|Year : 2015 | Volume
| Issue : 3 | Page : 309-312
Clinico-hematological profile and outcome of acute promyelocytic leukemia patients at a tertiary care center in North India
A Dayama, J Dass, T Seth, M Mahapatra, PC Mishra, R Saxena
Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||18-Feb-2016|
Department of Hematology, All India Institute of Medical Sciences, New Delhi
Source of Support: None, Conflict of Interest: None
Objectives: Acute promyelocytic leukemia (APL) is the only acute leukemia amenable to targeted therapy. However, there is limited Indian data on APL. We aimed to analyze data of APL patients treated with all trans retinoic acid (ATRA) and anthracycline based chemotherapy. Materials And Methods: A total of 34 cases of APL were treated at our center over 4 years. Induction chemotherapy consisted of a combination of ATRA and daunorubicin. Results: Most of our patients were intermediate risk (50%) followed by high risk (41.17%). Induction mortality was 14.7%. We observed a high incidence of febrile neutropenia (91%) and 50% of our patients developed ATRA syndrome. Four patients (11.76%) relapsed during follow-up (median - 15 months, range: 13-33 months). There was no correlation between risk status and death or relapse or ATRA syndrome. Median event free survival (EFS) duration was not reached however mean duration was 38.45 ± 3.84 months. Median overall survival (OS) duration was also not reached at 53 months of follow-up. The 4 year OS and EFS were 75.45% and 64.5% respectively. On multivariate analysis, only disseminated intravascular coagulation (DIC) significantly correlated with a poor OS and EFS. Discussion: Our data reflects that APL remains a highly curable malignancy with good response to ATRA plus anthracycline based chemotherapy even with a greater number of high and intermediate risk patients. Only DIC during induction chemotherapy bore an impact on survival in our patients.
Keywords: Acute promyelocytic leukaemia, all trans retinoic acid, India, outcome
|How to cite this article:|
Dayama A, Dass J, Seth T, Mahapatra M, Mishra P C, Saxena R. Clinico-hematological profile and outcome of acute promyelocytic leukemia patients at a tertiary care center in North India. Indian J Cancer 2015;52:309-12
|How to cite this URL:|
Dayama A, Dass J, Seth T, Mahapatra M, Mishra P C, Saxena R. Clinico-hematological profile and outcome of acute promyelocytic leukemia patients at a tertiary care center in North India. Indian J Cancer [serial online] 2015 [cited 2019 Jun 26];52:309-12. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/309/176731
| » Introduction|| |
Acute promyelocytic leukaemia (APL) was first described as a distinct clinical entity in 1957 by LK Hillestad. It was considered to be a rapidly fatal, though rare leukemia with bleeding as the major cause of death. Anthracycline therapy resulted in a significant improvement of survival.
The discovery of the genetic translocation and response to all trans retinoic acid (ATRA) led to APL becoming the first leukemia to be treated at a molecular level. The combination of ATRA and anthracyclines increased overall survival (OS) rate to 75-80% at 5 years. Recent European Leukemia Net guidelines have also recommended anthracycline and ATRA based chemotherapy as frontline therapy for APL.
There is a paucity of data from India regarding APL treatment and outcome., Many of the centers use arsenic trioxide as upfront therapy for newly diagnosed patients. We are presenting our experience of treating APL for the past 4 years.
| » Materials and Methods|| |
Retrospective data collection of patients admitted in the Department of Hematology was done from the year 2008 onward until September 2012. Data collected included presenting complaints, hematological investigations, therapy and review of complications during admission. Death records were also reviewed for the cause and timing of death.
