scholarly journals Primary Induction Failure

2020 ◽  
Author(s):  
Keyword(s):  
Primary Induction ◽  
Induction Failure

scholarly journals NUP-98 Rearrangements Led to the Identification of Candidate Biomarkers for Primary Induction Failure in Pediatric Acute Myeloid Leukemia

2021 ◽  
Vol 22 (9) ◽  
pp. 4575
Author(s):  
Vincenza Barresi ◽  
Virginia Di Bella ◽  
Nellina Andriano ◽  
Anna Provvidenza Privitera ◽  
Paola Bonaccorso ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutational Analysis ◽  
Integrated Analysis ◽  
Induction Phase ◽  
Pediatric Acute Myeloid Leukemia ◽  
Expression Arrays ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid

Conventional chemotherapy for acute myeloid leukemia regimens generally encompass an intensive induction phase, in order to achieve a morphological remission in terms of bone marrow blasts (<5%). The majority of cases are classified as Primary Induction Response (PIR); unfortunately, 15% of children do not achieve remission and are defined Primary Induction Failure (PIF). This study aims to characterize the gene expression profile of PIF in children with Acute Myeloid Leukemia (AML), in order to detect molecular pathways dysfunctions and identify potential biomarkers. Given that NUP98-rearrangements are enriched in PIF-AML patients, we investigated the association of NUP98-driven genes in primary chemoresistance. Therefore, 85 expression arrays, deposited on GEO database, and 358 RNAseq AML samples, from TARGET program, were analyzed for “Differentially Expressed Genes” (DEGs) between NUP98+ and NUP98-, identifying 110 highly confident NUP98/PIF-associated DEGs. We confirmed, by qRT-PCR, the overexpression of nine DEGs, selected on the bases of the diagnostic accuracy, in a local cohort of PIF patients: SPINK2, TMA7, SPCS2, CDCP1, CAPZA1, FGFR1OP2, MAN1A2, NT5C3A and SRP54. In conclusion, the integrated analysis of NUP98 mutational analysis and transcriptome profiles allowed the identification of novel putative biomarkers for the prediction of PIF in AML.

scholarly journals Decitabine as salvage therapy for primary induction failure of acute myeloid leukemia

2017 ◽  
Vol 56 (8) ◽  
pp. 1120-1121 ◽  
Author(s):  
Pasquale Niscola ◽  
Benedetta Neri ◽  
Gianfranco Catalano ◽  
Luciana Morino ◽  
Marco Giovannini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid

Allogeneic Hematopoietic Cell Transplantation Can Cure Some Patients with Acute Leukemia in Relapse or Primary Induction Failure: A CIBMTR Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 528-528
Author(s):  
Michel Duval ◽  
Wensheng He ◽  
John P. Klein ◽  
Martin S. Tallman ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
High Risk ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
Karnofsky Score ◽  
Risk Criteria ◽  
Primary Induction ◽  
Induction Failure

Abstract Abstract 528 Acute leukemia refractory to chemotherapy is uniformly fatal without hematopoietic cell transplantation (HCT). However, the benefit of transplantation for patients not in complete remission (CR) is controversial. PATIENTS AND METHODS: 2,255 patients transplanted (at 252 centers in 38 countries) with an allogeneic donor after myeloablative conditioning regimen between 1995 and 2004 for acute leukemia in relapse or with primary induction failure were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). 1,673 had acute myeloid leukemia (AML) and 582 acute lymphoblastic leukemia (ALL). Median age was 38 and 29 years for AML and ALL patients, respectively. Presence of circulating blasts, >25% marrow blasts, Karnofsky score < 90 %, or transplant in first relapse was observed in nearly half of the patients (see Table). RESULTS: 100 day mortality was 39% in AML and 41% in ALL. The median follow-up of survivors was 5 years. Overall survival (OS) was 19% (95% confidence interval (CI) 17-21) for AML and 16% (13-20) for ALL patients. For AML patients, five adverse pre-transplant variables significantly impacted OS : first CR duration < 6 months, blasts in the blood, donor other than HLA-identical sibling or partially matched unrelated, Karnofsky score < 90%, poor-risk cytogenetics. 106 AML patients had none of these high risk criteria, with a 3 years OS of 44% (35-54). For ALL patients, survival was worse with either: 1st refractory or ' 2nd relapse, ≥ 25% marrow blasts, CMV seropositive recipient, age ≥10 years. 8 ALL patients had no high risk criteria, with a 3 years OS of 85% (53-100). Grade 3-4 acute graft-vs-host disease (GVHD) occurred in 23% of AML and 27% of ALL patients. Chronic GVHD developed in 27%. Leukemia was the cause in 42 % of AML and 37% of ALL patients' deaths. CONCLUSIONS: 1. HCT can cure some patients with acute leukemia in relapse or with PIF, particularly those lacking defined high risk features. 2. These pre-transplant variables should be considered when deciding whether or not to offer HCT to such patients. Disclosures: No relevant conflicts of interest to declare.

