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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 731-733

(F)utility of day 14 bone marrow in acute myeloid leukemia on 3 + 7 induction – Is it time to bid adieu to day 14 bone marrow?

Department of Medical Oncology, Tata Memorial Centre, ACTREC, Navi Mumbai, Maharashtra, India

Date of Submission14-Nov-2021
Date of Decision21-Nov-2021
Date of Acceptance01-Dec-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Sumeet Prakash Mirgh
Department of Medical Oncology, Tata Memorial Centre, ACTREC, 211, Paymaster Shodhika, Navi Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_283_21

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How to cite this article:
Mirgh SP. (F)utility of day 14 bone marrow in acute myeloid leukemia on 3 + 7 induction – Is it time to bid adieu to day 14 bone marrow?. Cancer Res Stat Treat 2021;4:731-3

How to cite this URL:
Mirgh SP. (F)utility of day 14 bone marrow in acute myeloid leukemia on 3 + 7 induction – Is it time to bid adieu to day 14 bone marrow?. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Aug 20];4:731-3. Available from: https://www.crstonline.com/text.asp?2021/4/4/731/334221

Acute myeloid leukemia (AML) accounts for nearly half of all acute leukemias and 10% of all hematological malignancies, as per the data from the Tata Memorial Hospital, a tertiary cancer center in Mumbai, India.[1] With 3 + 7 induction chemotherapy, approximately 60%–70% patients achieve complete remission (CR) at the end of induction. This decreases to 40%–45% in older patients. The practice of performing a bone marrow examination 7-10 days after completion of induction chemotherapy, also known as “day 14 bone marrow”, came into existence to detect residual disease “early” during induction chemotherapy. This meant an early intervention in patients with residual disease (day 14 bone marrow >10% blasts), with a second induction chemotherapy to increase the likelihood of achieving CR, and consequently improving the clinical outcome. On the other hand, if a patient's day 14 bone marrow were hypoplastic (<5%–10% cellularity) with low residual blast count (<5%–10%), further induction chemotherapy was not recommended.[2] A hypocellular bone marrow with blast count of <5% on the day 14 bone marrow was also considered as “adequate” day 14 bone marrow response or absence of residual disease. However, it is important to revisit the clinical implications of a practice which has been ongoing for four decades.

Day 14 bone marrow has two clinical implications: first, its ability to predict the likelihood of a patient attaining CR and second, the decision to rescue a patient with re-induction chemotherapy, if there is evidence of residual disease. In their seminal study, Liso et al. took a variable cut-off for day 14 bone marrow as per age (<22% blasts for those aged <60 years, <15% blasts in those aged >60 years). However, 3 + 7 was not used as the induction regimen in this study.[3] Subsequent studies which included patients treated with 3 + 7 induction, reported a cut-off of 5% blasts, with a sensitivity ranging from 88% to 93%. This meant that 9 out of 10 patients with <5% blasts on the day 14 bone marrow, achieved remission at the end of induction.[4],[5],[6],[7] However, the utility of a day 14 bone marrow was questioned given its low specificity for the prediction of residual disease at the end of induction. Different co-operative groups have observed that the specificity of day 14 bone marrow in predicting treatment failure ranged from 35% to 50%.[7],[8] This implies that nearly 4 of out of 10 patients who have residual disease on day 14, can still achieve a CR at day 28, without a re-induction. Similarly, Yanada et al. showed that 62% patients with 20%–59% blasts on day 14 bone marrow ultimately achieved a CR, without any re-induction.[8] This is relevant for clinicians as treatment-related mortality is nearly four times higher in second induction (6.8%) versus first induction therapy (1.8%).[9] In addition, there are financial implications, the need for blood product support, and a longer neutropenic period implying prolonged hospitalization and antibiotic use, with second induction.[2]

In this issue, Manuprasad et al. from the Malabar Cancer Center, a tertiary cancer hospital in Kerala, India, report their retrospective data on the day 14 bone marrow in AML over a 7-year period. More than 80% of their patients who received 3 + 7 induction, underwent day 14 bone marrow assessment (n = 78). Nearly three-fourths (73%) of their patients had an adequate (<5% blasts) day 14 bone marrow response. All patients with <5% blasts on the day 14 bone marrow achieved a CR at the end of induction, i.e., a positive predictive value of 100%. On the contrary, amongst patients with >5% blasts on the day 14 bone marrow and who were observed till the end of induction (ruling out those who succumbed before day 28, and those who proceeded to re-induction), only 14% had residual disease at day 28. Thus, approximately 86% achieved a CR at day 28, despite having >5% blasts on the day 14 bone marrow. Besides, <50% patients with >5% blasts on day 14, could actually proceed to re-induction.[10] This means that while all patients without residual disease on day 14 bone marrow achieved CR at day 28, an additional 8 out of 10 patients even with residual disease on the day 14 bone marrow, still achieved remission at the end of induction. Furthermore, this highlights that the disease kinetics may be slower in a fraction of patients which may not be reflected in the day 14 bone marrow. The latter questions the need for re-induction, especially with the background that >50% subjects were unfit for the same.

