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Table of Contents
ORIGINAL ARTICLE
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 628-633

The utility of day 14 bone marrow response assessment in patients undergoing acute myeloid leukemia induction: A single institution retrospective experience


Department Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalaserry, Kerala, India

Date of Submission01-May-2021
Date of Decision21-Jun-2021
Date of Acceptance05-Nov-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Chandran K Nair
Department of Clinical Hematology and Medical Oncology, Malabar Cancer Centre, Thalaserry, Kannur - 670 103, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_90_21

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  Abstract 


Background: Examination of the bone marrow on day 14 of induction chemotherapy for acute myeloid leukemia (AML) is a common practice. However, the evidence for re-inducing the patient based on early bone marrow response is limited.
Objectives: This study was aimed at assessing the utility of bone marrow examination on day 14 of AML induction in predicting complete remission (CR) or residual disease and its impact on clinical decisions on re-induction in a resource-limited setting.
Materials and Methods: This retrospective study was conducted at the Malabar Cancer Center, a tertiary cancer center in Kerala, India. Adult patients with AML who received 3 + 7 (daunorubicin + cytarabine) induction chemotherapy from January 2011 to December 2018 and underwent an early bone marrow examination on day 14 were included in the study. Early marrow response was considered adequate if the marrow cellularity was less than 15%–20%, with less than 5%–10% blasts. Patients with inadequate bone marrow response were given re-induction chemotherapy, if eligible. Unfit patients were continued on supportive measures. The end-of-induction bone marrow was done on day 28 after count recovery. Case records of all patients were reviewed, and data including the baseline characteristics, day 14 bone marrow response, and post-induction marrow status were collected.
Results: Of the 96 patients who received induction chemotherapy during the study period, 78 underwent day 14 bone marrow assessment. The median age was 44 years (range, 15-66), and 43% of the patients were males. On day 14, 57 (73%) patients had adequate bone marrow response, 19 (24%) had inadequate response, and 2 (3%) had inconclusive results. Among the patients with inadequate responses, 12 attained CR at the end of induction, although only 9 received re-induction. Adequate day 14 bone marrow had a sensitivity of 89.8% (95% confidence interval [CI], 79–96) in predicting the remission status at the end of induction. The specificity of inadequate day 14 marrow response in predicting residual disease in post-induction bone marrow was 89% (95% CI, 79–96). Similarly, the positive predictive value was 100% and the negative predictive value was 14%.
Conclusion: Although assessment of day 14 bone marrow response is useful in predicting the chances of CR at the end of induction, its role in guiding the decision for re-induction is doubtful, and larger studies are needed to address this question.

Keywords: Acute myeloid leukemia, complete remission, day 14 bone marrow, India


How to cite this article:
Manuprasad A, Raghavan V, Shenoy PK, Krishnan A, Nair CK. The utility of day 14 bone marrow response assessment in patients undergoing acute myeloid leukemia induction: A single institution retrospective experience. Cancer Res Stat Treat 2021;4:628-33

How to cite this URL:
Manuprasad A, Raghavan V, Shenoy PK, Krishnan A, Nair CK. The utility of day 14 bone marrow response assessment in patients undergoing acute myeloid leukemia induction: A single institution retrospective experience. Cancer Res Stat Treat [serial online] 2021 [cited 2022 May 18];4:628-33. Available from: https://www.crstonline.com/text.asp?2021/4/4/628/334238




  Introduction Top


Acute myeloid leukemia (AML) accounts for about 23% of all cases of leukemia worldwide.[1] It is one of the hematological malignancies, for which the prognosis remains dismal despite the advances in chemotherapy and supportive care. Although multiple targeted agents have emerged, the conventional 3 + 7 induction with 3 days of anthracyclines and 7 days of cytosine arabinoside remains the standard.[2] One of the strategies used to improve the remission rates in AML is the utilization of a re-induction regimen based on the morphological examination of the bone marrow on day 14 of induction.[3] The “day 14 bone marrow” is considered to be adequate if the marrow cellularity is <20%, with <5% blasts as per the National Comprehensive Cancer Network guidelines.[2] Patients with inadequate response are considered for an additional cycle of induction chemotherapy to increase the chances of attaining remission. This practice is mainly based on opinions rather than evidence.

