Acute promyelocytic leukemia, study of predictive factors for Differentiation Syndrome, single center experience

Journal of the Egyptian National Cancer Institute (2013) 25, 13–19

Cairo University

Journal of the Egyptian National Cancer Institute www.nci.cu.adu.eg www.sciencedirect.com

Original article

Acute promyelocytic leukemia, study of predictive factors for Differentiation Syndrome, single center experience Omyma Elemam a b

a,*

, Doaa Abdelmoety

b

King Abdullah Medical City, Makkah, Saudi Arabia Research & Publication Center, King Fahad Medical City, Riyadh, Saudi Arabia

Received 4 September 2012; accepted 24 October 2012 Available online 29 November 2012

KEYWORDS Acute promyelocytic leukemia; ATRA syndrome; Predictive factors

Abstract Reports about patients with acute promyelocytic leukemia from the Middle East are few; in this study we are reporting our single center experience of treating 29 patients over 6 years. Acute promyelocytic leukemia treatment response is markedly improved after the introduction of ATRA. Treatment related complication is still an important issue particularly Differentiation Syndrome. Prediction to its occurrence has been tried by other groups. We aimed to study all the possible predictive factors of acute promyelocytic leukemia. Our chemotherapy induction protocol is AIDA protocol which includes ATRA 45 mg/m2/d in divided doses every12 h, and Idarubicin 12 mg/ m2/d IV on days 3, 5, 7, and 9. Differentiation Syndrome occurred in 48.3% of patients and was mainly presented by pulmonary symptoms in 55.2%, 6 cases died during induction. None of the predictive factors studied showed a statistically significant difference between patients who developed Differentiation Syndrome and those who did not. Differentiation Syndrome did not affect overall survival. Cox regression showed an inverse yet a non significant association between PETHEMA and overall survival probability (P = 0.168). In conclusion, Differentiation Syndrome has no clear predictive factor to date. The best approach is to hold ATRA and give dexamethasone which is quite effective as reported in the literature. PETHEMA risk model has a moderately significant prognostic value. ª 2012 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved.

Introduction * Corresponding author. E-mail addresses: [email protected], Elemam.o@kamc. med.sa (O. Elemam), [email protected] (D. Abdelmoety). Peer review under responsibility of The National Cancer Institute, Cairo University.

Production and hosting by Elsevier

Acute Promyelocytic Leukemia (APL) is a type of acute myeloid leukemia characterized by the morphology of M3 in the French–American–British classification and by the presence of translocation t (15; 17) [1,2]. All transretinoic acid is the main stay in treatment [3]. There are a few reports about this disease from our region compared to the western world. Our retrospective study focused on disease characteristics, response to treatment and utility of recent risk model. We aimed also to

1110-0362 ª 2012 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jnci.2012.10.004

14 look for all possible predictive factors of Differentiation Syndrome (DS) which were first described in 1992 by Frankel et al. [4] and represented the major complication through this disease course: studies had reported conflicting results about this [5,6]. In addition we will compare our data to other areas of the world. Patients and methods Twenty-nine patients with APL confirmed by molecular study were treated from August 2005 to June 2011 at King Fahad Medical City, Riyadh, Saudi Arabia. Laboratory studies at diagnosis included: hemogram of liver and renal function tests, bone marrow studies (cytogenetics, flowcytometry, FISH, and PML-RARa by RT-PCR analysis). CBC and coagulation parameter were monitored daily and coagulopathy was treated. All patients with fibrinogen levels <100 mg/dl –with or without active bleeding– received cryoprecipitate to maintain the fibrinogen above this level without the routine use of prophylactic heparin. Platelets were transfused to maintain the platelet count about 30,000/lL in patients not actively bleeding and above 50,000/lL in patients actively bleeding. Fresh frozen plasma was administered to patients actively bleeding with prolonged PT and PTT, but not to patients without active bleeding. Management of fever and neutropenia was according to our leukemia unit guidelines. Packed red cell transfusion was given if hemoglobin was less than 8 gm/dl. The treatment regimen consisted of [7]: I. Induction:  All Trans-Retinoic Acid (ATRA) 45 mg/m2/d (to CR or maximum of 56 days) administered in divided doses 12 h apart, after meals or with milk, rounded off to the nearest 10 mg. Young patients (<16 years) received reduced dose ATRA at 25 mg/m2/d.  Idarubicin 12 mg/m2/d IV on days 3, 5, 7, and 9. Patients older than 60 years received 3 doses only (5, 7, and 9).Patients with initial WBC > 10,000 started Idarubicin on day 1.  Prednisone 0.5 mg/kg/d PO for all patients D1–15 (IV Methylprednisone was used for patients unable to take PO).  Bone marrow studies including morphology, cytogenetics, FISH and molecular study to be performed on day 28 (and 56 if not in CR at day 28). II. Consolidation therapy:  First dose consolidation given within 2 weeks and no later than 4 weeks after confirmation of complete remission.  Idarubicin 12 mg/m2 IV repeated q 4 weeks (no later than 6 weeks) · 6. ATRA 45 mg/m2 given as induction daily for 2 weeks (started 24 h after Idarubicin dose) for a total of 6 cycles.  Peripheral blood for PCR obtained with each monthly cycle.  Bone marrow biopsy and aspirate studies including morphology, cytogenetics, and molecular studies to be done before the fourth Idarubicin consolidation, one month after the completion of the consolidation. III. Maintenance therapy started 4 weeks after completion of the consolidation therapy.

