scholarly journals The Treatment Related Mortality Score Predicts Early Adverse Events during Intensive Induction Chemotherapy for Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2276-2276
Author(s):  
Sarah A. Buckley ◽  
Megan Othus ◽  
Elihu H. Estey ◽  
Roland B. Walter
Keyword(s):  
Adverse Events ◽  
Supportive Care ◽  
Induction Chemotherapy ◽  
Independent Study ◽  
Recent Analysis ◽  
Study Cohort ◽  
Increased Risk ◽  
Icu Transfer ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Background: Despite improvements in supportive care, treatment of AML remains associated with complications. We have developed a multivariate model – the Treatment-Related Mortality (TRM) score – which includes age, performance status, and 6 other covariates to predict 28-day mortality with c-statistic = 0.82 (1.0 = perfect prediction, 0.5 = no prediction) (Walter et al. J Clin Oncol 2011). We investigated associations between TRM score and complications developing during AML treatment. Patients and Methods: 179 adults (median age 53 [range: 18-77] years) with newly diagnosed AML treated at our institution from 2002-2012 with 7 + 3 or similar therapy were included. Documented infections, ICU transfer, and death until the earlier of day 28 or administration of additional chemotherapy were recorded. Patients were categorized by quartiles of TRM score. All outcomes were treated as time-to-event endpoints. The survival probabilities in the absence of infection or ICU transfer were estimated using the Kaplan-Meier method; the 10 patients in the ICU at the start of chemotherapy were excluded from analysis of ICU transfer as an adverse event. Outcomes between TRM scores by quartile were assessed using log-rank test for trend; scores above and below the median were compared using Cox regression. Multivariate models were adjusted for gender, cytogenetic risk, baseline absolute neutrophil count, and year of treatment. Results: The median TRM score was 4.6 (quartiles 2.3 and 10.5). Documented infections occurred in 72 patients (40%), ICU transfer in 14 (8%), and death in 4 (2%) within 28 days of induction. Patients with higher ranges of TRM scores were more likely to develop infections (Ptrend=0.006; Fig 1a) and require ICU transfer (Ptrend=0.003; Fig 1b). In particular, TRM scores above the median were associated with increased risk of infection (P=0.02; Fig 1c) and ICU transfer P=0.0004; Fig 1d). After multivariable adjustment, the risk of documented infection was 1.72 (95% CI: 1.06-2.81)-fold higher for patients with TRM >4.5. Consistent with our recent analysis, baseline grade 4 neutropenia was also independently associated with infection (HR 2.2 [95% CI: 1.38-3.52]) (Buckley et al. Am J Hematol 2014). There was only one ICU transfer, and there were no deaths among the 92 patients with TRM score less than the median. Although supportive care measures have improved in recent years, a high TRM score was still associated with ICU transfer in the subset of patients treated from 2007-2012 (P=0.001). Conclusions: The TRM score is associated not only with death, but also with other early adverse events. A cut-point of 4.5, which will need to be confirmed in an independent study cohort, may separate low- from high-risk patients in terms of susceptibility to infection and likelihood of requiring an ICU transfer. The TRM score may thus improve assessment of the risks of intensive induction chemotherapy and help allocate health care resources. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