Studies have demonstrated the long-term predictive value of the day 14 bone marrow response, but its utility in clinical decision-making has always been debated.[3] In addition, the definition of an adequate bone marrow response and the optimal timing of assessment are unclear.[4] It is proposed that selecting patients with inadequate response on day 14 marrow for one more cycle of induction chemotherapy can improve the remission rates and ultimately, the outcomes. However, the second cycle of induction may result in significant toxicity and higher treatment-related mortality.[4] In general, most of the European cooperative groups practice the double induction strategy, whereas re-induction based on the day 14 bone marrow response is a common practice in the United States.[5]

Nevertheless, the utility of the day 14 bone marrow assessment and its impact on treatment decisions in resource-limited settings are not well studied. It is well known that in low- and middle-income countries, treatment of AML involves unique challenges such as financial issues, inadequate supportive care services, high incidence of baseline infection, and high induction mortality.[6],[7] There are high chances of patients being unfit for the second cycle of induction in these settings, despite an inadequate marrow response. However, given the limited access to newer targeted agents and stem cell transplant facilities, any strategy that helps improve the remission rates is important in a country like India. Here, we report our experience with the day 14 bone marrow evaluation and its utility in clinical decision-making during AML induction.


  Materials and Methods Top


General study details

This retrospective study was conducted in the Department of Clinical Hematology and Medical Oncology at the Malabar Cancer Center, a tertiary cancer center in Kerala in rural India. The study was approved by the Institutional Review Board–Scientific Review Committee on May 18, 2020 [Supplementary Appendix 1]. The need for obtaining written informed consent from the participants was waived by the ethics committee, in view of the retrospective study design. The study was not registered in a public clinical trials registry. No funding was obtained. The study was conducted according to the ethical guidelines established by the Declaration of Helsinki, principles of Good Clinical Practice, and the guidelines established by the Indian Council of Medical Research.

Participants

All patients aged more than 14 years with AML who received the standard 3 + 7 induction between January 2011 and December 2018 and who underwent early bone marrow assessment were included in the study.

Variables

The primary objective was to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of day 14 bone marrow assessment in predicting complete remission (CR) or residual disease at the end of induction. The secondary objectives were to assess the association between the day 14 marrow response and post-induction bone marrow response and to determine the proportion of patients who received re-induction based on the day 14 bone marrow response.

Study methodology

Our standard induction comprised 3 days of daunorubicin (60 mg/m2/day) and 7 days of cytosine arabinoside (100 mg/m2 as a continuous infusion/day). For baseline risk stratification, reverse transcription–polymerase chain reaction (PCR) was done for RUNX1-RUNX1T1 [t (8,21)], CBFB-MYH11(inv 16), and PML-RARA [t (15,17)] along with FLT3 ITD and NPM1. Conventional cytogenetics evaluation was not routinely performed. Early marrow assessment with bone marrow aspiration and biopsy was done on day 14, and early marrow response was considered adequate if the marrow cellularity was <20% with <5% blasts in the bone marrow aspirate.[2] Patients with an inadequate bone marrow response were given re-induction chemotherapy at the discretion of the treating physician, taking the patients' age, comorbidities, and performance status into account. Patients with a poor performance status and active infection who were unfit to receive re-induction were continued on supportive measures. End of induction bone marrow examination was done after the count recovery. Case records of all patients were reviewed, and the data including the baseline characteristics, day 14 bone marrow response, and post-induction marrow status were collected.

Statistics

Sample size calculation was not performed for this study. Statistical analysis was done using the Statistical Package for the Social Sciences (SPSS) version 20 (IBM Corp., Armonk, NY, USA). Descriptive analysis was used for frequency and percentages. We produced a 2 × 2 table for patients with both day 14 bone marrow and post-induction bone marrow results and used the McNemar's test to determine the level of significance. Results were considered true positive in patients with an adequate day 14 bone marrow response who achieved remission at the end of induction, while false positive results included those who did not attain CR. Results were considered false negative in those who had an inadequate day 14 response but achieved CR at the end of induction, and true negative results included an inadequate day 14 response and residual disease at the end of induction.

