Post-allogeneic stem cell transplant extramedullary relapse of acute megakaryoblastic leukemia initially detected by elevated WT1 mRNA levels in peripheral blood.

An 18-year-old male was admitted to our hospital for fever, and was diagnosed with acute megakaryoblastic leukemia (AML M7) based on the presence of CD42a and CD61 positive myeloblasts in peripheral blood (PB). Induction chemotherapy at our hospital resulted in complete remission (CR). Subsequently, he underwent unrelated HLA-DR one locus-mismatched allogeneic bone marrow (BM) transplantation. Although CR was maintained without development of graft-versus-host disease (GvHD), the WT1 mRNA level in PB was elevated on post-transplant day 134. As BM aspiration performed 1 week later confirmed maintenance of CR, and because the WT1 mRNA level in BM was not high in comparison with PB, we suspected extramedullary relapse. PET-CT demonstrated a thymic tumor and a gastric tumor with abnormal accumulation of FDG, and biopsy confirmed both to be extramedullary relapse of AML M7. Induction chemotherapy following local radiation therapy achieved a second CR, following which he received HLA haploidentical peripheral blood stem cell transplantation on day 256 after the first transplant. The patient is currently surviving free from both relapse and GvHD. High WT1 mRNA levels in PB as compared with BM should raise suspicion of extramedullary relapse, and PET-CT is very useful for whole body evaluation in such cases.

Two distinct effector memory cell populations of WT1 (Wilms' tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients.

Wilms' tumor gene 1 (WT1) protein is a promising tumor-associated antigen for cancer immunotherapy. We have been performing WT1 peptide vaccination with good clinical responses in over 750 patients with leukemia or solid cancers. In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1 mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/or WT1 mRNA levels increased relative to the initial state within 6 months of WT1 vaccination) prior to WT1 vaccination. Cluster and principal component analyses performed using 83 genes did not discriminate between responders and non-responders prior to WT1 vaccination. However, these analyses revealed that EM subset of WT1-specific CTLs could be divided into two groups: the "activated" and "quiescent" states; in responders, EM subset of the CTLs shifted to the "quiescent" state, whereas in non-responders, those shifted to the "activated" state following WT1 vaccination. These results demonstrate for the first time the existence of two distinct EM states, each of which was characteristic of responders or non-responders, of WT1-specific CTLs in AML patients, and raises the possibility of using advanced gene-expression profile analysis to clearly discriminate between responders and non-responders prior to WT1 vaccination.

Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.

It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, we identified 50 who had discontinued imatinib for at least six months; of these we analyzed 43. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was estimated to be 47% following imatinib discontinuation. Based on multivariate regression analysis, imatinib dose intensity and prior interferon-α administration were independently predictive of molecular recurrence within 12 months. The depth of the molecular response should be a factor influencing long-term sustained complete molecular response after discontinuation of imatinib. Additionally, an immunological mechanism modified by interferon-α might control chronic myeloid leukemia stem cells.

Fatal Trichosporon fungemia in patients with hematologic malignancies.

OBJECTIVE: Invasive Trichosporon infection has been increasingly recognized in patients with hematologic malignancies. Our study aims to clarify the clinical characteristics of this disease and factors influencing patient prognosis. PATIENTS AND METHODS: We retrospectively analyzed 33 cases of Trichosporon fungemia (TF) in patients with hematologic malignancies treated at our collaborating five hospitals in Japan between 1992 and 2007. RESULTS: The majority of these patients had acute leukemia (82%), neutropenia (85%), and a history of intensive chemotherapy (91%). TF occurred as a breakthrough infection during antifungal therapy in 30 patients (91%), 18 of whom were receiving micafungin. The surveillance cultures of most patients were negative for Trichosporon. Only a few patients exhibited elevated levels of 1,3-beta-d-glucan before positive blood culture. Twenty-five patients (76%) died of this infection. The resolution of infection was associated with neutrophil recovery (P = 0.0001), absence of hyperglycemia (P = 0.023), and azole inclusive therapy (P = 0.031). Survival was significantly longer in patients receiving antifungal therapies containing azole than in those who did not receive azole (P = 0.0034). CONCLUSIONS: At present, the diagnosis of invasive trichosporonosis depends on blood culture studies, and the mortality of this disease is high; however, azole therapy and control of blood glucose level, together with hematopoietic recovery could help in improving the clinical outcome. When we use antifungals lacking anti-Trichosporon activity, sufficient care should be taken to prevent the development of breakthrough trichosporonosis.

[Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR].

