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Cite this article: Yamamoto S, Miike T, Kubuki Y, Yamaji T, Nakamura K, et al. (2014) Gastrointestinal Bleeding in Acute Myeloid Leukemia Patients Receiving Intensive Induction Chemotherapy. JSM Gastroenterol Hepatol 2(3): 1019.

*Corresponding authorKazuya Shimoda, Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan, Tel: +81-985-85-9121; Fax: +81-985-85-5194; Email:

Submitted: 22 January 2014

Accepted: 05 March 2014

Published: 07 March 2014

Copyright© 2014 Shimoda et al.

OPEN ACCESS

Keywords•Gastrointestinal bleeding•Chemotherapy•Anti-ulcer prophylaxis

Research Article

Gastrointestinal Bleeding in Acute Myeloid Leukemia Patients Receiving Intensive Induction ChemotherapyShojiro Yamamoto1, Tadashi Miike1, Yoko Kubuki1, Takumi Yamaji1, Kenichi Nakamura1, Hiroo Abe1, Kanna Hashimoto1, Shuichiro Natsuda1, Mai H-Sakaguchi1, Yoshihiro Tahara1, Taku Harada1, Hisayoshi Iwakiri1, Satoru Hasuike1, Kenji Nagata1,2, Akira Kitanaka1, Takayuki Matsumoto3 and Kazuya Shimoda1,2*1Department of Gastroenterology and Hematology, Faculty of Medicine, University of Miyazaki, Japan2Liver Disease Center, University of Miyazaki Hospital, Japan3Medicine and Clinical Science, Graduate School of Medical Science, Kyushu University, Japan

Abstract

Background: We wanted to clarify which type of anti-ulcer prophylactic agent is effective for the prevention of gastrointestinal (GI) bleeding in acute myeloid leukemia (AML) patients receiving intensive induction chemotherapy.

Methods: We analyzed GI bleeding in a retrospective cohort of 90 AML patients who received intensive chemotherapy as induction therapy. Patients were divided into three groups according to the ulcer prophylaxis drug used: proton pump inhibitors (PPI), histamine H2 receptor antagonists (H2A), and other drugs (non-antacid) for ulcer prophylaxis. The agent used for ulcer prophylaxis was chosen by each treating physician based on available clinical data.

Results: Four patients (4%) experienced a GI bleed (melena, n=2; fecal occult blood (OB), n=2) after induction chemotherapy. The incidence of GI bleeding was comparable among patients who took PPI, H2A, or other drugs for ulcer prophylaxis. There was no difference between those with or without GI bleeding in the duration of thrombocytopenia or coagulopathy and the daily steroid dose.

Conclusion: The incidence of GI bleeding after intensive chemotherapy for AML is relatively low, and the choice of acid-reducing drug used for ulcer prophylaxis has little impact on the incidence of GI bleeding after induction chemotherapy for AML.

ABBREVIATIONSPPIs: Proton Pump Inhibitors; H2 blockers: Histamine H2

Receptor Antagonists; GI: Gastrointestinal; AML: Acute Myeloid Leukemia; APL: Acute Promyelocytic Leukemia; OB: Occult Blood; OS: Overall Survival; EGD: Esopha Gogastro Duodenoscopy

INTRODUCTIONCancer therapy frequently causes significant damage to

the oral and gastroesophageal mucosa. In lung cancer patients, endoscopic evaluation of the effects of cisplatin plus etoposide chemotherapy on the gastric and duodenal mucosa showed

that approximately half (15 out of 32 patients) developed multiple erosions or ulcers in the stomach or duodenum after chemotherapy [1]. Management of these complications is important for achieving better survival. Both proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2RA) are widely used to prevent chemotherapy-induced damage to the upper gastrointestinal (GI) tract. A randomized study of PPI or H2RA versus placebo for the prevention of gastroduodenal injury induced by cyclophosphamide, methotrexate, fluorouracil (CNF) therapy or fluorouracil alone reported that acute ulcers were significantly less frequent in patients receiving PPI or H2RA than in those receiving placebo [2]. This investigation used

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EGD to evaluate the effect of PPI or H2RA on chemotherapy-induced gastroduodenal injury, and concluded that only PPI was effective for preventing endoscopically documented global worsening caused by chemotherapy. Acute leukemia is a disease potentially curable with chemotherapy, but intensive induction chemotherapy induces not only mucosal damage, but also severe thrombocytopenia, which is suspected to exacerbate GI bleeding. To prevent GI bleeding after intensive induction chemotherapy, some kind of prophylactic anti-acid drug is usually used in daily medical practice. We examined which type of anti-ulcer prophylactic agent is effective for the prevention of GI bleeding in acute myeloid leukemia (AML) patients receiving intensive induction chemotherapy using a previously reported population-based AML cohort in Miyazaki prefecture, Japan [3].