A Network of Treatment Centers and Standardisation of Treatment Protocol Leads to Reduction in Mortality in Acute Promyelocytic Leukemia (APL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4317-4317 ◽  
Author(s):  
Anand P. Jillella ◽  
Farrukh Awan ◽  
Ravindra B. Kolhe ◽  
Jeremy M Pantin ◽  
Devi D Morrison ◽  
...  
Keyword(s):  
High Risk ◽  
High Mortality ◽  
Causes Of Death ◽  
Population Based ◽  
Low Risk ◽  
Recent Analysis ◽  
Cumulative Survival ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 4317 Background: APL is widely accepted as a curable leukemia with most multi-institutional studies showing very low treatment related mortality. This is in contrast to treatment in clinical practice outside the study population where the treatment related mortality is higher. A few recent population based studies show that mortality maybe as high as 30% in APL patients during induction. A recent analysis of SEER data from 13 population-based cancer registries with 1400 APL patients in the US showed that 17% of all patients and 24% of patients greater than 55 years of age die within one month of diagnosis. Swedish registry data and Brazilian data also show this high mortality during induction. The most common causes of death are bleeding, infection, differentiation syndrome and multi-organ failure. Patients who survive induction have an excellent cure rate with few late relapses. Hence, decreasing early deaths is a high priority both at experienced as well as smaller centers with limited leukemia treatment experience in this highly curable disease. Methods: At Georgia Health Sciences University, between 7/2005 and 6/2009, 19 patients were diagnosed with APL. Seven patients (5 high-risk and 2 low-risk) died during induction resulting in an unusually high mortality rate of 37%. All patients who survived induction are still in remission at present. The high early death rate prompted us to develop a simple, 2 page treatment algorithm that focuses on quick diagnosis, prompt initiation of therapy, and proactive and aggressive management of all the major causes of death during induction. We also developed a network of physicians in smaller community based treatment centers and gave them access to our protocol and helped them manage these patients in the induction period with the hypothesis that this standardized treatment approach will result in decreasing induction mortality. Results: From 11/2010 to 7/2012, we treated 5 patients at GHSU and helped manage 4 patients at 2 outreach sites. The age range was 30 to 60; two patients were high-risk, 6 intermediate- and one low-risk. In the pre-algorithm cohort the cumulative survival was 63.1% at 1 year with all deaths happening within 31 days. In contrast, after the implementation of a standardized algorithm the cumulative survival was 100% with no deaths during the induction or subsequent follow-up period, log rank p-value=0.05, with a median follow-up of more than 4-years in surviving patients. Conclusions: While we recognize that this is a small cohort, our own experience and a similar approach pioneered by investigators in Brazil clearly shows that this centralized, algorithm-based management under the direct supervision of a leukemia expert can be an effective intervention to decrease early deaths in APL. Based on the Brazilian experience an international consortium was formed to reduce the mortality and interim data show a reduction in early mortality to 7.5% with this networking of treatment centers. We believe our experience warrants large scale implementation with development of a network of physicians and standardization of treatment in the United States to improve early outcomes in this highly curable leukemia. Disclosures: Awan: Allos Therapeutics: Speakers Bureau.

Related transplantation with HLA-1 Ag mismatch in the GVH direction and HLA-8/8 allele-matched unrelated transplantation: a nationwide retrospective study

Blood ◽  
2012 ◽  
Vol 119 (10) ◽  
pp. 2409-2416 ◽  
Author(s):  
Junya Kanda ◽  
Hiroh Saji ◽  
Takahiro Fukuda ◽  
Takeshi Kobayashi ◽  
Koichi Miyamura ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelogenous Leukemia ◽  
Unrelated Donor ◽  
Hla Dr ◽  
Increased Risk ◽  
Related Donor ◽  
Risk Of Treatment ◽  
Standard Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)–matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell–replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P < .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-related mortality. The HLA-C Ag mismatch or multiple allelic mismatches were frequently observed in the HLA-B Ag-mismatched group, and were possibly associated with the poor outcome. In conclusion, an 8/8-MUD should be prioritized over an RD/1AG-MM-GVH donor during donor selection. In particular, an HLA-B Ag mismatch in the GVH direction has an adverse effect on overall survival and treatment-related mortality in patients with standard-risk diseases.