Imatinib mesylate has significantly improved the outcome of patients with CML. In the IRIS trial, major molecular response (MMR), which is defined as the achievement of > or =3 log reduction in bcr-abl mRNA from the standardized baseline, was observed in 40% of CML patients by 12 months. Achievement of an MMR at 18 months is associated with 100% probability of transformation-free survival at 60 months, and MMR is an important goal of therapy. The nucleic acid quantitative "DNA probe FR Amp-CML" kit based on the transcription-mediated amplification method, can measure major bcr-abl mRNA in peripheral blood leukocytes. In this study, we studied the clinical usefulness of Amp-CML for monitoring minimum residual disease by comparison with the European standard nucleic acid quantitative method and real-time quantitative PCR (RQ-PCR) with GAPDH as an internal control, using peripheral leukocytes obtained from patients receiving imatinib treatment. The results indicated that Amp-CML had a significant correlation with Fusion Quant M-BCR (R>0.971, P<0.01), a standard nucleic acid quantitative method used in Europe and RQ-PCR (R>0.974, P<0.01), especially in samples with more than 100 copies/microg RNA of major bcr-abl mRNA. These data suggest that Amp-CML is reliable for monitoring major bcr-abl mRNA in patients having achieved an MMR.

Ponatinib in Japanese patients with Philadelphia chromosome-positive leukemia, a phase 1/2 study.

In this ongoing Phase 1/2 study (NCT01667133), we evaluated ponatinib and assessed its recommended dose in Japanese patients with chronic myeloid leukemia (CML) resistant/intolerant to dasatinib or nilotinib, or with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant/intolerant to ≥1 tyrosine kinase inhibitor (TKI). The primary endpoints were safety of the recommended dose (Phase 1) and major cytogenetic response (MCyR) by 12 months in chronic-phase CML (CP-CML) patients or major hematologic response (MaHR) by 6 months in patients with advanced phase disease (Phase 2). MCyR was achieved/maintained by 12 months in 65% of CP-CML patients; MaHR was achieved by 6 months in 61% of patients with advanced phase disease. The most common nonhematologic grade 3/4 treatment-emergent adverse event (AE) was hypertension (37%); common hematologic grade 3/4 AEs were thrombocytopenia (57%), neutropenia (34%), and leukopenia (26%). Overall, five (14%) patients experienced arterial occlusive events (AOEs); no grade 5 AOEs were reported. The steady-state accumulation ratio of ponatinib (based on area under the curve) ranged from 2.6 (15 mg/day) to 1.3 (45 mg/day). In summary, ponatinib demonstrated efficacy in Japanese patients with CML and Ph+ALL resistant/intolerant to prior TKI treatment; safety data support a recommended starting dose of 45 mg/day in these patients.

Low p53 expression of acute myelocytic leukemia cells with t(8;21) chromosome abnormality: association with low p14(ARF) expression.

In this study, the mRNA expression of p14(ARF) in t(8;21)AML cells was found to be significantly lower than acute myelocytic leukemia (AML) cells without t(8;21) chromosome abnormality, which was concordant with previous observation by Linggi et al. that AML1-MTG8 represses the transcription of p14(ARF). Although p53 mRNA expression level of t(8;21)AML cells was not low, p53 protein expression was reduced in t(8;21)AML cells. Genotoxic damage by ionizing radiation did not induce p53 upregulation in t(8;21)AML cells. Since p14(ARF) has been demonstrated to inhibit p53 degradation by binding to MDM2, repression of p14(ARF) expression in t(8;21)AML may facilitate the degradation of p53 by MDM2. Low p14(ARF) in t(8;21)AML may also account for the absence of upregulation of p53 by ionizing radiation. Then, we have shown that p53 expression level was inversely correlated with S/G2/M population of cell cycle in AML cells. Most of the t(8;21)AML are considered to be in p53(low) S/G2/M(high). It is now widely known that formation of AML1-MTG8 by t(8;21) translocation is a very early event in leukemogenesis, and AML1-MTG8 alone might have limited proliferative potential. Then, secondary oncogenic events such as activated receptor tyrosine kinase (like c-kit mutation), is necessary to become full-blown leukemia. Low p53 protein expression and insufficient induction of p53 by genotoxic damage might increase the opportunity to obtain additional oncogenic events, since genome guard function of p53 does not work in t(8;21)AML cells.

Breakthrough fungemia caused by fluconazole-resistant Candida albicans with decreased susceptibility to voriconazole in patients with hematologic malignancies.

A 7-year retrospective analysis of candidemia in patients with hematologic malignancies demonstrated that ten patients, who received itraconazole and fluconazole during neutropenia, developed breakthrough fungemia caused by fluconazole-resistant Candida albicans (C. albicans) with decreased susceptibility to voriconazole. Eight of these ten patients died of candidemia despite amphotericin B administration. Karyotype analysis of C. albicans isolates revealed that all isolates were genetically unrelated? Our findings suggest that blood isolates of C. albicans in neutropenic patients receiving azoles could be azole cross-resistant, and that the patients should be treated by other antifungals such as echinocandins.