Hypercvad+Bortezomib Is a Well Tolerated Salvage Regimen for Relapsed/Refractory Adult Acute Lymphoblastic Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4345-4345
Author(s):  
Jyotishankar Raychaudhuri ◽  
Mudhasir Ahmad ◽  
Manas Kalra ◽  
Harsh Dua ◽  
Rakesh Chopra ◽  
...  
Keyword(s):  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
High Dose ◽  
Salvage Regimen ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
Primary Induction ◽  
Induction Failure ◽  
High Dose Melphalan

Abstract Abstract 4345 We report the excellent tolerability of a regimen of HyperCVAD+Bortezomib for relapsed/refractory ALL in adults. The regimen consisted of addition of two doses of Bortezomib 2 mg(1mg/m2) on day 1 and day 4 of the HyperCVAD regimen(arm A). The doses of bortezomib were given an hour after the second dose of cyclophosphamide on day 1 and on day 4. GCSF 10 mcg/kg was used from nadir to recovery of ANC > 500. Two patients, one with relapsed ALL and the second with primary induction failure were treated with this regimen after informed consent. The first patient was a 38 year male who was diagnosed with Ph+ ALL four years ago and had relapsed three years later on maintenance treatment. He was subsequently treated with Adriamycin, Etoposide and Cyclophosphamide with minimal response. Last bone marrow showed 35–40% blasts. The second patient was 40 year female with CALLA + Pre-B cell ALL with primary induction failure with a BFM regimen. Both patient reached nadir counts by day 10–11 and recovered the absolute neutrophil counts > 500 by day 16. There was minimal blood product requirement and minimal episodes of neutropenic fever which were treated as per institutional protocol. All cultures were negative. Isolation was not required. Strict aseptic precautions were maintained. Minimal grade I mucositis occurred in the first patient. Minimal diarrhea with nausea and vomiting occurred in the second patient on day 15. No neuropathy was noted. On day +21, the first patient, who was resistant to multiple chemo agents still has 40% blasts in the marrow but also shows recovery of the normal marrow elements. The second patient, who had primary induction failure is in complete remission in the marrow. One report of a phase I trial by Messinger et al from Minnesota showed the feasibility and tolerability of Bortezomib added to VXLD in pediatric ALL. Horton et al from a COG phase I study did not find any objective responses to single agent Bortezomib in resistant leukemia even though it suppressed NfKB activity. This is the first report to our knowledge on the use of salvage bortezomib based regimen in relapsed/refractory adult ALL. We used low dose bortezomib(1 mg/m2) after the administration of chemotherapy on day 1 and day 4. The timing of bortezomib just after chemotherapy is probably important. One ASH abstract #949(2007) by Lonial et al suggested that Bortezomib following high dose melphalan in multiple myeloma results in increased apoptosis of MM cells than if Bortezomib precedes melphalan. We plan to proceed to a phase II trial to test this regimen in relapsed/refractory ALL. Disclosures: Off Label Use: Bortezomib as chemosensitizer with Hyper CVAD in ALL.

scholarly journals Hematopoietic Stem-Cell Transplantation for Acute Leukemia in Relapse or Primary Induction Failure

2010 ◽  
Vol 28 (23) ◽  
pp. 3730-3738 ◽  
Author(s):  
Michel Duval ◽  
John P. Klein ◽  
Wensheng He ◽  
Jean-Yves Cahn ◽  
Mitchell Cairo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Predictive Score ◽  
Hematopoietic Stem ◽  
Primary Induction ◽  
Induction Failure