Treatment Related Mortality of AML Pediatric Patients in a Single Center in Saudi Arabia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4291-4291
Author(s):  
Wasil Jastaniah ◽  
Mohammed Burhan Abrar ◽  
Taha Khattab
Keyword(s):  
Supportive Care ◽  
Pediatric Patients ◽  
Conflicts Of Interest ◽  
Contributing Factors ◽  
Significant Difference ◽  
Medical City ◽  
Lost To Follow Up ◽  
The Impact ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 4291 Despite minimal changes in therapeutic approach, the outcome of acute myeloid leukemia (AML) in pediatric patients has improved significantly in the past two decades. Supportive care measures may have contributed to this success by reducing treatment related mortality (TRM) and thereby improving the overall survival (OS) of patients. Yet their impact on outcome remained unknown and masked under protocol effect. To assess the impact of supportive care measures on outcome, we undertook a retrospective review of all pediatric patients diagnosed with AML between 1986 and 2011and treated in our institution, the Princess Norah Oncology Center, King Abdulaziz Medical City, Jeddah. A total of 87 patients were reviewed. Of these, two patients whose parents refused treatment and one lost to follow-up were excluded. A total of 84 patients were qualified for the study. These patients were treated with two different protocols based on treatment eras. Patients diagnosed between 1986 and 1995 (era 1) were treated following AML-BFM-78 protocol while patients diagnosed between 1996 and 2011 (era 2) were treated following the MRC AML10. The cumulative TRM incidence was 76% in era1 compared to 11.5% in era 2 (P = 0.0001). This resulted in an improved 5-year OS from 10.5% in era 1 to 56% in era 2 (P = 0.007). The protocols used in both eras were different and may have improved OS. Significant difference in TRM however, suggests that other factors contributed to the improved OS. To gain further insight of the contributing factors, patients who received only MRC AML10 protocol (in era2) were partitioned into two sub-eras based on supportive care measures introduced sequentially in our institution as follows: 1996 to 2002 (era 2a) and 2003 to 2011 (era 2b).The cumulative TRM incidence was 48.6% in era 2a and 4.7% in era 2b (P = 0.001). This also resulted in an improved OS from 33.3% in era 2a to 56.2% in era 2b despite using the same protocol (P = 0.007). Our findings highlight the importance of supportive care as a significant factor in outcome of children. Comparing protocols per se masks the importance of supportive care measures in impacting outcome. We suggest devising a standardized scoring system to evaluate center-specific supportive care measures to quantify the impact of supportive care on TRM and survival outcomes while simultaneously allowing us to distinguish the effect of supportive care from that of protocol and other factors such as ethnicity. Disclosures: No relevant conflicts of interest to declare.

Conditional Survival and Cause-Specific Mortality in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Hematologic Malignancy Over Three Decades

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 606-606
Author(s):  
Saro H. Armenian ◽  
Can-Lan Sun ◽  
Tabitha Vase ◽  
George Mills ◽  
Liezl Atencio ◽  
...  
Keyword(s):  
General Population ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
Mortality Rates ◽  
Conditional Survival ◽  
Risk Of Death ◽  
Increased Risk ◽  
Risk Of Relapse ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 606 Background: alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT. Methods: From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records. Results: As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table. Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD. Conclusions: The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Optimum Induction Chemotherapy for Pediatric Acute Myeloid Leukemia: Experience From A Developing Country

2020 ◽  
Vol 25 (4) ◽  
pp. 288-294
Author(s):  
Tariq Ghafoor ◽  
Shakeel Ahmed ◽  
Sumaira Khalil ◽  
Tanzeela Farah
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Fungal Infections ◽  
Disease Free Survival ◽  
Induction Treatment ◽  
Pediatric Aml ◽  
Treatment Related Mortality ◽  
Related Mortality ◽  
Acute Myeloid

