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    -  Golamari KR
    -  Mikkilineni A
    -  Chappidi S

 
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ORIGINAL ARTICLE
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Early death in acute promyelocytic leukemia: Evidence from a rural cancer center


1 Department of Medical Oncology, Manipal Hospitals, Vijayawada, Andhra Pradesh, India
2 Department of Pathology, Manipal Hospitals, Vijayawada, Andhra Pradesh, India

Date of Submission25-Feb-2019
Date of Decision24-Jun-2019
Date of Acceptance27-Jun-2019
Date of Web Publication14-Sep-2020

Correspondence Address:
Krishna Reddy Golamari,
Department of Medical Oncology, Manipal Hospitals, Vijayawada, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_177_19

  Abstract 


Background: Early death is still the characteristic feature of acute promyelocytic leukemia (APL) despite the advances in the treatment regimen. Analyzing the incidence of early death would prove beneficial as no much substantial information is available pertaining to the rural population. The present study analyzed the incidence of APL-associated early death, its clinical characteristics, and outcome among acute myeloid leukemia patients.
Methods: This retrospective study included patients catering to the rural areas of Vijayawada (Andhra Pradesh, India) from January 2013 to June 2017. Chi-square test, Fisher's exact test, independent sample median test, and Kaplan–Meier test for probability of survival were used.
Results: Of the 204 acute myeloid cases, 24% cases (median age = 30 years; range=8 to 68 years) were identified as APL. Early death rate was 34.6%, who expired within 30 days from diagnosis with 65% suffering high disease risk. The median time from admission to death was 2 days (range 0–18). Cause of early death was majorly due to hemorrhage (64%). Moreover, 47.1% of early death patients received no prior antileukemic treatment. The overall 5-year cumulative disease-free survival rate among patients with APL was 76% where high disease risk patients had the least disease-free survival (65%–75%), whereas intermediate and low-risk patients had >80% and 100% disease-free survival rate, respectively.
Conclusion: Early diagnosis and timely intervention might help to prevent early death as our findings clearly indicate poor awareness of disease and lack of early intervention among the rural population.


Keywords: Acute promyelocytic leukemia, early death, hemorrhage, India, rural



How to cite this URL:
Golamari KR, Mikkilineni A, Chappidi S. Early death in acute promyelocytic leukemia: Evidence from a rural cancer center. Indian J Cancer [Epub ahead of print] [cited 2020 Sep 28]. Available from: http://www.indianjcancer.com/preprintarticle.asp?id=295071





  Introduction Top


Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by a distinctive morphology of blast cells, life-threatening coagulopathy, and a specific balanced reciprocal translocation t(15;17) that fuses the PML (promyelocyte) gene on chromosome 15 to the RARα (retinoic acid receptor-α) gene on chromosome 17.[1] The differentiating agent all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) have significantly improved treatment for patients with APL, making it the subtype of adult AML with the best outcomes. The early death (ED) rates of APL are well above 20% in the real-world setting, as opposed to 5%–10% reported in multicenter clinical trials.[2],[3] A novel attempt by Jillela et al.[4] replicated the phenomenal success rates that were being achieved only in clinical trials; they adopted a treatment algorithm that focused on quick diagnosis, prompt initiation of therapy, and proactive and aggressive management of all major causes of death during induction. The most significant challenges in treating patients with APL, in developing nations, occur before they visit a tertiary center with the requisite expertise. Absence of definitive diagnostic tools in rural areas, lack of adequate awareness among primary healthcare providers leading to delayed referrals, and unaffordability are unique problems. Moreover, accurate data on the incidence and outcomes of APL are scarce. Therefore, we conducted a study to estimate the proportion and causes of ED due to APL at Manipal Hospitals, Vijayawada, Andhra Pradesh, India.


  Subjects and Methods Top


This retrospective study included 49 consecutive patients with APL registered at a rural hospital in Vijayawada (Andhra Pradesh, India) between January 2013 and June 2017. Diagnosis of APL was confirmed by demonstrating PML-RARα [t(15;17)(q22;q12)] gene fusion using fluorescence in situ hybridization in 48 of 49 patients and by reverse-transcription polymerase chain reaction in one patient, among a total 204 patients with AML. The diagnostic procedures included complete blood evaluation, bone marrow studies, and cytogenetic analyses. Fibrinogen and blood count analyses were performed twice a day during the first week to detect fibrinolysis. Owing to their poor economic status, most patients in this rural center did not undergo other diagnostic procedures such as flowcytometry.