We used the standard definitions for sensitivity, specificity, PPV and NPV, i.e., sensitivity = true positives/true positives + false negatives; specificity = true negatives/true negatives + false positives; PPV = true positives/true positives + false positives; and NPV = true negatives/true negatives + false negatives.


  Results Top


Baseline characteristics

During the study period, a total of 96 patients underwent 3 + 7 induction. Among them, 78 (82%) underwent day 14 bone marrow assessment for interim response. Our patients had a median age of 44 years (range, 15-66), and 44 (56%) were female. Other baseline characteristics are provided in [Table 1]. The majority of our patients had intermediate risk based on the PCR results. Twenty-seven (35%) patients presented with a baseline infection. Three (4%) patients required modification to 2 + 5 induction due to toxicity.
Table 1: Baseline characteristics of patients

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Day 14 bone marrow response

Of the 78 patients who underwent day 14 bone marrow assessment, 19 (24%) did not have an adequate response; 57 (73%) patients had an adequate response, while in 2 (3%) patients, the response was inconclusive. Among patients with an inadequate response, only 9 (47%) could undergo re-induction. Re-induction regimens included high-dose ara C (n = 2), FLAG – combination of fludarabine, cytarabine, and GCSF (n = 3) and 2 + 5 induction (n = 4). The rest of the patients were unfit for further chemotherapy at that point and were continued on supportive measures. Ten patients died during induction before undergoing post-induction bone marrow assessment, amounting to an induction mortality rate of 13% in the study population [Figure 1].
Figure 1: Outcomes of patients with acute myeloid leukemia who underwent day 14 bone marrow assessment. Day 14 bone marrow response adequate = cellularity <15%–20%, blasts <5%. CR: Complete remission, RD: Residual disease

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A 2 × 2 table was produced for patients who underwent both day 14 and post-induction bone marrow assessment. Patients with an inadequate bone marrow response in the day 14 bone marrow study assessment and those who received re-induction were excluded, as these factors could have confounded the results [n = 60; [Table 2]]. Patients who had an inconclusive day 14 bone marrow response and those patients who died during induction were also excluded [Figure 1]. We used the McNemar's test for the day 14 bone marrow response and post-induction bone marrow findings with Yates' continuity correction for cells with a value below 5. The proportion of patients with a CR in the post-induction bone marrow was significantly different from that of those with an adequate response on day 14 (98% vs. 88%), with a Chi-square value of 4.1 and P = 0.04. Adequate day 14 bone marrow had a sensitivity of 89.8% (95% confidence interval [CI], 79–96) in predicting the remission status at the end of induction. The specificity of inadequate day 14 marrow response in predicting residual disease in post-induction bone marrow was 89% (95% CI, 79–96). The PPV of the day 14 bone marrow response in predicting a CR was 100% and the NPV was 14%.
Table 2: 2×2 association between day 14 bone marrow response and complete remission in post-induction bone marrow assessment (n=60)

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  Discussion Top


In this retrospective study, we examined the utility of assessing the bone marrow response on day 14 of induction in patients with AML receiving the 3 + 7 induction regimen. Among 78 patients in our study, almost three-quarters achieved an adequate response in the day 14 bone marrow assessment. Except for the 4 patients who died during induction, all patients who achieved a day 14 response attained remission at the end of induction. In addition, a significant number of patients with an inadequate marrow response on day 14 also attained remission, even though only 50% of those with an inadequate response could undergo re-induction. Our study critically evaluated the role of the day 14 bone marrow assessment as a prognostic, predictive, and a clinical decision-making tool in a resource-limited setting. Our experience highlights the limitations of using the day 14 bone marrow response to identify patients requiring additional chemotherapy to achieve CR at the end of induction.