Diagnosis: A total of 42 patients presented to hematology department with a presumptive diagnosis of APL. Diagnosis was carried out by evaluation of hemogram, peripheral smear, bone marrow aspirate with immunophenotyping, cytogenetics and reverse-transcriptase polymerase chain reaction (RT-PCR) for promyelocytic leukemia/retinoic acid receptor alpha (PML/RARA). All the patients underwent investigations for disseminated intravascular coagulation (DIC) which were prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen level. Out of these, 7 patients presented with intracerebral bleed, in critical condition and died immediately after admission. Their diagnosis of APL could not be confirmed and they did not receive any therapy. One patient was referred to us after induction with ATRA plus arsenic. Hence these eight patients were excluded from analysis. Thus data of 34 patients was analyzed and is presented.
Supportive care: Patients received fresh frozen plasma in case of any PT/APTT/TT derangement and to keep fibrinogen >150 mg/dL. Platelet counts were kept ≥50000/µL by either single donor platelet or platelet rich plasma transfusion. Patients were categorized based on white blood cells (WBC) and platelet counts at presentation into Sanz risk groups.
Induction therapy comprised of combination of ATRA (45 mg/m 2 in adults or 25 mg/m 2 in children) plus daunorubicin (45-60 mg/m 2 for 3 days) at the start of therapy. Those with WBC < 5 × 109/L received daunorubicin starting on day 4 of ATRA therapy. ATRA was continued till achievement of remission or day + 45 whichever was later. Patients were monitored strictly for development of ATRA syndrome. Indeterminate ATRA syndrome is defined as the presence of any two symptoms out of fever, dyspnea, pleural and/or pericardial effusion, pulmonary infiltrates and unexplained weight gain greater than 5 kg.
Consolidation therapy consisted of 2-3 cycles of 15 days of ATRA along with 3 days of daunorubicin at 45-60 mg/m 2 depending upon anthracycline dose given in induction. Maintenance was with 15 days of ATRA every 3 months with daily 6-mercaptopurine (60 mg/m 2) and weekly oral methotrexate (20 mg/m 2) for 2 years. Monitoring was done with 3 monthly RT-PCR for PML-RARA.
Definitions of outcome
Complete remission (CR) was defined as normalization of leucocyte counts with normal differentiation, normal platelet counts, no organomegaly and normal marrow cellularity with <5% blasts plus promyelocytes on bone marrow examination. Event free survival (EFS) was defined as the time to any event (relapse or death) from the time of presentation. OS was defined as the duration from the time of presentation to the time of death.
Due to the low number of low risk patients, low and intermediate risk categories have been clubbed together for analysis. Fischer's exact test was used to calculate any significance between the groups when the number of events such as relapse/death was small. For other comparison and univariate analysis, Pearson's Chi-square test was used. Survival analysis was done by Kaplan and Meier estimate and log-rank tests. Comparison of the two groups for death/relapse/ATRA syndrome was done with the Mann-Whitney test. Survival estimates are reported as values ± 1 SE. Multivariate analysis was carried out by binary logistic regression analysis. Analysis was performed on statistical package for the social sciences version 14. (SPSS for Windows, Version 14.0. Chicago, SPSS Inc.).
| » Results|| |
The patient characteristics are summarized in [Table 1]. The median follow-up duration was 22 months (range: 0-53 months). The median total leukocyte count (TLC) at presentation was 4160/µL. Majority of the patients, as is evident from [Table 1] presented with intermediate/high risk.
There were 5 (14.67%) induction deaths in total. Out of these five deaths, four were early deaths (<7 days of induction). One patient died of sepsis after achieving remission. All of the patients who survived past 7 days achieved remission. The CR rate achieved was thus 88.23% (30/34). Of the five deaths three were due to infection, 1 (20%) each was due to ATRA syndrome and DIC causing intracerebral bleed. Ninety one percent (31/34) patients had febrile neutropenia. The most common site of infection identified was pulmonary in 10 patients (32.3%) followed by oral cavity and central line in six patients each (19.3%). The median duration of febrile neutropenia was 16 days (range 3-42 days). As indicated by [Table 1], 50% of our patients presented with infection.