O. Elemam, D. Abdelmoety 6-Mercaptopurine 75 mg/m2 PO QD. Methotrexate 15 mg/m2 PO once a week. ATRA 45 mg/m2/d 14 days every 3 months. Doses of 6-Mercaptopurine and Methotrexate decreased by 50% if ANC < 1500 and discontinued if ANC < 1000.  Maintenance given for 24 months.    

Differentiation Syndrome was diagnosed based on the following clinical features: respiratory distress, pulmonary infiltrate, fever, weight gain, pleural effusion, renal impairment, pericardial effusion, and hypotension. Once we diagnosed it, we discontinued ATRA and dexamethasone (10 mg IV bid) was given for a minimum of 3 days with or without Lasix for reducing body weight. ATRA treatment was resumed once symptoms of Differentiation Syndrome resolved. All other complications at presentation and during treatment course were recorded. Patients were classified according to the risk of relapse (PETHEMA) on the basis of WBC and platelet counts (PLT) at diagnosis: Low risk WBC < 10 · 109/L and PLT > 40 · 109/L; Intermediate risk WBC < 10 · 109/L and PLT < 40 · 109/L, and High risk WBC > 10 · 109/L [8]. We calculated the body mass index (BMI) with the following categories: Underweight = <18.5, Normal weight = 18.5–24.9, Overweight = 25–29.9 and Obesity = BMI of 30 or greater. Complete Remission (CR) required patients to have ANC > 1.5 · 109/L, platelet count of more than 100 · 109/L and normo to hypocellular bone marrow with <5% blasts plus promyelocytes. Survival time was calculated from the time of diagnosis to the last follow-up. Resistant disease is defined as: the persistence of greater than 5% leukemic promyelocytes 56 days after the start of ATRA treatment. Statistical methods Data of quantitative variables (counts and measures) were presented as the median and the range because most of the variables were not found to be normally distributed; data of categorical variables were presented as percentages. Comparisons between patients with and without Differentiation Syndrome were performed using the non-parametric Mann Whitney U test for quantitative variables and the chi squared test for categorical variables. When the expected observation was too few as to violate the chi square test assumptions the Fisher Exact test was used. Survival data were presented using the Kaplan Meier method and comparisons were done by the log rank test. Cox regression was used to examine the relation between the overall survival and the PETHEMA risk category. For all hypothesis tests used, the a priori alpha two tailed level was set at 0.05 for statistical significance. All analyses were done using SPSS statistical package, Version 16. Results Patient characteristics are summarized in (Table 1). A total of 29 patients were treated from August 2005 to June 2011. The age of patients ranged from 16 to 81 years, 75.9% were Saudi, and 48.3% were females. At diagnosis, one patient had extramedullary skin disease and the main presenting symptom was

Acute promyelocytic leukemia, study of predictive factors for Differentiation Syndrome Table 1

Patient characteristics at diagnosis.