Data such as age, sex, hemoglobin level, white blood cell (WBC) count, platelet count, creatinine level, and treatment protocols of the patients were collected from hospital-based patient records. Furthermore, symptoms, duration of symptoms before admission, duration from admission to the initiation of ATRA therapy were also collected.

Sanz risk score was used to classify patients by risk of ED based on their WBC and platelet counts at diagnosis (high risk: WBC >10,000/mm3; intermediate risk: WBC <10,000/mm3, and platelet count <40,000/mm3; low risk: WBC <10,000/mm3 and platelet count >40,000/mm3).[5] To assess the performance status of patients with APL, the Eastern Cooperative Oncology Group (ECOG) scale of performance status was used.[6] ED was defined as death from any cause within 30 days of diagnosis of APL.

Differences between groups were analyzed using the Chi-square test, Fisher's exact test, and independent sample median test. The probability of survival was estimated using the product limit method of the Kaplan–Meier test and compared using the log-rank test. All P values were two-sided, with values <0.05 indicating statistical significance. Statistical analysis was performed using SPSS statistics for Windows, version 18.0 (SPSS, Chicago, IL, USA). This study was approved by the Institutional Ethics Committee (Human Studies) of the Dr. Pinnamaneni Siddhartha Institute of Medical Sciences & Research Foundation (Date of approval- 15 September 2018).


  Results Top


Demographic details

Of the 204 patients with AML registered between January 2013 and June 2017, 49 had APL (24%). In this cohort, the median age at diagnosis was 30 years (range=8 to 68 years), and of the 49 patients, 31 (63%) were men and 18 (37%) were women. Among the 49 patients, 36 (73.4%) patients with APL were aged between 17 and 50 years, with highest incidence seen in the second decade.

Early death

Of the 49 patients with APL, 17 (34.6%) died early. The median time from admission to death was 2 days (range 0–18 days). Of all the 17 EDs, 7 (41.1%) occurred on the same day of admission and 12 (70.5%) within the first week of admission; 3 EDs occurred 14 days after admission [Figure 1]. Furthermore, majority of the ED patients' belonged to high-risk (65%) and intermediate-risk category (35%), whereas none of the low-risk patients died early [Table 1].
Figure 1: Early death among patients with APL

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Table 1: General and disease characteristics of ED and non-ED patients with APL (n=49)

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Causes of ED

Hemorrhage (64%) was found to be the most common cause of ED among patients with APL; other causes included bronchopneumonia (12%), space-occupying lesions (6%), febrile neutropenia with sepsis (6%), febrile neutropenia with pneumonia (6%), and differentiation syndrome (6%) [Figure 2].
Figure 2: Causes of early death among patients with APL. CNS=Cnetral Nervous System; GI=Gastrointestinal

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Clinical presentation

Most ED patients (47.1%) presented with Central Nervous System (CNS) bleed at the time of admission, as opposed to one (3.1%) and two (6.3%) non-ED patients presenting with CNS bleed and pulmonary bleed, respectively. [Table 1] also shows significant differences between ED and non-ED patients by their platelet counts (P = 0.02), where ED patients had lower platelet counts. With regard to WBC counts, a positive linear trend was observed (median [range]: 23,050/mm3 [400–194,500 per cubic millimeter]), with the counts being higher among ED patients; however, no statistical difference was found between the patients.

Treatment regimen

With respect to the treatment regimen, 78% (n = 25) of non-ED patients had received ATRA + arsenic trioxide treatment, given its low cost, easy administration, outpatient treatment during consolidation, and low mortality rate; 19% patients (n = 6) had received North American Leukemia Intergroup Study C9710 protocol,[7] and one patient had received arsenic trioxide alone. Among the ED patients, 17.6% (n = 3) had received only ATRA, 5.9% (n = 1) had received ATRA + arsenic trioxide, and 29.4% (n = 5) had received the Intergroup C9710 protocol. However, 47.1% (n = 8) of the ED patients had not received any antileukemic therapy.

In addition, 97% (n = 30) of non-ED patients were immediately initiated on ATRA. Only 59% (n = 10) of ED patients received ATRA treatment within 24 hours, and the remaining ED patients did not receive ATRA as they died within 6–7 hours of admission, representing cases of very early death [Table 1]. It is to be noted that 25% (n = 8) of non-ED patients suffered from ATRA syndrome.