OBJECTIVES Treatment outcome in children with acute myeloid leukemia (AML) has improved in the developed world but remains poor in developing countries. We assessed the role of etoposide in induction chemotherapy in pediatric AML. METHODS This analysis retrospectively compared 2 induction chemotherapy regimens consisting of daunorubicin and cytarabine with etoposide (ADE) and without etoposide (AD). All newly diagnosed cases of AML younger than 18 years from January 1, 2012, onwards who completed their treatment before January 31, 2019, were included. Data of 186 cases, including 117 males (62.9%) and 69 females (37.1%), were analyzed. Demographic, initial presentation blood counts, and AML subtypes were almost identical in both groups. RESULTS Complete remission rates were almost identical for the ADE versus the AD group (78.8% vs 80.0%, p = 0.980). Treatment-related mortality was higher, albeit not significantly, in the ADE (25 of 105; 23.8%) versus the AD (16 of 81; 19.8%) group (p = 0.508). Overall survival was 32 of 105 (30.5%) in the ADE and 43 of 81 (53.1%) in the AD group (p = 0.079), and disease-free survival was 29 of 105 (27.6%) and 39 of 81 (48.1%) in ADE and AD groups (p = 0.056), respectively. CONCLUSIONS Etoposide in induction treatment of pediatric AML is associated with increased episodes of bacterial and fungal infections and high treatment-related mortality. Moreover, it does not offer any survival benefit. In low- and middle-income countries like Pakistan, it should not be used in the induction treatment protocol.

Myeloid Leukemia of Down Syndrome: The Results of An International Retrospective Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2718-2718
Author(s):  
Marjolein Blink ◽  
Marry M. Van den Heuvel-Eibrink ◽  
Válerie de Haas ◽  
Henrik Hasle ◽  
Maureen O'Brien ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
The Other ◽  
Leukemic Cells ◽  
Trisomy 8 ◽  
Treatment Protocols ◽  
Increased Risk ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 2718 Children with Down Syndrome (DS) have an increased risk of developing acute myeloid leukemia. Myeloid leukemia of Down Syndrome (ML-DS) has a better prognosis than sporadic pediatric AML, using reduced-intensity treatment protocols as the leukemic cells of these patients are relatively sensitive to chemotherapy. Moreover, ML-DS patients have an increased risk of side-effects, hence there is a delicate balance between anti-leukemic efficacy and treatment related mortality. So far, no prognostic factors in ML-DS have been identified that allow a risk-stratified approach in future ML-DS treatment protocols. The majority of the ML-DS cases are characterized by additional karyotypic changes in their leukemic cells besides the constitutional trisomy 21 (Forestier et al, Blood 2008), but the potential prognostic impact of these cytogenetic abnormalities is not known. We therefore conducted a large international retrospective study and collected clinical and cytogenetic data of 451 children with ML-DS from 13 collaborative study groups. Patients were eligible between 6 months and up to 5 years of age, and were diagnosed between Jan 1, 1995 and Jan 1, 2005. Patients who were not treated with curative intent were excluded. All karyotypes