The incidence of indeterminate ATRA syndrome was 44.11% (15/34). The median day of onset of ATRA syndrome was day 8 of therapy (range 13-33 days). All of the patients were managed by cessation of ATRA and administration of Dexamethasone (10 mg iv q12 h). All patients responded to the therapy, except one death due to ATRA syndrome.
Patients received consolidation and maintenance as per protocol mentioned above. One patient died during maintenance due to fulminant hepatic failure the cause of which could not be determined. One patient developed dilated cardiomyopathy during maintenance and she later relapsed and died due to DIC. During follow-up a total of four patients relapsed (11.8%). Two out of the four died after admission due to intracerebral bleed. The median time to relapse was 15 months (range: 13-33 months).
The median EFS duration was not reached, however, mean duration was 38.45 months. The median OS duration was also not reached at 53 months of follow-up. The 4 year OS and EFS were 75.45% and 64.5% respectively. Kaplan Meier EFS and OS curves are in [Figure 1]a and [Figure 1]b. There was no correlation between Sanz risk status and death (P = 0.689), relapse (P = 0.627) or ATRA syndrome (P = 0.101). Univariate and multivariate analysis was carried out for the following variables to assess the impact on events and death: DIC, ATRA syndrome, infection at presentation and Sanz risk group. In both univariate and multivariate analysis, only DIC had an influence on both EFS and OS. The odds ratio of DIC in multivariate analysis for deaths was 13.770 (95% confidence intervals [CI] - 1.548-122.515, P = 0.019) while for events (deaths and relapses) was 8.803 (95% CI-1.057-73.289; P = 0.044).
|Figure 1: (a) The 4 year overall survival curve of 34 acute promyelocytic leukaemia (APL) patients, (b) the 4 year event free survival curve of 34 APL patients|
Click here to view
On comparison of OS and EFS between low/intermediate risk with high risk patients, no significant differences were obtained [Figure 2]a and [Figure 2]b.
|Figure 2: A comparison between Low/intermediate risk and high risk with overall survival (a) and event free survival (b)|
Click here to view
| » Discussion|| |
As is evident from our data, intermediate/high risk patients comprised the majority of our patients. Another problem is due to inadequate awareness of the seriousness of the disease and economic reasons, patients present late.
The median age of our patients was similar to that reported by other data from India. However it was less when compared to that of Sanz et al. and Mandelli et al. High risk patients were over-represented compared with Bajpai et al. (23%), PETHEMA (22.9%) and GIMEMA groups (22.2%). Referral delay can explain this difference between our study and the western studies. Median TLC in our patients was 4600/µL which is higher than that reported by Sanz et al. (1900/µL) and Mandelli et al. (2500/µL).
The induction mortality in present study was 14.7%. This is similar to the prior reported induction mortality of 15%, 10.1% respectively. A study by Mandelli et al. reported a lower incidence at 5%. Mathews et al. also reported 14% induction mortality with single agent arsenic trioxide. Infection was the most common cause of death in our study. However, Sanz et al. reported hemorrhage as the major cause of early death followed by infection. This difference can be explained by the death of seven patients who presented to us with intracerebral bleeds and died even prior to confirmation of diagnosis, thus excluding their analysis.
We observed a high incidence of febrile neutropenia (91%) which was higher than 64% reported in a prior Indian study. The most common site of infection in the present study was pulmonary while that reported by Bajpai et al. was genitourinary. The high incidence of infection at presentation is due to delay in presentation for treatment.
Median day of onset of ATRA syndrome was D + 8, which was similar to Bajpai et al. (7.5 days) and Sanz et al. (9 days). All our patients who developed ATRA syndrome responded to dexamethasone therapy except for one death. ATRA syndrome was seen in 44% of our patients which was higher than previously reported.,, Over representation of high risk patients and a lower threshold for diagnosis may be responsible for the high incidence of suspected ATRA syndrome observed in our study.