Performance status

Most non-ED patients (93.3%) had better performance status (ECOG score 1–2) than ED patients (47%), who predominantly had moderate to worse performance status (ECOG score 3–4). ED patients who presented with CNS bleed, pneumonia, or pulmonary bleed had significantly poorer performance status. Therefore, evidently, poor performance status is predictive of ED (P = 0.01).

Remission rate and relapse

All the 32 patients who survived the first 30 days achieved hematological remission at the end of induction therapy. No mortality occurred during consolidation therapy. Of the 32 patients, 29 had completed consolidation therapy and achieved molecular remission. One patient experienced relapse during follow-up and underwent autologous transplantation. Most of the non-ED patients (94%) were disease-free at the last follow-up; one patient was lost to follow-up and another patient died of a cause unrelated to cancer [Table 1].

Survival analysis

A Kaplan–Meier survival analysis was performed on all patients with disease risk as an influencing factor. A log-rank test was performed to assess differences in survival based on Sanz risk score (high, intermediate, and low). A 5-year overall survival analysis of patients with APL was performed. Results indicated that the overall survival rate among patients with APL was 76% [Figure 3]a.
Figure 3: (a) Overall cumulative survival of patients with acute promyelocytic leukemia (APL). (b) Cumulative disease-free survival among patients with APL by disease risk

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Similarly, a log-rank test was performed to assess the differences in survival among patients with APL based on the disease risk category. No significant difference was found on survival (X2 [2, N = 49] = 2.331, P = 0.312). [Figure 3]b shows the cumulative survival curve based on disease risk of patients with APL. The estimated 5-year cumulative disease-free survival (60 months) was 100% and >80% for low-risk and intermediate-risk patients with APL, respectively; for high-risk patients, the median survival was only 65%–75%. The results show that disease-free survival among patients with APL does not differ remarkably by disease risk regardless of the protocol administered.


  Discussion Top


Utmost care is required to prevent ED during APL treatment. Among patients with AML, 24% were confirmed to have APL. Shah et al.[8] reported similar results: 26 of 96 patients with AML had APL. We observed a higher incidence of APL in the younger age group as opposed to very low incidence in the higher age group. The median age at diagnosis was 30 years, which is much less than that reported in previous studies.[2],[3],[9],[10] The proportion of men (63%) was higher in this study, which is in contrast to the results of a study from Sweden.[2] An equal sex distribution was observed in a pan-Canadian epidemiological study.[11]

The ED rate observed among patients with APL in our study was significantly (34.6%) higher than that reported by Paulson et al. (21.8%),[11] McClellan et al. (26%),[3] Park et al. (17.3%),[12] and Lehmann et al. (30%).[2] This can be explained by a higher proportion of high-risk patients and a lower proportion of low-risk patients in our study; a higher proportion of high-risk patients died early.

The chief cause of ED was hemorrhage: 52.9% of ED patients presented with CNS bleed and 11.8% with gastrointestinal bleed. Hemorrhagic diathesis is a typical feature of APL and increases the mortality risk substantially, often causing mortality even before diagnosis or initiation of treatment. In our study, 41.2% of ED patients died on the same day of admission. In majority of Indian and Western population-based studies, hemorrhage has been reported to be the primary cause of ED (12.12%,[13] 70%,[14] 60.5%,[15] 54%,[3] and 41%[2]) similar to our study (64%). Other causes reported are sepsis, cardiac and respiratory failure, differential syndrome, multiorgan failure, cerebral infarction, cerebral leukostasis, and undetermined cause.[2],[3]

We also compared several clinical and biochemical parameters between ED patients and non-ED patients. ED patients had higher WBC counts, lower platelet counts, and poorer performance status. These results are in line with those of other studies.[2],[16],[17]

Excluding patients who died on the same day of admission (41.2%), no difference in time to initiation of ATRA was noted among ED and non-ED patients, as ATRA was initiated promptly for all patients. This observation shows that time to initiation of ATRA was not contributory to ED. Consistent with our finding, previous studies have also shown no significant association between immediate initiation of ATRA and ED.[15],[18] Studies have shown that ATRA combined with chemotherapy results in cure rates >80%.[19] Similarly, in this study, most non-ED patients (78%, which included a significant proportion of high-risk patients) received ATRA and arsenic trioxide as part of the treatment protocol and had complete remission. However, only 5.9% of ED patients received ATRA and arsenic trioxide treatment, and 29.4% received the Intergroup C9710 protocol. No prior antileukemic treatment was administered to 47.1% of ED patients. This might have been because of the delay in presentation owing to the lack of awareness among the community physicians and low literacy rates in the rural population. However, the exact cause for the delay in presentation to the hospital must be evaluated in multicenter prospective studies. Survival analysis of non-ED patients showed that the survival rate did not differ significantly across all risk groups regardless of the protocol administered.