MATERIALS AND METHODS We previously reported a retrospective population-based

cohort study of AML patients in Miyazaki Prefecture, Japan [3].

There were a total of 211 adult AML patients included during the study period, between January 1, 2003 and December 31, 2008 (Figure 1). Ten acute promyelocytic leukemia (APL) patients were excluded from this study due to differences in therapy. As previously reported, some of the remaining AML patients received intensive induction chemotherapy. A majority of patients less than 65 years in age were treated with intensive chemotherapy, while approximately half of patients aged 65–74 years and less than 10% of patients aged over 75 years received intensive chemotherapy as induction therapy, respectively. In total, 105 patients received intensive induction chemotherapy. Due to unavailable clinical data, 15 patients were excluded. We retrospectively analyzed GI bleeding in 90 patients who received intensive chemotherapy as induction therapy.

Patients were monitored for signs of GI bleeding on a daily basis by the care team according to standards of care at each institution in our study group. Chart review was conducted to identify patients who developed overt or occult GI bleeding. An

Figure 1 Retrospective chart analysis profile. One hundred and five patients out of 211 adult AML patients during the study period received intensive induction chemotherapy. The agent used for ulcer prophylaxis was chosen by each treating physician based on available clinical data and local standards of care. AML-acute myeloid leukemia, APL-acute promyelocytic leukemia, PPI- proton pump inhibitors, H2RA- histamine H2 receptor antagonists.

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overt GI bleed was defined as hematemesis, melena, or gross hematochezia. The initial screening for occult bleeding consisted of monitoring for decreases in the concentration of hemoglobin greater than 1 g/dL over a 3 day period that was not attributable to the effects of chemotherapy. Next, fecal occult blood immunochemical testing was performed to identify patients with occult bleeding. Patients were divided into three groups according to the ulcer prophylaxis drug used: PPI, H2A, and non-antacid. The non-antacid group consisted of patients not taking PPIs or H2As. The agent used for ulcer prophylaxis was chosen by each treating physician based on available clinical data and local standards of care.

This study was approved by the institutional review board of the University of Miyazaki.

Statistical methods

All data were analyzed using SPSS software, version 20 (SPSS Inc. , Chicago, IL, USA). A two-sided P value <0.05 were considered statistically significant. The Kaplan–Meier method was used to estimate probabilities of overall survival (OS), and the log-rank test was used to compare OS across groups.

RESULTSThere were 22 patients in the PPI group and 45 patients in

the H2RA group. Of the 23 patients in the non-antacid group,

15 were taking rebamide, and 8 were not taking any kind of gastroprotective drug during and after hemotherapy. Baseline characteristics of the patients are summarized in Table 1. The median platelet count was 43 x 109/L, and 49 (54%) patients had platelet counts less than 5 x 109/L.

The median interval between the start of intensive induction chemotherapy and subsequent consolidation chemotherapy (or second induction chemotherapy in cases of induction failure) was 45. 5 days (range, 24–132). During this period, 86 patients (96%) had thrombocytopenia (<20 x 109/L) requiring platelet transfusion. Two patients presented with thrombocytopenia but did not require platelet transfusions, and two other patients did not have thrombocytopenia. The median duration of thrombocytopenia (<20 x 109/L) was 17 days (range, 0–126).

Four patients (4%) experienced GI bleeding (melena, n=2; stool OB, n=2) during this period (Table 2). One of the two patients who experienced melena (patient number 1 in table 2) underwent esophagogastroduodenoscopy (EGD), which revealed a duodenal ulcer (Figure 2). He had the history of the duodenal ulcer and underwent Billroth II resection for his ulcer 5 years before AML. Anastomotic ulcer with bleeding was sealed off by ethanol local injection and the ablation using argon plasma coagulation. Endoscopy performed 16 days after the onset of GI bleeding showed that the ulcer was healing. EGD

Ulcer prophylaxis regimen PPI H2RA Non-antacid All patients p value

n (%) 22 (24.4) 45 (50.0) 23 (25.6) 90 (100)

Age (years), median (range) 56.5 (36-74) 55 (19-80) 63 (29-77) 58 (20-80)

Male gender, n (%) 11 (50) 30 (66.7) 12 (52.2) 53 (58.9)