Patient characteristics Gender Male Female Median age Age range Nationality Saudi Non Saudi Extramedullary disease Main presenting symptoms Fever Bleeding Bleeding site Mucosal and skin Intracranial hemorrhage Median WBC Range Median HGB Range Median platelets Range DIC High LDH Hypogranular variant Hypercellular marrow Flowcytometry positive for CD11b CD11c CD14 CD33 HLADR CD34 CD45 Negative forCD56 Differentiation Syndrome YES NO ATRA symptoms Fever Weight gain Pulmonary symptoms Increase creatinine Complete remission Relapse Picc line related thrombosis Pethema risk model Low risk Intermediate risk High risk BMI(obese category) Status of last follow up Alive free of disease Alive with disease Died Median follow up

No

%

15 14 32 16–81 years

51.5% 48.3%

22 7 1

75.9% 3.4%

21 25

72.4% 86.2%

28 1 5 0.4–115 8 6–15 20 9–70 2 20 5 19

96.6% 3.4%

2 1 1 24 1 3 25 24

6.9% 3.4% 3.4% 82.8% 3.4% 10.3% 86.2% 82.8%

14 15

48.3% 51.7%

12 5 16 1 23 4 5

41.4% 17.2% 55.2% 3.4% 79.3% 13.8% 17.2%

6 8 15 13

20.6% 27.5% 51.7% 44.8%

21 0 8 17.13 months

72.4%

6.9% 69.0% 17.2% 65.5%

27.5%

bleeding (mucosal and skin), another patient had intracranial hemorrhage, and two patients had DIC. The median WBC at presentation was 1.5 · 109/L. The hypogranular variant was found in 5 cases. Additional cytogenetic abnormalities were found in 3 patients and included t (8; 15) and t (5; 7). One patient who had t (5; 17) and was negative for t (15; 17) died with septic shock during induction.

15

Differentiation Syndrome occurred in 48.3% of patients and mainly presented with pulmonary symptoms (55.2%) followed by fever (41.4%) and weight gain (17.2%). Apart from febrile neutropenia, other recorded complications were pseudo obstruction of the large bowel, intracranial hemorrhage, subhyoid and intraretinal bleeding. One patient developed pseudotumor cerebri that manifested with persistent headache, papilledema, diplopia with negative CSF and MRI brain. The patient was treated with acetazolamide plus ATRA discontinuation and shifting to ATO. ATRA was resumed during consolidation with no adverse events. One patient developed visual and auditory hallucinations related to voriconazole. Peripherally inserted central line (picc) related thrombosis occurred in 5 patients (17.2%). Six cases died during induction. Causes of early death were massive hemoptysis, intracranial hemorrhage, acute myocardial infarction, septic shock and alveolar hemorrhage (2 cases). Complete remission was achieved in 79.3% of patients, 4 patients relapsed and 2 patients achieved remission with second line treatment. We studied all the possible predictive factors for Differentiation Syndrome (see Table 2); none showed a statistically significant difference between patients who developed Differentiation Syndrome and those who did not except one, the percentage of females in patients with Differentiation Syndrome is significantly greater than that of males (P value 0.027). Differentiation Syndrome did not affect the overall survival. (Fig. 2) shows a Kaplan Meier curve of the overall survival in relation to development of Differentiation Syndrome (P value 0.390). At diagnosis, 6 patients were in the low PETHEMA risk group, 8 in the intermediate risk group, and 15 in the high risk group. For the effect of PETHEMA risk category on the cumulative overall survival, Cox regression showed a hazard ratio of 2.19 (i.e. almost twice the hazard for each unit increase in PETHEMA score). But this did not reach statistical significance (P = 0.168) (Fig. 1). Thirteen patients are in the obese category (44.8%) and there was no difference in median BMI between males and females. Out of 29 patients in this study, 23 are still alive and free of disease with a median follow up time of 17.13 months. Discussion In this retrospective study, we evaluated 29 patients of APL treated over 5 years in our tertiary care center. The baseline characteristics were similar to other reports. But based on the risk score, 51.7% of our patients were in the high risk category which is double the percentage reported by Pethema and Gimema groups [8]. The complete remission rate was 79.3%. This is slightly lower compared to that mentioned in other reports since we have more high risk patients in our group for being a tertiary care center accepts patients from all over the country and so a delay in transferring patient may be expected. All patients who survived the induction achieved complete remission. Six patients died during induction (20.6%). The main cause of induction death was hemorrhage. This was similarly reported in a study which explored the causes and predictive factors of induction death in patients with acute promyelocytic leukemia [9]. All our patients were treated with the AIDA protocol; except for a female patient who received