Most studies in this area have reported that about 70%–80% of the patients achieve an adequate bone marrow response by day 14, which was similar to our study results.[8] One of the well-studied aspects of the day 14 bone marrow response is its prognostic significance.[9] In a prospective study on more than 800 patients, the GOELAMS study group showed that patients with >5% blasts on the day 14 bone marrow had inferior remission rates and inferior survivals despite the fact that the majority of them received re-induction chemotherapy.[10] Similarly, the German AML Cooperative Group study showed that those with >10% blasts in the day 14 bone marrow had a remission rate of 54% compared to those with <10% blasts who had a remission of 84%. However, all patients in this study except those aged >60 years received double induction, irrespective of the day 14 bone marrow status.[11] In a study by Liso et al., in patients with <22% blasts on the day 14 bone marrow, the remission rates were 80% in those younger than 60 years of age and 67% in older patients.[12] However, only 19% of patients with a higher blast percentage could achieve a CR. In this study, patients received only one cycle of induction irrespective of the day 14 bone marrow status. The results from these studies should be interpreted with caution, in view of the varying definitions for an adequate response, inter-observer and intra-observer variations in blast counting, the use of different chemotherapeutic regimens, and the lack of response-adapted treatment protocols.[13]

Multiple retrospective studies have assessed the predictive value of the day 14 marrow response. In a study by Hussein et al., the day 14 bone marrow had a 90% sensitivity for predicting a CR in the day 28 bone marrow. However, an inadequate day 14 bone marrow had a specificity of only 43% in predicting residual disease in the day 28 bone marrow.[14] In another retrospective study on 75 patients, it was observed that there was no association between the nadir and recovery outcomes using Fisher's exact test. The sensitivity and specificity were 40% and 80%, respectively. In addition, the authors showed a PPV of 15% and NPV of 79%.[15] Similarly, Alseleh et al., in a retrospective study, showed a significant difference in the percentage of CR in the day 14 and day 28 bone marrow.[8] The study reported a sensitivity of 82% in predicting a CR, which was similar to the findings of our study. However, the specificity of an inadequate response in the day 14 bone marrow in predicting an absence of complete remission was only 60%. In our study, the specificity was 89%. Re-induction was used in only 2 patients with a suboptimal response in the day 14 marrow and both of them died due to sepsis. Of the 17 patients who were observed despite a suboptimal bone marrow response, 14 (82.4%) achieved a CR on day 28.[8]

In another Indian study, a cut off of >15% blasts in the day 14 bone marrow showed a trend towards early relapse, but the NPV for relapse was poor.[16] Similarly, Prabhu et al. studied the role of the day 5 peripheral blood blasts and the day 14 bone marrow response in predicting the response to treatment. About 90% of the patients without blasts in the peripheral blood on day 5 and 96% of those without blasts in day 14 bone marrow achieved remission.[17] In addition, at the end of 48 months, the overall survival was 62% for patients who had no blasts in the day 14 bone marrow and 32% for patients who had persistent disease, thus stressing the predictive role of the day 14 response. In our study, 93% of the patients with an adequate day 14 response could achieve remission at the end of induction.

Although in our study the sensitivity and specificity of the day 14 marrow response in predicting CR or residual disease were higher than that reported by many other studies, its impact on the prognosis and decision of re-induction was questionable. It has been reported that retrospective studies may overestimate the sensitivity and predictive value for CR due to factors such as selection bias.[3] Even among patients with an inadequate bone marrow response on day 14, almost 63% could attain a CR. The rates of remission were similar for patients who received re-induction and who were only followed up. At the same time, all the patients with an adequate day 14 bone marrow response could attain a CR, except for those who died during induction, suggesting that an adequate day 14 bone marrow response could be an indicator of a favorable prognosis.

Our study has a few limitations including its retrospective design and small sample size. However, it is one of the few studies from India and other developing countries to examine the utility of the day 14 bone marrow assessment and its impact on treatment decision-making, thus highlighting the unique issues in our setting. The day 14 bone marrow response can have a prognostic significance, but treatment modification based on an inadequate marrow response may be challenging and can unnecessarily expose some patients who might eventually attain remission to one additional cycle of re-induction. Integrating the findings of the day 14 marrow with other parameters including disease characteristics and patient features may be helpful in choosing the right patients for re-induction.[5] Therefore, we need more robust prospective, randomized studies with a larger sample size to establish the utility of assessing the early marrow response and modifying the treatment based on the results.