Purpose Patients with acute leukemia refractory to induction or reinduction chemotherapy have poor prognoses if they do not undergo hematopoietic stem-cell transplantation (HSCT). However, HSCT when a patient is not in complete remission (CR) is of uncertain benefit. We hypothesized that pretransplantation variables may define subgroups that have a better prognosis. Patients and Methods Overall, 2,255 patients who underwent transplantation for acute leukemia in relapse or with primary induction failure after myeloablative conditioning regimen between 1995 and 2004 were reported to the Center for International Blood and Marrow Transplant Research. The median follow-up of survivors was 61 months. We performed multivariate analysis of pretransplantation variables and developed a predictive scoring system for survival. Results The 3-year overall survival (OS) rates were 19% for acute myeloid leukemia (AML) and 16% for acute lymphoblastic leukemia (ALL). For AML, five adverse pretransplantation variables significantly influenced survival: first CR duration less than 6 months, circulating blasts, donor other than HLA-identical sibling, Karnofsky or Lansky score less than 90, and poor-risk cytogenetics. For ALL, survival was worse with the following: first refractory or second or greater relapse, ≥ 25% marrow blasts, cytomegalovirus-seropositive donor, and age of 10 years or older. Patients with AML who had a predictive score of 0 had 42% OS at 3 years, whereas OS was 6% for a score ≥ 3. Patients with ALL who had a score of 0 or 1 had 46% 3-year OS but only 10% OS rate for a score ≥ 3. Conclusion Pretransplantation variables delineate subgroups with different outcomes. HSCT during relapse can achieve long-term survival in selected patients with acute leukemia.

scholarly journals External Validation of the Revised PAM Score for Patients with AML Scheduled for Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3495-3495
Author(s):  
Frederike Kollinger ◽  
Jan Moritz Middeke ◽  
Maria Hardtmann ◽  
Christian Klesse ◽  
Friedrich Stölzel ◽  
...  
Keyword(s):  
External Validation ◽  
Disease Stage ◽  
Rank Test ◽  
Reduced Intensity Conditioning ◽  
Hematopoietic Stem ◽  
Log Rank Test ◽  
Donor Type ◽  
Primary Induction ◽  
Induction Failure ◽  
Reduced Intensity

Abstract Purpose Counselling of patients with AML about allogeneic hematopoietic stem cell transplantation (alloHSCT) is still an ambitious task in the light of the potential curative perspective after alloHSCT, poor outcomes after non-transplant approaches but a high risk of transplant-associated complications and still a significant risk of relapse even after HSCT. Several scores have been developed to predict outcome after HSCT, such as the HCT-CI and the Pre-transplant Assessment of Mortality (PAM) score. The PAM score has been revised recently, thereby acknowledging the shift to more frequently used reduced intensity conditioning. This score utilizes information on pts.age, donor type, disease risk, theserostatus for the CMV of pts.and donor, and the forcedexspiratory volume in the 1 second (FEV1). The aim of this study was to analyze the predictive power of the PAM score in an independent, large cohort of AML pts.who receivedalloHSCT within the last 12 years. Patients and Methods We selected all adult AMLpts.whoreceived the firstalloHSCTat the University Hospital of Dresden, a tertiary care hospital with a large transplant program, from January, 1, 2003 to July, 1, 2015.Pts.withhaplo-identical donors or after cord-blood transplantation were excluded. All patients gave their informed consent on analysing data. The PAM score was calculated as published (Au et al., BBMT 2015) and stratified into 4 groups: scores <17,scores17 to <24, scores 24 through 30, and scores >30. Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after alloHSCTwereanalyzed according to several factors known to impact outcome using the log-rank test for univariate comparison. Age, AML type (de novo vs. sAMLvs. t-MN), sex match (female donor/male recipient vs. all other), CMV match (negative/negative vs. all other), donor type (sibling vs. matched unrelated vs. mismatched unrelated), ELN risk classification, type of conditioning (RIC vs. MAC), disease stage (CR1 vs. primary induction failure vs. >= first relapse) and the PAM score as a continuous variable were selected a priori for multivariate Cox regression analyses. Results Overall, 544 pts.metthe inclusion criteria and were analyzed,the median age was 57 years (range, 18 to 76). Two-hundred-three pts.(37%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts. received reduced intensity conditioning (RIC). Donors were siblings in 120 (22%), matched unrelated in 295 (54%) and mismatched unrelated donors in 129 (24%) pts. With a median follow up of 47 months (range, 1 to 161), the estimated OS for the whole cohort at five years was 43%, with a CIR of 30% and a NRM of 31% up to that time-point. The probability for OS at five years for pts.in PAM score group 0, 1, 2, and 3 was 65%, 50%, 33%, 22%, respectively (log-rank test, p= <.001). Both the CIR and NRM increased with increasing PAM scores (gray-tests, p= .005 and p= <.001, respectively). Notably, the PAM score contributed significantly to the prediction of OS even when added to a multivariate regression model which contained the single components of the score. In the final multivariate model, age (HR 1.02 per year, p= .004), disease stage (primary induction failure versus CR1, HR 1.5, p= .03), and the PAM score (HR 1.04, p= .03) had a significant impact on OS. Conclusion We validated the revised PAM for the prediction of OS after HLA-compatiblealloHSCTin a large, well characterised cohort of AMLpts.treatedat a large German transplantcenter. To the best of our knowledge, this is the first external validation of the revised PAM score. OS prediction based on this tool will be useful for counselling of futurepts.withAML. Figure OS after HSCT according to the PAM score Figure. OS after HSCT according to the PAM score Disclosures Middeke: Sanofi: Honoraria. Thiede:AgenDix: Employment, Other: Ownership. Schetelig:Sanofi: Honoraria.