16 Table 2

O. Elemam, D. Abdelmoety Characteristics of patients with and without Differentiation Syndrome.

Gender Male Female Age (median + range) Fever at presentation Bleeding Median WBC (range) Median HGB (range) Median Platelets (range) Median promyelocytes (range) Median PT(range) Median PTT(range) Median Fibrinogen (range) Median D-Dim (range) Median LDH (range) Hypo granular CD 11b Positive Negative CD 11c Positive Negative CD 13 Positive Negative CD 14 Positive Negative CD 33 Positive Negative CD 34 Positive Negative CD 45 Positive Negative Median weight (range) Median height (range) Median BMI ALL (range) Median BMI male (range) Median BMI female (range)

RAS(yes)

RAS (no)

P value

4 (13.8%) 10 (34.5%) 35 (24–61) 13 (44.8%) 11 (37.9%) 2.08 (1–115) 10 (6–14) 25(4–70) 66.50 (1–90) 13.55 (11.30–18.30) 28.60 (25–41) 2.5 (0.9–4.7) 2.0 (1.0–2.0) 423 (203–1073) 4(13.8%)

11(37.9%) 4(13.8%) 28 (13–53) 8 (27.6%) 14 (48.3%) 9.30 (1–101) 8.0 (6–15) 19.80(5–69) 60.00 (1–94) 15.10 (10.00–17.90) 29.35 (24–97) 1.7 (1.1–2.7) 2.0 (1.0–2.0) 339.5 (183–768) 1(3.4%)

0.027

1(3.4%) 7(24.1%)

1(3.4%) 7(24.1%)

1.000

1(3.4%) 3(10.3%)

0 7(24.1%)

0.308

10(34.5%) 3(10.3%)

11(37.9%) 2(6.8%)

0.827

0 12(41.4%)

1(3.4%) 11(37.9%)

1.000

0 12(41.4%)

1(3.4%) 12(41.4%)

0.368

1(3.4%) 12(41.4%)

2(6.8%) 11(37.9%)

0.5

13(44.8%) 0 68.65 (54–95) 158.0 (146.9–190.00) 30.2 (20.8–263.6) 24.8(14.5–63.6) 32.5(20.8.5–263.6)

12(41.4%) 1(3.4%) 74.0 (39.2–157.00) 163.9 (150–170.3) 31.2 (14.59–63.69)

0.308

ATO (Arsenic trioxide) with a temporary stoppage of ATRA due to pseudotumor cerebri. ATO was well tolerated and after improvement treatment with ATRA was continued. Although our induction protocol contained oral prednisone Differentiation Syndrome, occurred in 48% of our patients and this is higher than the incidence reported in other studies which ranged from 6% to 36% [10–14]. This may be due to multiple factors as the type of induction chemotherapy, differences in diagnostic criteria, delay in starting treatment in most cases, and a great proportion of high risk patients in our cohort. The high Differentiation Syndrome incidence may also be due to its better recognition especially that the diagnosis of this syndrome is only made by clinical criteria with multiple differential diagnoses. The pathogenesis of this syndrome is still poorly understood; its clinical manifestations are suggesting a role for cytokines, including interleukin-1b (IL-1b), IL-6, IL-8, and tumor necrosis factor (TNF) a. APL cells undergoing differentiation with ATRA have been demonstrated. Organ infiltration by APL cells found in postmortem studies in

0.137 0.035 0.583 0.462 0.229 0.912 0.765 0.350 0.258 0.125 0.897 0.285 0.282

0.255 0.319 0.422 0.52

Differentiation Syndrome suggests that ATRA induces APL cells to acquiesce leukemic cell–endothelial cell adhesion followed by extravascular extravasation. In vitro, ATRA also leads to aggregation of APL cells, which appears to be mediated by induction by ATRA of the expression of high-affinity b2 integrins especially leukocyte function-associated antigen-1 [LFA-1] and their counter structure on the cell surface (in particular intercellular adhesion molecule [ICAM]-2). Methyl prednisolone rapidly inhibits APL cell aggregation in a dosedependent manner, consistent with its prompt clinical effectiveness in vivo [15]. Most of our patients were successfully treated with dexamethazone which is reported to be effective in other studies [6,16,17]. Two of our patients died with alveolar hemorrhage which has been reported to be a manifestation of Differentiation Syndrome [16]. So the best way is to try to predict its occurrence. Regarding the predictive factors of Differentiation Syndrome, there are conflicting results, some pointed to the high leucocytic count at presentation [13,18]. Others found no correlation between leucocytic count and Dif-