  Conclusion Top


Our results show that effort made toward prevention of ED will increase survival rates. Devising appropriate public health strategies such as continuous medical education and sensitization of both healthcare providers and public is the need of the hour. This can facilitate prompt identification of the disease, thereby preventing ED, given that APL is a medical emergency regardless of its high remission rates.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Grignani F, Ferrucci PF, Testa U, Talamo G, Fagioli M, Alcalay M, et al. The acute promyelocyticleukemia-specific PML-RARα fusion protein inhibits differentiation and promotes survival of myeloid precursor cells. Cell 1993;74:423-31.   Back to cited text no. 1
    
2.
Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Möllgård L, et al. Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 2011;25:1128-34.   Back to cited text no. 2
    
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McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Maeti R, Alizadeh AA, et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica 2012;97:133-6.   Back to cited text no. 3
    
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Jillella AP, Awan F, Kolhe RB, Pantin JM, Morrison DV, Kota V. A network of treatment centers and standardisation of treatment protocol leads to reduction in mortality in Acute Promyelocytic Leukemia (APL). Blood 2012;120:4317.   Back to cited text no. 4
    
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Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayón C, Barbui T, et al. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: A joint study of the PETHEMA and GIMEMA cooperative groups. Blood 2000;96:1247-53.   Back to cited text no. 5
    
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Oken M, Creech R, Tormey D, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.   Back to cited text no. 6
    
7.
Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010;116:3751-7.  Back to cited text no. 7
    
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Shah AM, Gupta A, Kaur S, Gousuddin M. A retrospective study of acute promyelocytic leukemia. IOSR J Pharm 2012;2:52-9.   Back to cited text no. 8
    
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Zawam HM, Mokhtar MM, Salama R, Alsirafy SA, Bishr MK. Factors affecting treatment outcome of acute promyelocytic leukemia in Egyptian patients. J Clin Anal Med 2017;8:480-4.   Back to cited text no. 9
    
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Karim F, Shaikh U, Adil SN, Khurshid M. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukemia: A five-year experience at a tertiary care centre. Singapore Med J 2014;55:443-7.   Back to cited text no. 10
    
11.
Paulson K, Serebrin A, Lambert P, Bergeron J, Everett J, Kew A, et al. Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: A pan-Canadian epidemiological study. Br J Haematol 2014;166:660-6.   Back to cited text no. 11
    
12.
Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2014;118:1188-9.   Back to cited text no. 12
    
13.
Bajpai J, Kumar L, Kumar R, Raina V, Dabkara D, Kochupillai V, et al. Acute promyelocytic leukemia: An experience from a tertiary care centre in north India. Indian J Cancer 2011;48:316.   Back to cited text no. 13
[PUBMED]  [Full text]  
14.
Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Durable remissions with minimal toxicity. Blood 2006;107:2627-32.   Back to cited text no. 14
    
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Jacomo RH, Melo RA, Souto FR, de Mattos ER, de Oliveira CT, Fagundes EM, et al. Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica 2007;92:1431-2.   Back to cited text no. 15
    
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Zhang L, Zhu X. Epidemiology, diagnosis and treatment of acute promyelocytic leukemia in children: The experience in China. Mediterr J Hematol Infect Dis 2012;4:e2012012.   Back to cited text no. 16
    
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Breccia M, Lo Coco F. Thrombo-hemorrhagic deaths in acute promyelocytic leukemia. Thromb Res 2014;133:S112-6.   Back to cited text no. 17
    
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Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al. Management of acute promyelocytic leukemia: Recommendations from an expert on behalf of the European Leukemia Net. Blood 2009;113:1875-91.   Back to cited text no. 18
    
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Lo-Coco F, Donato L, Schlenk, RF. Targeted therapy alone for acute promyelocytic leukemia. N Engl J Med 2016;374:1197-8.  Back to cited text no. 19
    


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