Similar to majority of studies on the day 14 bone marrow,[4],[5],[7],[8] the study by Manuprasad et al. too had the inherent limitations of a retrospective design.[10] Moreover, while reverse transcription polymerase chain reaction was performed (FLT3-ITD, NPM1, RUNX1-RUNX1T1, CBFB-MYH11 and PML-RARA) in all patients, conventional karyotyping was not routinely performed. In addition, there is an inter-observer and intra-observer variation in reporting the blast percentage in a dilute marrow, which was not accounted for in this study. The number of patients with an inadequate response on the day 14 bone marrow was too low (n = 19) to derive meaningful conclusions. Nonetheless, the study reiterates the fact that at least half of our patients with an inadequate day 14 response are unfit for re-induction. It would be prudent to see amongst patients who achieved a CR in both groups, whether patients with <5% blasts on the day 14 bone marrow had earlier count recovery at the end of induction and shorter hospital stay compared to the others. This has not been addressed in any study yet.

It is interesting to note that despite being a common practice in many centers for decades, there are only two prior studies from India,[11],[12] reporting the utility of the day 14 bone marrow. However, the cut-off for blast percentage in the study by Nataraj et al. was 15%.[11] An important clinical practice in some centers that could have been alluded to in this study is the utility of the day 14 bone marrow in administering granulocyte-colony stimulating factor (GCSF) in patients with <5% blasts. By day 14 i.e., mid-cycle during nadir neutropenia, many patients are susceptible to infections, which is the primary reason for induction mortality in India.[13] GCSF administration post day 14 bone marrow has been shown to hasten neutrophil recovery by 48 hours, consequently reducing the duration of antibiotics and hospital stay, without an effect on CR rates at the end of induction, disease relapse, and survival.[14] While the utility of day 14 bone marrow is limited by its poor predictive value for treatment failure in 3 + 7 induction, it remains to be explored in the era of novel induction regimens which are less toxic. With the increasing use of azacytidine and venetoclax combination for induction chemotherapy in patients who are unfit by virtue of infections (especially in India)[15] or comorbidities, an early bone marrow assessment has been shown to help in tailoring the duration of venetoclax.[16] Whether an interim assessment of minimal residual disease by more sensitive techniques like multiparametric flow cytometry or next-generation sequencing will increase precision, remains to be proven.

The million-dollar question is whether we should bid adieu to the day 14 bone marrow in routine practice? In my opinion, while the day 14 bone marrow is sensitive in predicting the possibility of a CR at day 28, its routine use needs re-evaluation. It should not be used for treatment decision making for administering a second induction therapy, as a significant proportion of “slow responders” will attain a CR at the end of induction. It is said, “Every 'good' of a particular time becomes 'evil' as time changes,” and we should learn to “evolve” with time.

  References Top

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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.  Back to cited text no. 2
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. 3
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.  Back to cited text no. 4
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. 5
Deutsch YE, Campuzano-Zuluaga G, Salzberg MP, Arteaga AG, Watts JM, Chapman JR, et al. Clinical utility of morphological evaluation of day 14 bone marrow biopsies in acute myeloid leukemia patients undergoing standard induction chemotherapy: Time to change practice? Blood 2014;124:1004.  Back to cited text no. 6
Norkin M, Chang M, An Q, Leather H, Katragadda L, Li Y, et al. A new model to predict remission status in AML patients based on day 14 bone marrow biopsy. Leuk Res 2016;46:69-73.  Back to cited text no. 7
Yanada M, Borthakur G, Ravandi F, Bueso-Ramos C, Kantarjian H, Estey E. Kinetics of bone marrow blasts during induction and achievement of complete remission in acute myeloid leukemia. Haematologica 2008;93:1263-5.  Back to cited text no. 8
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. 9
Manuprasad A, Ragahavan V, Shenoy PK, Krishnan V, Nair C. 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.  Back to cited text no. 10
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Nataraj KS, Mandal PK, Ghosh MK, Bhattacharyya M. Does day 14 bone marrow status predict response to chemotherapy in acute myeloid leukemia? Experience of a hemato-oncology care center from Eastern India. Clin Cancer Investig J 2020;9:221-6.  Back to cited text no. 11
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Jain H, Rengaraj K, Sharma V, Bonda A, Chanana R, Thorat J, et al. Infection prevalence in adolescents and adults with acute myeloid leukemia treated in an Indian tertiary care center. JCO Glob Oncol 2020;6:1684-95.  Back to cited text no. 13
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