Acute promyelocytic leukemia, study of predictive factors for Differentiation Syndrome

Figure 1

17

Kaplan Meier curve of overall survival in relation to development of Differentiation Syndrome, P value 0.390.

Figure 2 Kaplan Meier curve of overall survival of all studied patients adjusted for PETHEMA risk category (beta coefficient = 0.784, beta exponent = 2.19, 95% CI (0.72–6.67).

ferentiation Syndrome incidence [5]. One study suggested that patients with WBC more than 5000 on day 1, 6000 on day 5, 10000 on day 10 or 15000 on day 15 are at a high risk of development of Differentiation Syndrome [19]. Our study

found no association between WBC count at presentation and Differentiation Syndrome development and this is similar to the study of 413 cases of newly diagnosed acute promyelocytic leukemia reported by the European APL group [15].

18 Steroid prophylaxis has been tested by other researchers, where steroid was given to the patients whose WBC rose more than 10,000 while on ATRA; none developed pulmonary toxicity but the number of patients studied was small and no randomized trials were carried out to confirm this [13,20,12,21]. Another study found that systemic steroids at the initiation of ATRA and for 15 days lead to a lower incidence of severe DS compared to IV dexamethazone given when the count was more than 5 · 10 · 109/L before and during treatment [22]. Our protocol did include prednisone from day 1 to 15 and the syndrome’s incidence approach 50%. We found no association between Differentiation Syndrome occurrence and the expression of CD11b, CD11c, CD13, CD14, CD33, CD34, or CD45. Other authors found that the basal expression of CD13 (aminopeptidase N) –a cell surface enzyme previously linked to tumor cell invasion and an inferior outcome in patients with acute myeloid leukemia– to be significantly associated with both the development of the syndrome and an elevated leukocyte count [6]. In the meantime, investigators returned to clinical examination and its value in predicting the occurrence of this syndrome. The percentage of females in patients with Differentiation Syndrome is significantly greater than that of males and this could not be explained by BMI which showed no statistical difference between males and females. Multiple studies suggested that BMI is a predictive factor for Differentiation Syndrome which may be explained by the over-expression of Leptin receptors on APL cells that can enhance their release of cytokines after ATRA exposure leading to its complication [23,24]. BMI was the most powerful predictor in the multivariate analysis of Differentiation Syndrome as well as the disease relapse in 144 patients treated with the AIDA protocol [25]. In this study, we could not confirm this, may be because most of our patients were obese. In conclusion, Differentiation Syndrome has no clear predictive factors to date. The best approach is to hold ATRA and give dexamethasone which is quite effective as reported in the literature. We report a higher incidence of Differentiation Syndrome coupled with a great proportion of high risk patients attending our institution. Conflict of interest All authors declare no competing financial interest. References [1] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposals for the classification of the acute leukaemias. French–American–British (FAB) co-operative group. Br J Haematol 1976;33(4):451–8. [2] Larson RA, Kondo K, Vardiman JW, Butler AE, Golomb HM, Rowley JD. Evidence for a 15; 17 translocation in every patient with acute promyelocytic leukemia. Am J Med 1984;76(5):827–41. [3] Kantarjian HM, Keating MJ, Walters RS, Estey EH, McCredie KB, Smith TL, Dalton Jr WT, Cork A, Trujillo JM, Freireich EJ. Acute promyelocytic leukemia. M.D. Anderson Hospital experience. Am J Med 1986;80(5):789–97. [4] Frankel SR, Eardley A, Lauwers G, Weiss M, Warrell Jr RP. The ‘‘retinoic acid syndrome’’ in acute promyelocytic leukemia. Ann Intern Med 1992;117(4):292–6.

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