Platelet Recovery Prior to Stem Cell Transplantation Predicts for Post- Transplant Outcomes in Patients with AML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3000-3000
Author(s):  
Gheath Alatrash ◽  
Matteo Pelosini ◽  
Rima M Saliba ◽  
Gabriela Rondon ◽  
Weiqing Zhang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Platelet Count ◽  
Gold Standard ◽  
Disease Status ◽  
Platelet Recovery ◽  
Remission Status ◽  
Hazard Ratios ◽  
First Relapse ◽  
Primary Induction ◽  
Induction Failure

Abstract Achievement of complete remission (CR), with &lt;5% blasts in bone marrow (BM), and peripheral blood platelet count &gt;100K/ml remains the gold standard achievement of chemotherapy for AML. A significant fraction of patients proceed to HSCT with &lt;5% blasts but without ever achieving platelet counts &gt;100K/ml (CRp). It is possible that with new AML therapies, the proportion of patients in such a situation will increase. We hypothesized that achievement of CRp has a worse prognostic connotation than ‘classically’ defined CR, and sought to investigate this hypothesis in a cohort of AML patients transplanted between 7/1995 to 12/2007 at our institution (N=427). Methods: Patients were eligible for this analysis if they were in the following disease status at transplantation: compete remission (CR); first CR (CR1; &lt;5% BM blasts and platelet count &gt;100K/ml); second CR (CR2); first CRp (CRp1): patients that had &lt;5% BM blasts but no platelet recovery following induction chemotherapy; primary induction failure (PIF): no CR with induction therapy (&gt;5% and no platelet recovery); CRp2: patients that after first relapse achieved &lt;5% BM blasts with salvage chemotherapy, but no platelet recovery; refractory: patients in first relapse that did not respond to salvage therapy (rel). A minimum of 30 days from the last day of chemotherapy to start of conditioning regimen elapsed for patients to be scored as CRp. Diagnosis were AML (n=376) or high-risk MDS (n=51). Conditioning included TBI-based (2%; n=8), oral/IV busulfan based-ablative regimens (61%; n=261), fludarabine/melphalan-based reduced intensity conditioning regimens (RIC) (36%; n=153), or other (1%; n=5). Fifty-eight percent of patients received matched sibling transplants (n=248), while 42% (n=179) received unrelated donor (UD) HSCT. Tacrolimus and methotrexate were used for graft-versus-host disease (GVHD) prophylaxis. ATG was administered to those who received grafts from UD. Results: Median age was 50 years (range 6–74); 51% of patients were 50 years or older (n=218); 55% were male (n=236). Disease status at HSCT was CR1 in 38% (n=164), CR2 in 24% (n=102), CRp1 in 11% (n=48), CRp2 in 7% (n=30); PIF 11% (n=47), and rel1 8% (n=36). Cytogenetics data were available for 90% (n=386) of patients. The proportion of poor-risk cytogenetics was comparable in patients who were in CR1 (39%) and CRp1 (44%), p=0.3, and in patients who were in CR2 (15%) and CRp2 (24%) p=0.2. Source of stem cells was BM in 41% of patients (n=174) and peripheral blood in 59% of patients (n=253). Ninety-six percent of patients engrafted. Fifty-one percent of patients have died (n=219); actuarial survival at 36-months was 49% for all patients. Thirty-one percent of patients (n=134) have progressed. Median follow-up among survivors is 42 months (range 3–131months). Non-relapse mortality (NRM) (figure 1), overall survival (OS) (figure 2), and hazard ratios for OS and NRM at 1-year (Table) favored patients who were transplanted in CR1 (vs. patients in CRp1 or PIF), or in CR2 (vs. CRp2 or rel1). Conclusion: In this cohort of patient with AML and MDS, patients in CR (CR1 or CR2) demonstrated significantly better OS and NRM compared to patients who underwent HSCT in CRp (CRp1 or CRp2). CRp conferred an intermediate prognostic status, better than refractory disease, but significantly worse than ‘classic’ CR. Our results suggest that achieving a CR prior to HSCT should remain the gold standard for patient in AML or MDS receiving allogeneic HSCT. Table. Hazard Ratios (HR) for non-relapse mortality (NRM) and overall survival (OS) at 1 year. NRM OS CR=complete remission; CRp=pathologic CR; PIF=primary induction failure. CR1 (n=164) Reference Reference CR2 (n=102) 1.4 (p=0.3) 1.3 (p=0.3) CRp1 (n=48) 2.4 (p=0.01) 2.4 (p=0.001) CRp2 (n=30) 1.7 (p=0.2) 1.9 (p=0.05) PIF (n=47) 3.7 (p=0.001) 3.6 (p=0.001) First relapse (n=36) 4.6 (p=0.001) 6.7 (p=0.001) Figure 1. NRM by Pre-Transplant Remission Status Figure 1. NRM by Pre-Transplant Remission Status Figure 2. OS by Pre-Transplant Remission Status Figure 2. OS by Pre-Transplant Remission Status

