especially in the subgroups of patients with acute or chronic GVHD. Methods and patients: A total of 229 patients who had serum ferritin level data available within one-year post HCT were enrolled into this retrospective study. These patients underwent HCT at Princess Margaret Cancer Centre, Toronto, Canada between 2001-2013. Patients' characteristics and transplant procedures were: median age: 51 (range:19-70); refined disease risk index: low (n=70), intermediate (n=108), high (n=51); donor type: HLA-matched related donors (n=94), HLA-matched or partially-matched unrelated donors (n=135); conditioning regimen: myeloablative (n=120), reduced intensity (n=109). Acute and chronic GVHD were respectively classified using the 1994 consensus conference and NIH consensus criteria. Primary outcomes were overall survival (OS), non-relapse mortality (NRM), and relapse. Kaplan-Meier method was used for OS; cumulative incidences were used for NRM and relapse, considering competing risks. Multivariate analysis employed Cox or Fine-Gray proportional hazard regression model. Factors evaluated included recipient age and CMV status, donor-recipient sex, comorbidity score, performance index, GVHD prophylaxis, post-transplant serum ferritin level (ferritinPost-HCT), and serum ferritin level prior to HCT (ferritinPre-HCT). Recursive partitioning was used to stratify patients into low or high risk groups based on ferritinPost-HCT (≤3,169 vs >3,169 ng/mL) and ferritinPre-HCT (≤669 vs >669 ng/mL). Results: Median follow-up duration among survivors was 46 months post-HCT (range:2.8-147.2 months). Median ferritinPost-HCT was 2,178 ng/mL (range: 45-30,647; Figure A), measured at a median of 137 days post-HCT. There was a weak correlation between ferritinPost-HCT and ferritinPre-HCT (Pearson's correlation r=0.242, p=0.002). Compared to the group with low ferritinPost-HCT, the high ferritinPost-HCT group had lower three-year OS (40.0% vs 66.7%, p<0.001; Figure B) and higher NRM (48.6% vs 17.8%, p<0.001 Figure C), but no difference in cumulative incidence of relapse (10.5% vs 19.7%, p=0.079; Figure D). A landmark analysis was performed where the day of ferritinpost-HCT measurement was considered day 0. Results of this landmark analysis showed consistent findings: high ferritinPost-HCT showed lower three-year OS (38.3% vs 65.4%; p<0.001) and higher NRM (50.6% vs 17.7%; p<0.001) compared to low ferritinPost-HCT, but no difference in relapse (10.7% vs 21.3%, p=0.077). In multivariate analysis, ferritinPost-HCT was found to be an independent prognostic factor for OS (p=0.001, HR 2.323) and NRM (p<0.001, HR 3.905). However, pre-transplant ferritin level (ferritinPre-HCT) did not stratify well for OS (57.0% vs 61.8%, p=0.636) or NRM (30.8% vs 22.7%, p=0.247). Out of 229 patients, 171 (74.6%) developed any grade of acute GVHD, and 61 (26.6%) developed chronic GVHD. Median onset of acute and chronic GVHD were, respectively, 33.5 days and 145 days. Level of ferritinPost-HCT was significantly higher in the group that developed acute GVHD than in those without acute GVHD. However, there was no difference in ferritinPost-HCT between patients with or without chronic GVHD. FerritinPost-HCT was found to be an independent prognostic marker in the subgroup with acute GVHD for OS (p=0.001, HR 2.531) and NRM (p<0.001, HR 3.584), and in the subgroup with chronic GVHD for OS (p=0.042, HR 3.226) and NRM (p=0.009, HR 14.130). Conclusions: In our cohort, high ferritinPost-HCT levels were significantly associated with decreased OS and increased NRM, independent of other prognostic factors including ferritinPre-HCT or GVHD. Further prospective study including larger number of patients is warranted. Figure. Figure. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Paladin: Consultancy.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Karnofsky Performance Status Score Equal or Lower Than 80%. a Study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2038-2038 ◽  
Author(s):  
Francesco Saraceni ◽  
Myriam Labopin ◽  
Edouard Forcade ◽  
Nicolaus Kröger ◽  
Gerard Socie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Chronic Gvhd ◽  
Hematopoietic Stem ◽  
Reduced Risk ◽  
Acute Myeloid