Performance status 0.374

0–1 16 25 14 55

2 5 12 6 23

3–4 1 7 3 11

Hemoglobin (g/dL), median (range) 8.8 (4.1-15.6) 7.8 (3.7-13.7) 7.1 (4.1-12.8) 7.8(3.7-15.6) 0.217

Platelets (x109/L), median (range) 46 (5-148) 41 (2-179) 41 (3-586) 43 (2-586) 0.543

Creatinine (mg/dL), median (range) 0.8 (0.5-5.8) 0.8 (0.3-1.4) 0.8 (0.4-14.6) 0.8 (0.3-14.6) 0.283

History of GD ulcers*, n 3 1 1 5 0.156

Table 1: Baseline characteristics.

Abbreviations: PPI, Proton Pump Inhibitor; H2RA, Histamine 2 Receptor Antagonist; non-antacid, patients who took neither PPI nor H2RA, but some were given rebamipide* Patients with a previous history of gastroduodenal ulcers

Patient The kind of GI bleeding

Hb on the day of AML diagnosis(g/dL)

Hb on the day of GI bleeding(g/dL)

The amount of RBC transfusions between the day of AML diagnosis and that of GI bleeding

anti-ulcer prophylactic agent

1 melena, duodenal ulcer 9.4 3.3 10 units / 18 days omeprazole sodium 40

mg

2 melena 11.2 8.2 0 units / 5 days omeprazole sodium 20 mg

3 stool occult blood positive 5.8 6.5 10 units / 12 days famotidine

40 mg

4 stool occult blood positive 10.6 7.5 16 units/ 26 days famotidine

20 mg

Table 2: Changes in hemoglobin values in 4 patients who experienced gastrointestinal bleeding.

Abbreviations: GI, Gastrointestinal; Hb, Hemoglobin; AML, Acute Myeloid Leukemia; RBC, Red Blood CellIt should be noted that one unit of RBC transfusion is made from 200 mL of peripheral blood in Japan.

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Figure 2 Esophagogastroduodenoscopic findings in one patient who experienced melena after intensive induction chemotherapy for acute myeloid leukemia. (A). an anastomotic ulcer with bleeding in the duodenum on the day of gastrointestinal bleeding. (B): the ulcer on the second day after the onset of gastrointestinal bleeding. (C): the ulcer healing stage on the 16th day after the onset of gastrointestinal bleeding.

was not performed in the other patient due to the presence of coagulopathy. In these two patients, PPI therapy was continued, and RBC products were transfused (8 units in one patient and 4 units in the other). No deaths occurred in the four patients who experienced GI bleeding.

These four patients all had thrombocytopenia requiring platelet transfusion. However, the duration of thrombocytopenia, number of units of platelets transfused, duration of coagulopathy, and daily steroid dose were comparable between patients with and without GI bleeding. Only the number of units of transfused red blood cells (RBCs) was greater in patients with GI bleeding (Table 3). Two melena events occurred in patients prescribed PPIs, and two stool OB positive events occurred in patients prescribed H2RAs. There were no incidents of GI bleeding in the non-antacid group. The incidence of GI bleeding was comparable among the three groups (p=0. 335). In addition, the odds ratio for GI bleeding events in the H2RA group was 0. 465 (95% confidence interval, 0. 061–3. 543; p=0. 46) compared to the PPI group.

Ten patients (3, 3, and 4 patients receiving PPI, H2RA, and no ulcer prophylaxis, respectively) died between the start of intensive induction chemotherapy and the start of consolidation or second induction chemotherapy. The 45 day-OS rate in the PPI, H2RA, and non-antacid groups was 86%, 93%, and 83%, respectively (p=0. 395).

DISCUSSIONInjury to the mucosa of the upper GI tract is one of the most

common adverse effects associated with cancer treatment. In AML patients who received intensive induction chemotherapy in this retrospective analysis, H2RA was prescribed about twice as frequently as PPI. The incidence of GI bleeding was as low as 4%. Since only two patients had a positive fecal occult blood test, the incidence of overt GI bleed was 2%. Intensive induction chemotherapy for AML is a regimen that can easily induce GI bleeding, and Ara-C is generally considered to be the most injurious of the agents used in induction chemotherapy [4,5]. Almost all patients experience severe thrombocytopenia requiring platelet transfusion. Despite these conditions, in our cohort, the rate of overt GI bleeding was as low as 2% after intensive induction chemotherapy, and in three of four with GI bleeding, hemorrhage was self-limited, resolving with vigorous supportive care. The

incidence of GI bleeding was much lower than in a previous study that reported a 7.4% incidence of overt GI bleeding when H2RAs were used prophylactically in patients undergoing bone marrow transplantation [6]. However, the rate of overt GI bleeding in this study was nearly identical to the incidence of grade 4 bleeding (2%) reported in a study of patients who underwent intensive