Mitoxantrone and Etoposide with or without Intermediate-Dose Cytarabine for the Treatment of Patients with Primary Induction Failure or Relapsed Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2174-2174
Author(s):  
Steven Trifilio ◽  
Alfred Radamaker ◽  
Diane Newman ◽  
Kathryn Coyle ◽  
Katrin Carlson Leuer ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Prospective Trial ◽  
Response To Treatment ◽  
High Dose ◽  
Cell Transplant ◽  
Significant Difference ◽  
Primary Induction ◽  
Induction Failure ◽  
Acute Myeloid ◽  
Intermediate Dose

Abstract Abstract 2174 Introduction: The prognosis for patients with primary induction failure (PIF) or relapsed acute myeloid (Rel-AML) is poor. Mitoxantrone (M) plus etoposide (E)- based salvage regimens (ME), in particular, either alone or with intermediate dose cytarabine (MEC) are effective in these high risk patients; However, these regimens have not been directly compared. Heterogeneity in chemotherapy dose, dose escalation and age have been important limitations in the evaluation of previous studies. Also problematic, historically patients were classified according to FAB criteria. Since then, karyotype has been shown to be a main determinant of prognosis. The influence of karyotype on response to ME or MEC is currently unknown. Herein, we report the response to treatment with a fixed dosing schedule of ME or MEC in 66 patients treated for PIF or Rel-AML with intermediate(intermed-) or unfavorable(unfav-) risk cytogenetics. Differences in CR between ME and MEC subsets were analyzed to determine the effect of adding of C to ME. Methods: 66 consecutive patients with PIF or Rel-AML treated with either ME(n=37)or MEC(n=29) between 10/2004-12/2008 were evaluated. All patients had received initial induction therapy with daunorubicin 45–60mg/m2 IV bolus d1-3 and cytarabine 100mg/m2 CI d1-7(7+3), and consolidation with HIDAC if CR was achieved. ME and MEC were dosed according to previously published studies. The decision to use a given salvage was left to the discretion of the treating physician. Chi-Square test was used for statistical analysis. Results: Table1 shows there was no difference between the ME and MEC groups with regards to age, sex, % blasts at initial diagnosis, and %CR after initial induction with 7+3, or % patients who received inter- to high dose C prior to ME or MEC. Length of CR (after 7+ 3 and consolidation) was significantly longer in the MEC group. A significantly higher number of CR's was observed in the MEC group compared to ME(p=0.05). Within the MEC group, no difference in CR was observed between patients with intermed- and unfav-risk cytogenetics(p=0.96). The same was true within the ME group(p=0.13). When MEC was compared to ME, a significant difference in CR was observed in patients with unfav-risk cytogenetics(p=0.044) and patients <60years old. Prior to therapy, MEC patients had higher number of blasts. MEC patients had a significantly longer duration of remission. One patient in both the ME and MEC group died before hematopoetic reconstitution. Conclusion: In clinical practice, as observed in the present study, we observed a greater overall CR rate in patients who received MEC compared to those treated with ME, particularly in younger patients with unfav-risk cytogenetics. For those who achieved CR after MEC or ME, a longer duration of CR was observed in the MEC group compared to ME. These results could be particularly beneficial for those patients receiving salvage therapy as a temporizing measure prior to allogeneic hematopoetic stem cell transplant ion, and encourages confirmation from a prospective trial. Disclosures: No relevant conflicts of interest to declare.

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