  Conclusions Top


Our results suggest that the practice of day 14 bone marrow study assessment can provide important predictive information about the response to treatment, but its benefit in clinical decision-making during AML induction is uncertain. In a resource-limited setting, re-induction based only on an inadequate response in the day 14 bone marrow assessment may not be appropriate in a significant proportion of the patients and may result in higher morbidity.

Acknowledgments

We acknowledge Dr Jesu Pandian for the help with data collection and Mrs Maya Padmanabhan and Mr Riyas M for the help with statistical analysis

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.


  Supplementary Appendix Top


Supplementary Appendix 1: Study protocol

Utility of Day 14 Bone Marrow Response in AML Induction

Avaronnan Manuprasad, Chandran Nair, Jesu Pandian, Vineetha Raghavan, Praveen Kumar Shenoy


  Introduction Top


Acute myeloid leukemia (AML) is one of the hematological malignancies where the prognosis remains dismal despite all the advances.[1] Although multiple targeted agents have emerged, conventional 3 + 7 induction with 3 days of anthracyclines and 7 days of cytosine arabinoside remains the standard.[2] One of the strategies used to improve the remission rates in AML induction is introduction of a re-induction regimen based on the morphological examination of bone marrow on day 14 of induction.[3] This “Day 14 bone marrow” is considered to be adequate if the marrow cellularity is <15%–20% with <5%–10% blasts. Those patients with inadequate response will be considered for an additional cycle of chemotherapy to increase the chances of attaining remission. Although this practice is recommended by many guidelines, the role of day 14 bone marrow is not tested in any randomized trials. There are multiple studies looking at the utility of a day 14 marrow, but they have given varying and conflicting results.[1] Here, we retrospectively analyze the utility of day 14 bone marrow response in predicting remission and its impact on treatment decisions.


  Review of Literature Top


Although there are studies showing the long-term predictive value of day 14 bone marrow response, its utility in clinical decision-making is questionable. Furthermore, there are a lot of debates about the optimal timing of assessing the response and definition of adequate bone marrow response.[4] It is proposed that selecting patients with inadequate response in day 14 marrow for one more induction chemotherapy will improve the remission rates and, ultimately the outcome. However, the second cycle of induction may result in significant toxicity and higher treatment-related mortality.[5] In low middle-income countries, treatment of AML involves unique challenges ranging from financial issues, inadequate supportive care services, high incidence of baseline infection, and high induction mortality.[6] There are high chances of patients being unfit for a second induction in these settings despite having an inadequate marrow response. But having less access to newer targeted agents and stem cell transplant facilities, any strategy which aids to improve the remission rates is important in a country like India.[7],[8]

One of the well-studied aspects of day 14 BM response was its prognostic significance. In a prospective study involving more than 800 patients, GOELAMS Study Group showed that patients with day 14 BM >5% had inferior remission rates and inferior survival despite majority of the patients receiving re-induction chemotherapy.[9] Similarly, German AML Cooperative Group study showed that those with >10% blasts in day 14 BM had a remission rate of 54% compared to 84% in those with <10% blasts.[10] However, all patients in this study except those with age >60 years received double induction irrespective of the day 14 BM status. In a study by Liso et al., patients with day 14 BM blasts <22%, 80% of the patients younger than 60 years and 67% of the patients older than 60 years attained complete remission (CR). Only 19% of patients with higher blast percentage could achieve CR. In this study, patients received only one cycle of induction irrespective of the day 14 BM status. The results from these studies should be interpreted with caution considering the differences in definition of adequate response, use of different chemotherapy regimens, and lack of response adapted treatment protocols.