were centrally reviewed before assigning patients to cytogenetic groups. The Kaplan-Meier method was used to estimate the 5-years OS and 5-years EFS, and outcome estimates were compared using the log-rank test. Cumulative incidence functions of relapse (CIR) were compared by the Gray test. For multivariate analysis, the Cox proportional-hazard regression model was used. The median age of all ML-DS patients (n= 451) was 1.8 years (range 0.5 – 5.0) and the median white blood cell count (WBC) was 7.0 × 109/l (range 0.8 – 290). The overall 5-years EFS was 78%, the 5-years OS 79%, the 5-years CIR 8%, and treatment related mortality (TRM) was 11%. The main groups were the patients with a normal karyotype (NK) (n= 103; 29%), trisomy 8 (n= 63; 18%) and ‘other’ patients (n= 187; 53%). Outcome estimates showed large differences across these different cytogenetic groups. There were no significant differences in age between the NK, trisomy 8, and the other patients. However, trisomy 8 patients did have a significantly lower median WBC (6.3 × 109/l; P25=4.0 – P75=10.3) compared to both other groups (7.2 × 109/l; P25=4.6 – P75=16.7); P= 0.03). The NK patients had a significantly worse 5-years OS, EFS, and CIR compared to the other patients and the trisomy 8 group (OS 69% vs. 83% vs. 90%; P= 0.002 and 0.006; EFS 68% vs. 81% vs. 88%; P= 0.006 and P= 0.005; and CIR 19% vs. 9% vs. 5%; overall p(Gray)= 0.002). TRM was highest in the NK patients (13%). In addition, patients with a loss of 7q/monosomy 7 (n=16) had a 5-years EFS of 69%, which is remarkably high compared to non-DS AML (39%) (Hasle et al, Blood 2007). Furthermore, younger patients, age < 3 years showed a significantly better 5-years EFS and CIR than patients aged ≥ 3 years (EFS 79% vs. 65%; P = 0.04; CIR 9% vs. 21%; P = 0.03). OS was not significantly different (80% vs. 69%; P = 0.10). Patients with a WBC < 20 × 109/l had a borderline significantly better 5-years EFS and CIR than patients with a WBC ≥ 20 × 109/l (EFS 80% vs. 70%; P = 0.05, CIR 9% vs. 16%; P = 0.05). OS was not significantly different. Multivariate analysis revealed NK patients (hazard ratio [HR] = 1.82, P = 0.027), WBC ≥ 20 × 109/l (HR = 1.77, P = 0.029) and age > 3 years (HR = 2.37, P = 0.005) as independent predictors for poor EFS. The trisomy 8 group was not independently associated with a favorable outcome, which may be explained by the fact that the WBC of these patients was significantly lower and hence that there is interference between these 2 characteristics. In conclusion, this study shows independent risk-groups within ML-DS that may benefit from stratified therapy. It has to be mentioned that patients were treated on different treatment protocols, which were sometimes adjusted for DS. As NK ML-DS patients have a higher CIR than TRM, therapy reduction is not an option for this group. To improve the prognosis of these patients, the biological background has to be investigated. As known in non-DS AML normal karyotype patients, mutations in WT1 and FLT3 are associated with poor outcome. FLT3 mutations are not found in ML-DS patients and as WT1 mutations have not yet been well studied in this group, this may be subject of further research. Disclosures: No relevant conflicts of interest to declare.