Thanks to the recent developments in transplant procedures, an increasing number of patients with acute myeloid leukemia (AML) with a poor Karnofsky Performance Status (KPS) score are currently offered an allogeneic hematopoietic stem cell transplantation (allo-HCT). Nevertheless, little data is available about outcome of this fragile population. We report here the results of a retrospective study designed to evaluate outcome of patients with AML undergoing allo-HCT with KPS score ≤80%. The analysis included patients with AML aged ≥18 years, undergoing allo-HCT in first remission between 2000 and 2018, with a KPS score at the time of transplant between 50% and 80%. Patients who received manipulated grafts or had incomplete data about cytogenetics were excluded. Conditioning intensity was defined according to EBMT definitions. A total of 2,963 patients were identified. Median age at transplant was 55 years (18-77 years). Median year of transplant was 2014. The KPS score was =80% in 85% of the patients and <80% in 15% of the patients. Cytogenetic risk was good, intermediate or poor in 6%, 68% and 26% of the patients, respectively. Donor type was sibling (MSD), matched (10/10 UD), mismatched (9/10 UD) unrelated, haploidentical (haplo) or cord blood (CB) in 47%, 35%, 8%, 6% and 4% of patients, respectively. Conditioning was myeloablative (MAC) or reduced-intensity (RIC) in 42% and 58% of patients. Stem cell source was PBSC or BM in 84% and 14% of the patients. Anti-thymocyte globulin (ATG) was administered to 55% of the patients. Cumulative incidence of grade II-IV and III-IV acute GVHD (aGvHD) was 26% and 8%, respectively. The 2-year cumulative incidence of chronic GVHD (cGvHD) and severe cGVHD was 38% and 18%. Non-relapse mortality (NRM) and relapse incidence (RI) at 2 years were 19% and 27%, respectively. Notably, in the subgroup of patients with KPS <80% NRM rate was as high as 27%. At 2 years, leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) rates were 54%, 59% and 41%, respectively. On multivariate analysis, transplant from a MSD was associated with a reduced risk of aGvHD (10/10 UD HR 1.8, 9/10 UD HR 2.4, haplo HR 1.9, CB HR 3.4, p<10-4, MSD as reference) and NRM (10/10 UD HR 1.4, 9/10 UD HR 2.4, haplo HR 1.8, CB HR 2, p<10-3, MSD as reference) as compared to all other donor types (Table 1). Transplant from 10/10 UD was associated with lower GRFS (HR 1.2, p=0.03), while 9/10 UD predicted inferior LFS, OS and GRFS (HR 1.6, 1.7, and 1.5, respectively, p<0.001) as compared to MSD. Patients with KPS score of 80% had significantly lower NRM and improved survival as compared to patients with KPS score <80% (NRM: HR 0.6, p<10-4; OS: HR 0.7, p<10-4). Other factors independently associated with improved OS were younger age, female sex, good or intermediate risk cytogenetics and de-novo AML. Notably, administration of ATG was associated with reduced risk of developing grade II-IV aGVHD (HR 0.7, p<10-4), cGVHD (HR 0.6, p<10-4), severe cGVHD (HR 0.5, p<10-4) and predicted improved GRFS (HR 0.8, p<0.01). In order to compare outcome following MAC and RIC conditioning the analysis was restricted to patients receiving transplant from MSD or UD. Patients with a KPS score =80% or <80% were analyzed separately. In the group of patients with a KPS score of 80%, a RIC regimen was associated with higher RI (HR 1.4, p<0.01), higher incidence of severe cGVHD (HR 1.6, p<0.001), and inferior GRFS (HR 1.3, p<0.001) as compared to MAC. NRM was not significantly different following RIC or MAC in this population. In contrast, in patients with a KPS score <80%, RIC was associated with lower NRM (HR 0.3, p<0.0001) and better LFS (HR 0.6, p<0.01), OS (HR 0.5, p<0.0001) and GRFS (HR 0.6, p<0.01) as compared to MAC. In conclusion, allo-HCT is feasible in patients with acute myeloid leukemia in first remission and KPS score <80%, with acceptable NRM and survival rates. As for the conditioning regimen, in patients with a KPS score of 80% a MAC regimen was associated with lower relapse rate, similar NRM and better GRFS as compared to RIC, while in patients with a KPS score lower than 80% RIC was associated with reduced NRM and improved OS as compared to MAC. In addition, transplant from a MSD predicted a reduced risk of NRM and aGVHD as compared to other donor types. Notably, 9/10 UD was associated with significantly inferior survival as compared to MSD. Finally, administration of ATG correlated with reduced acute and chronic GVHD and improved GRFS. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Kröger:Sanofi-Aventis: Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding; JAZZ: Honoraria; Medac: Honoraria; Neovii: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Riemser: Research Funding. Socie:Alexion: Consultancy. Blaise:Pierre Fabre medicaments: Honoraria; Jazz Pharmaceuticals: Honoraria; Sanofi: Honoraria; Molmed: Consultancy, Honoraria. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Esteve:Astellas: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation for Acute Myeloid Leukemia (AML) with 11q23 (MLL) Rearrangement (MLL-r AML). A Retrospective Analysis From the Acute Leukemia Working Party of EBMT

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 498-498
Author(s):  
Arnaud Pigneux ◽  
Myriam Labopin ◽  
Johann Maertens ◽  
Ulrike Bacher ◽  
Gérard Socié ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Good Prognosis ◽  
Hematopoietic Stem ◽  
Long Term Outcome ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract 498 Acute myeloid leukemia (AML) with 11q23 (MLL) rearrangement (MLL-r AML) belongs to the intermediate or high risk cytogenetic classification. It prognosis is known to depend on the translocation partner. Data from multicenter studies suggest that most patients with t(11q23) achieve complete remission after induction chemotherapy. However, the impact of different t(11q23) on long-term outcome is less clear, with overall survival (OS) rates at 5 years ranging from 0% to 45%. A more favourable outcome has been reported in patients receiving an alloHSCT in an early phase. To investigate the potential role of alloHSCT for the management of t(11q23) AML we analyzed the outcome of the cases reported to the ALWP between 2000 and 2010 (median year of transplant: 2007). Overall, we identified 172 patients (median age: 41, 18–70; 43% male) allografted. The following rearrangements were identified: t(9;11) in 82 patients, t(11;19) in 20, t(6;11) in 21, t(10;11) in 17, t(4;11) in 5, t(11;17) in 5 and others in 22. Most transplants were performed in complete response (CR1=148, 86%; CR2=21, 12%, CR3=3, 2%). Donor was an HLA-identical sibling in 84 transplants (49%), and an unrelated in 88 (51%). Conditioning regimen consisted of a myeloablative regimen in most patients (n=113, 65%), and source of stem-cells was peripheral blood in 110 (64%), bone marrow in 49 (28%), and cord blood in 13 (8%). One hundred sixty-six patients engrafted and 57 presented an acute GVHD ≥ 2. After a median follow-up of 24 months (2–123), 2-year overall survival (OS) was 56 ± 4%, 2-year leukemia-free survival (LFS) was 52 ± 4%, CI of relapse incidence (RI) was 35±3%, non-relapse mortality (NRM) was 16±4% and the rate of chronic GVHD was 47±4%. The outcome was significantly different (p<10−4) according to the rearrangement with a 2-year LFS for patients with t(9;11) of 61±6%, t(11;19) of 65±11%, t(6;11) of 12±10%, t(10;11) of 34±12%. LFS was improved by CR status with a 2-y LFS for CR1 patients of 56 ± 5% and only 23 ± 9% for patients in more advanced disease. We subsequently restricted our analysis on the population of 148 patients in first CR in which the 2-year LFS was for patients with t(9;11) of 64±6%, t(11;19) of 68±12%, t(6;11) of 16±10%, t(10;11) of 40±13%, the 2-year RI was for patients with t(9;11) of 23±5%, t(11;19) of 26±11%, t(6;11) of 55±15%, t(10;11) of 36±14%, the 2-year NRM was for patients with t(9;11) of 24±13%, t(11;19) of 6±5%, t(6;11) of 29±13%, t(10;11) of 24±13%. Multivariate analysis on LFS identified as poor prognostic factors: the presence of a t(6;11)(p<0.0001) or t(10,11) (p = 0.034) and an interval from diagnosis to CR1 greater than 43 days (p=0.008). This preliminary study confirms the known good prognosis of t(9;11) and poor outcome of t(6;11), while it highlights the good prognosis of t(11;19) AML patients submitted to alloHSCT in CR1, suggesting that this procedure might overcome the adverse prognosis associated to this entity. Disclosures: No relevant conflicts of interest to declare.

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