Similarly, multiple retrospective studies looked at the predictive value of day 14 marrow response. In a study by Hussein et al., day 14 BM had a 90% sensitivity in predicting CR in day 28 BM. However, the inadequate day 14 BM had a specificity of only 43% in predicting residual disease in day 28 BM.[11] In another retrospective study of 75 patients, it was seen that there was no association between the nadir and recovery outcomes using Fisher's exact test. Sensitivity and specificity were 40% and 80%, respectively. in addition, they showed a positive predictive value (PPV) of 15% and negative predictive value (NPV) of 79%.[12] Similarly, Khalid Alseleh et al., in a retrospective study, showed a significant difference in the percentage of CR in day 14 BM and day 28 BM. Furthermore, their report showed a sensitivity of 82% in predicting CR.


  Research Question Top


Does the day 14 bone marrow response predict CR in patients undergoing 3 + 7 induction for AML in Malabar Cancer Center?

Aim

To find out the utility of day 14 bone marrow study in predicting the outcome.

Primary objective

To find out the sensitivity, specificity, PPV, and NPV of day 14 BM study in predicting the CR/residual disease.

Secondary objective

To study the impact of day 14 marrow response in clinical decision-making during AML Induction.

Study setting

Malabar Cancer Center.

Study period

April 2020.

Study population

Inclusion criteria

Patients with AML who underwent 3 + 7 induction during the period of January 2011–December 2018.

Exclusion criteria – Incomplete data

Patients who did not undergo day 14 BM study.


  Methods Top


This is a retrospective study conducted in a tertiary cancer center located in rural India. All patients more than 14 years with AML who received standard 3 + 7 induction from January 2011 to December 2018 will be included. Our standard induction consisted of 3 days of daunorubicin (60 mg/m2) and 7 days of cytosine arabinoside (100 mg/m2 as a continuous infusion). Early marrow assessment was done on day 14. Early marrow response is considered as adequate if the marrow cellularity is <15%–20% with <5%–10% blasts. Patients with inadequate bone marrow response were given re-induction chemotherapy at the discretion of the treating physician taking patient's age, comorbidities, and performance status into account. Unfit patients were continued on supportive measures. End of induction bone marrow was done on day 28 after the count recovery. Case records of all patients will be reviewed and data including baseline characteristics, day 14 bone marrow response, and post-induction marrow status will be collected.

Statistical methods

Data variables

Pro forma was attached.

Statistical methods

Data will be entered into Excel sheet and statistical analysis will be done using SPSS version 20.0. Descriptive statistics will be used wherever appropriate. We will plot a 2 × 2 table with patients having both day 14 bone marrow results and post-induction bone marrow results and used the McNemar's test to determine the level of significance. We claculated the sensitivity, specificity, PPV, and NPV of day 14 BM to predict post-induction BM biopsy results using the standard methods.

Ethical considerations

Since this is a retrospective study, consent is not required. However, patient anonymity will be maintained.

Dissemination of results

All efforts will be taken to present the data in national or international conferences and publish in national or international journals.

Project management

IRB presentation – April 2020.

Data Collection – April 2020.

Analysis and write up – April 2020.

Publication – May 2020.


  Potential Impact of Current Research Top


This is the first study looking at the impact of day 14 marrow in a developing country. This will help us to understand the value of this test in a resource-limited setting.