Declining Rates of Treatment-Related Mortality in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) Given “Intensive” Induction Regimens: A Report From the Southwest Oncology Group (SWOG) and MD Anderson Cancer Center (MDA)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 129-129 ◽  
Author(s):  
Megan Othus ◽  
Hagop M. Kantarjian ◽  
Stephen Petersdorf ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Supportive Care ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Cancer Center ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Secondary Aml ◽  
Over Time ◽  
Treatment Related Mortality ◽  
Related Mortality

Abstract Abstract 129 Background Recent emphasis has been placed on administration of induction regimens less intense than standard 3+7 for patients with newly diagnosed AML. A primary goal is to reduce the presumed average treatment related mortality (TRM) rate of 10% occurring within the first 28 days after start of 3+7 or higher intensity therapies; TRM rates have been > 30% in patients who are older and/or have poor performance status (PS]. (Walter et al. JCO 2012). This practice presupposes that TRM rates with higher intensity induction regimens are static, a notion seemingly difficult to reconcile with advances in supportive care (e.g. newer anti-aspergillosis drugs) that have sharply reduced rates of non-relapse mortality after allogeneic hematopoietic cell transplant (Gooley et al. NEJM 2010). Methods We thus addressed rates of TRM from 1991–2009 in 1,409 patients given 3+7 induction regimens on SWOG protocols (cytarabine dose 100 mg/m2 daily × 7) and 1,933 patients given induction regimens containing higher cytarabine doses (at least 1.0 g/m2 daily × 4–5 days) at MDA, variably combined with idarubicin, fludarabine or other agents. Multivariate analyses were used to account for confounding factors. Results TRM rates declined both in SWOG and at MDA. However this reduction must account for the declining ages of patient given 3+7 or more intense induction (p<0.001 in both SWOG and at MDA) and their improved PS (p<0.001 SWOG and MDA);the considerably younger nature of SWOG patients during 2006–2009 reflects the switch to less intense induction regimens for many older patients; such regimens were not included in this analysis. Additionally other covariates associated with TRM (more blood blasts, lower platelets, secondary AML) by Walter et al. (JCO 2012)were unevenly distributed in the various time periods(for example no secondary AML in SWOG 2006–2009). Multivariate logistic regression was thus performed to account for the effect of age, PS, and these other covariates in the reduction in TRM. After such accounting, odds ratios (ORs) for TRM at MDA were (relative to 1995) 0.89, 0.7, and 0.36 for 1996–2000,2001–2005, and 2006–2009 respectively with the null hypothesis of no change over time rejected at p = 0.006. For SWOG, not including secondary AML as a covariate ORs were (relative to 1991– 1995) 0.75,0.78, and 0.42 for 1996–2000,2001–2005,and 2006–2009 respectively; again the hypothesis of no change with time was rejected (p = 0.037). There were no interactions between reduced TRM and age, WBC or performance status suggesting the reduction in TRM was a general phenomenon. Conclusion There has been a reduction over time in TRM after “intensive” induction possibly due to better supportive care. Although various selection biases cannot be excluded, this decline is not due to younger age or better performance status and needs to be considered when choosing AML induction therapy. Disclosures: No relevant conflicts of interest to declare.

Risk of treatment-related death in carriers of pathogenic DPYD polymorphisms treated with fluoropyrimidine chemotherapy: A systematic review and patient-level analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15132-e15132 ◽  
Author(s):  
Karan Rai ◽  
Bhavina D O Batukbhai ◽  
Gabriel A. Brooks
Keyword(s):  
Systematic Review ◽  
Standard Dose ◽  
Patient Level Data ◽  
Risk Of Death ◽  
Patient Level ◽  
Level Data ◽  
Increased Risk ◽  
Risk Of Treatment ◽  
Treatment Related Mortality ◽  
Related Mortality

e15132 Background: Polymorphisms of the DPYD gene are present in 3-5% of the population and are associated with increased risk for grade ≥3 toxicity during treatment with fluoropyrimidine (FP) chemotherapy. Fatal toxicities in carriers of DPYD polymorphisms have been described in published reports, however reliable estimates of the risk of treatment-related mortality are lacking. Methods: We conducted a systematic review of the MEDLINE database to identify relevant manuscripts published before January 28, 2018. We searched for published studies of patients receiving standard-dose FP chemotherapy (5-fluorouracil or capecitabine) who had pre-treatment testing for ≥1 of 4 pathogenic DPYD polymorphisms (c.1236G > A/HapB3, c.1679T > G, c.1905+1G > A/*2A, and c.2846A > T) and who were systematically assessed for treatment-related toxicities. In the case of retrospective studies, we required that the cohort be defined by pretreatment characteristics (e.g., patients were not included on the basis of observed toxicity). Two reviewers extracted study- and patient-level data, with discrepancies resolved by consensus. The pooled data were analyzed to estimate the risk of treatment-related mortality among polymorphism carriers. Results: Of the 1290 references screened, 37 publications were included in the final analysis. Patient-level data identified 485 of 14,377 patients (3.4%) with pathogenic DPYD polymorphisms. There were 12 deaths among polymorphism carriers, resulting in a 2.5% risk of treatment-related mortality (95% CI 1.3-4.4%). Only 2 treatment-related deaths were reported in 13,892 patients without identified polymorphisms. Risk of death by genotype is shown in the table; two decedents were compound heterozygotes. Conclusions: Patients with pathogenic DPYD polymorphisms who are treated with standard-dose FP chemotherapy are at significant risk of death and can be prospectively identified through pharmacogenetic testing. [Table: see text]

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