Relapse rate in our study was 11.8% at a median follow-up of 22 months, which was similar to Sanz et al. in their combined analysis of GIMEMA and PETHEMA group trial (12.4%) at a median follow-up of 27 months. A study done by Bajpai et al. reported a relapse rate of 12% at median follow-up of 13 months. This was an interesting observation since we had more high risk patients and no further therapy modifications were performed for these patients.
A comparison of OS and EFS between the present study and the prior reported Indian and western literature is provided in [Table 2]. Table shows that the CR rate and the OS achieved were similar to western literature.
|Table 2: Comparison of outcomes of APL patients with reported Indian and western literature|
Click here to view
In the present study, DIC had a statistically significant adverse impact on both OS and EFS in multivariate analysis. Multivariate analysis for factors having an adverse impact on EFS by Mathews et al. was that prolonged PT had a high relative risk with a trend to statistical significance. On the other hand, coagulopathy had no significant impact on OS in the study by Sanz et al.
In the last few years, a combination of arsenic trioxide has been used with ATRA. In a randomized study comparing ATRA and arsenic trioxide with ATRA and chemotherapy, Lo-Coco et al. have reported 100% CR with 2 year EFS of 97%. This was better than the ATRA and chemotherapy arm with CR rate of 95% and 2 year EFS of 86%. The OS in this study with ATRA and arsenic combination was significantly better than ATRA and chemotherapy combination. Arsenic trioxide has traditionally been given as an intravenous infusion. There is new data comparing an oral arsenic formulation with intravenous arsenic given in combination with ATRA. In a randomized trial conducted on 240 patients of APL, the disease free survival, CR rate and OS in both arms were similar. The trial demonstrated that oral arsenic plus ATRA is not inferior to intravenous arsenic plus ATRA as first-line therapy for APL.
Better supportive care with early diagnosis and prompt referral of patients might improve the outcome of our patients. The study lacks the large sample size of other studies. Collaborative work with uniform protocols will help in collection and analysis of Indian data on this rare disease. A combination of ATRA and arsenic appears to be a promising approach for treatment of APL.
| » Acknowledgment|| |
The authors would like to thank Dr. Sonal Dayama for statistical analysis.
| » References|| |
Wang ZY, Chen Z. Acute promyelocytic leukemia: From highly fatal to highly curable. Blood 2008;111:2505-15.
Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: Results of treatment by daunorubicin. Blood 1973;41:489-96.
Sanz MA, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH, et al
. Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009;113:1875-91.
Bajpai J, Sharma A, Kumar L, Dabkara D, Raina V, Kochupillai V, et al
. Acute promyelocytic leukemia: An experience from a tertiary care centre in North India. Indian J Cancer 2011;48:316-22.
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.
Sanz MA, Lo Coco F, Martín 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.
Frankel SR, Eardley A, Heller G, Berman E, Miller WH Jr, Dmitrovsky E, et al
. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Ann Intern Med 1994;120:278-86.
Mandelli F, Diverio D, Avvisati G, Luciano A, Barbui T, Bernasconi C, et al
. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano-Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups. Blood 1997;90:1014-21.
Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, et al
. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: A multicenter study by the PETHEMA group. Blood 2004;103:1237-43.
Sanz MA, Martín G, Rayón C, Esteve J, González M, Díaz-Mediavilla J, et al
. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group. Blood 1999;94:3015-21.
Mathews V, George B, Chendamarai E, Lakshmi KM, Desire S, Balasubramanian P, et al
. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Long-term follow-up data. J Clin Oncol 2010;28:3866-71.
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al
. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013;369:111-21.
Zhu HH, Wu DP, Jin J, Li JY, Ma J, Wang JX, et al
. Oral tetra-arsenic tetra-sulfide formula versus intravenous arsenic trioxide as first-line treatment of acute promyelocytic leukemia: A multicenter randomized controlled trial. J Clin Oncol 2013;31:4215-21.
[Figure 1], [Figure 2]
[Table 1], [Table 2]