  References Top


  1. Terry CM, Shallis RM, Estey E, Lim SH. Day 14 bone marrow examination in the management of acute myeloid leukemia. Am J Hematol 2017;92:1079-84.
  2. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424-47.
  3. Ofran Y. Is the D14 bone marrow in acute myeloid leukemia still the gold standard? Curr Opin Hematol 2016;23:108-14.
  4. Ofran Y, Leiba R, Ganzel C, Saban R, Gatt M, Ram R, et al. Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the “3 + 7” induction regimen for acute myeloid leukemia. Am J Hematol 2015;90:1159-64.
  5. Pullarkat V, Aldoss I. Prognostic and therapeutic implications of early treatment response assessment in acute myeloid leukemia. Crit Rev Oncol Hematol 2015;95:38-45.
  6. Pandian J, Raghavan V, Manuprasad A, Shenoy PK, Nair CK. Infection at diagnosis – A unique challenge in acute myeloid leukemia treatment in developing world. Support Care Cancer 2020;28:5449-54.
  7. Alsaleh K, Aleem A, Almomen A, Anjum F, S Alotaibi G. Impact of day 14 bone marrow biopsy on re-induction decisions and prediction of a complete response in acute myeloid leukemia cases. Asian Pac J Cancer Prev 2018;19:421-5.
  8. Campuzano-Zuluaga G, Deutsch Y, Salzberg M, Gomez A, Vargas F, Elias R, et al. Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better? Am J Hematol 2016;91:277-82.
  9. Bertoli S, Bories P, Béné MC, Daliphard S, Lioure B, Pigneux A, et al. Prognostic impact of day 15 blast clearance in risk-adapted remission induction chemotherapy for younger patients with acute myeloid leukemia: Long-term results of the multicenter prospective LAM-2001 trial by the GOELAMS study group. Haematologica 2014;99:46-53.
  10. Kern W, Haferlach T, Schoch C, Loffler H, Gassmann W, Heinecke A, et al. Early blast clearance by remission induction therapy is a major independent prognostic factor for both achievement of complete remission and long-term outcome in acute myeloid leukemia: Data from the German AML Cooperative Group (AMLCG) 1992 Trial. Blood 2003;101:64-70.
  11. Hussein K, Jahagirdar B, Gupta P, Burns L, Larsen K, Weisdorf D. Day 14 bone marrow biopsy in predicting complete remission and survival in acute myeloid leukemia. Am J Hematol 2008;83:446-50.
  12. Morris TA, DeCastro CM, Diehl LF, Gockerman JP, Lagoo AS, Li Z, et al. Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia. Leuk Res 2013;37:28-31.




 
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Ofran Y. Is the D14 bone marrow in acute myeloid leukemia still the gold standard? Curr Opin Hematol 2016;23:108-14.  Back to cited text no. 3
    
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Ofran Y, Leiba R, Ganzel C, Saban R, Gatt M, Ram R, et al. Prospective comparison of early bone marrow evaluation on day 5 versus day 14 of the “3 + 7” induction regimen for acute myeloid leukemia. Am J Hematol 2015;90:1159-64.  Back to cited text no. 4
    
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9.
Campuzano-Zuluaga G, Deutsch Y, Salzberg M, Gomez A, Vargas F, Elias R, et al. Routine interim disease assessment in patients undergoing induction chemotherapy for acute myeloid leukemia: Can we do better? Am J Hematol 2016;91:277-82.  Back to cited text no. 9
    
10.
Bertoli S, Bories P, Béné MC, Daliphard S, Lioure B, Pigneux A, et al. Prognostic impact of day 15 blast clearance in risk-adapted remission induction chemotherapy for younger patients with acute myeloid leukemia: Long-term results of the multicenter prospective LAM-2001 trial by the GOELAMS study group. Haematologica 2014;99:46-53.  Back to cited text no. 10
    
11.
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Liso V, Albano F, Pastore D, Carluccio P, Mele G, Lamacchia M, et al. Bone marrow aspirate on the 14th day of induction treatment as a prognostic tool in de novo adult acute myeloid leukemia. Haematologica 2000;85:1285-90.  Back to cited text no. 12
    
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Pullarkat V, Aldoss I. Prognostic and therapeutic implications of early treatment response assessment in acute myeloid leukemia. Crit Rev Oncol Hematol 2015;95:38-45.  Back to cited text no. 13
    
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Morris TA, DeCastro CM, Diehl LF, Gockerman JP, Lagoo AS, Li Z, et al. Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia. Leuk Res 2013;37:28-31.  Back to cited text no. 15
    
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  [Full text]  
17.
Prabhu S, Nataraj KS, Damodar S, Sinha S, Bhat S, Badiger S, et al. Day 5 peripheral blood blasts and day 14 bone marrow studies as predictors for response to therapy in acute myeloid leukemia (AML): An experience from Indian subcontinent. Blood 2017;130 Suppl 1:5019.  Back to cited text no. 17
    


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