No bleeding(n=86)

Bleeding(n=4) p value

Objective evidence, n (%)

Melena - 2

Stool occult blood positive - 2

Ulcer prophylaxis therapy, n (%) 0.335

PPI 20 2

H2RA 43 2

Non-antiacid 23 0

Duration of thrombocytopenia*1 17 (0-126) 22 (10-26) 0.991

Transfusion amount*2

RBC 12 (2-30) 2 0 (12-32) 0.007

Plt 70 (30-250) 100 (80-100) 0.458

Coagulopathy, n (%)*3 39 (45.3) 3 (75) 0.336

Corticosteroid use, n (%) 50 (58.1) 4 (100) 0.147Hydrocorton equivalent (mg/day) 2.5 (0-55.2) 30.1 (11.8-

135) 0.305

Table 3: Characteristics of gastrointestinal bleeding associated with intensive induction chemotherapy.

Abbreviations: Unless otherwise indicated, data are presented as median (range).PPI, patients who took proton pump inhibitors; H2RA, patients who took histamine 2 receptor antagonists; non-antacid, patients who took neither PPI nor H2RA, but some were given rebamipide; RBC, red blood cell product; Plt, platelet preparation*1: the number of days in which patients had a platelet count < 20 x109/L or required platelet transfusion*2: the number of units patients received between induction chemotherapy and the next chemotherapy, either consolidation therapy or second induction therapy if complete remission was not achieved. *3: the number of days in which patients had a prothrombin international normalized ratio (PT-INR) >1.5, activated partial thromboplastin time (APTT) >43 seconds, or fibrin degradation products (FDP) ≥10 μg/dL.

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chemotherapy for AML or autologous hematopoietic stem cell transplantation for hematological cancers [7]. No difference in the duration of thrombocytopenia and coagulopathy in patients with or without GI bleeding may indicate that increased bleeding tendency induced by intensive chemotherapy is not the main cause of GI bleeding. The use of corticosteroids also had little impact on the incidence of GI bleeding.

The type of anti-ulcer prophylactic agent used had no influence on the incidence of GI bleeding after induction chemotherapy, which was comparable between the PPI and H2RA groups. This is partly consistent with a previous report that both PPIs and H2RAs were effective in reducing the incidence of acute ulcers in chemotherapy patients. Furthermore, the two cases of overt GI bleeding in our cohort occurred in patients receiving PPI for prophylaxis. This finding may lend support to the hypothesis that the pathophysiology of chemotherapy-induced gastrointestinal damage is not solely attributable to the degree of gastric acid secretion, since PPIs are superior to H2RAs in terms of acid suppression.

There are some limitations in our analysis. The study design is the retrospective one with small sample size. The agent used for ulcer prophylaxis was not randomized, but was chosen by each treating physician based on available clinical data and local standards of care. Of note, since EGD was not performed in our patients before and after chemotherapy, we could not rule out the possibility that the effect in preventing the global endoscopic worsening caused by such treatment was different between two groups.

CONCLUSIONThe incidence of GI bleeding after intensive chemotherapy

for AML is relatively low, and the type of medication for ulcer prophylaxis has little or no impact on the incidence of GI bleeding after induction chemotherapy for AML.

ACKNOWLEDGEMENTSThe authors appreciate the work of data manager and

statistical support from Takaaki Hamasa ki and Chieko Nagatomo. This study was conducted by Miyazaki Hematology Group. The authors are grateful to Drs. Kiyoshi Yamashita, Takanori Toyama, Kouichi Maeda, Noriaki Kawano, Seiichi Sato, Hiroshi Kawano, Junzo Ishikawa, Takuro Kameda, Tadashi Sasaki, Masaaki Sekine, Ayako Kamiunten, Tomonori Hidaka, Haruko K-Shimoda, Kotaro Shide, Takuya Matsunaga and Hitoshi Matsuoka in Miyazaki Hematology Group.

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Yamamoto S, Miike T, Kubuki Y, Yamaji T, Nakamura K, et al. (2014) Gastrointestinal Bleeding in Acute Myeloid Leukemia Patients Receiving Intensive Induction Chemotherapy. JSM Gastroenterol Hepatol 2(3): 1019.

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