Prognostic Significance of New-Onset Atrial Fibrillation in Patients With Non-Hodgkin's Lymphoma Treated With Anthracyclines.

Cancer therapeutics-related cardiac dysfunction induced by anthracycline is highly problematic, and its early recognition is of importance. Atrial fibrillation (AF) is sometimes seen after anthracycline chemotherapy. We aimed to test whether new-onset AF predicts anthracycline-induced heart failure. We prospectively studied 249 lymphoma patients who received anthracyclines. The patients were followed up with a frequent electrocardiographic examination. Fifteen patients (6%) newly developed AF after the chemotherapy, and during a mean follow-up of 34 months, they had a higher incidence of acute heart failure (40% vs 3.8%; p <0.001) and greater all-cause mortality (60% vs 14.1%; p <0.001) than those without AF. The onset of AF preceded the development of heart failure by a mean of 2.4 months. New-onset AF was independently associated with both acute heart failure (hazard ratio 12.78; p <0.001) and all-cause mortality (hazard ratio 4.77; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure, yet it was another independent predictor of the mortality. In conclusion, new-onset AF may predict unfavorable outcomes after anthracycline chemotherapy in patients with malignant lymphoma.

Relationship between HMGB1 and PAI-1 after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Conditioning regimens including total body irradiation (TBI) or cyclophosphamide can mobilize high-mobility group box 1 (HMGB1) to peripheral blood. Additionally, increased plasminogen activator inhibitor (PAI)-1 levels are associated with post-allogeneic hematopoietic stem cell transplantation (aHSCT). However, changes to circulating levels of HMGB1 after aHSCT are poorly understood. MATERIALS AND METHODS: The study cohort included 289 patients who underwent aHSCT at one of 25 institutions in Japan. We have investigated the relationship between HMGB1 and PAI-1 following aHSCT. A significant increase in HMGB1 levels occurred after conditioning treatment. Additionally, levels of HMGB1 at day 0 were significantly increased in TBI+ patients and cyclophosphamide/TBI patients. CONCLUSION: Our data revealed that an increased level of HMGB1 at day 0 following aHSCT correlates with increased PAI-1 after aHSCT, which is consistent with previous reports. Increased HMGB1 at day 0 after a conditioning regimen may play a role in transplantation-associated coagulopathy following aHSCT, because PAI-1 can accelerate procoagulant activity.

Biological implications of somatic DDX41 p.R525H mutation in acute myeloid leukemia.

The DDX41 gene, encoding a DEAD-box type ATP-dependent RNA helicase, is rarely but reproducibly mutated in myeloid diseases. The acquired mutation in DDX41 is highly concentrated at c.G1574A (p.R525H) in the conserved motif VI located at the C-terminus of the helicase core domain where ATP interacts and is hydrolyzed. Therefore, it is likely that the p.R525H mutation perturbs ATPase activity in a dominant-negative manner. In this study, we screened for the DDX41 mutation of CD34-positive tumor cells based on mRNA sequencing and identified the p.R525H mutation in three cases among 23 patients. Intriguingly, these patients commonly exhibited acute myeloid leukemia (AML) with peripheral blood cytopenias and low blast counts, suggesting that the mutation inhibits the growth and differentiation of hematopoietic cells. Data from cord blood cells and leukemia cell lines suggest a role for DDX41 in preribosomal RNA processing, in which the expression of the p.R525H mutant causes a certain ribosomopathy phenotype in hematopoietic cells by suppressing MDM2-mediated RB degradation, thus triggering the inhibition of E2F activity. This study uncovered a pathogenic role of p.R525H DDX41 in the slow growth rate of tumor cells. Age-dependent epigenetic alterations or other somatic changes might collaborate with the mutation to cause AML.

Prognostic Relevance of Cytokine Receptor Expression in Acute Myeloid Leukemia: Interleukin-2 Receptor α-Chain (CD25) Expression Predicts a Poor Prognosis.

A variety of cytokine/cytokine receptor systems affect the biological behavior of acute leukemia cells. However, little is known about the clinical relevance of cytokine receptor expression in acute myeloid leukemia (AML). We quantitatively examined the expression of interleukin-2 receptor α-chain (IL-2Rα, also known as CD25), IL-2Rß, IL-3Rα, IL-4Rα, IL-5Rα, IL-6Rα, IL-7Rα, the common ß-chain (ßc), γc, granulocyte-macrophage colony-stimulating factor (GM-CSF)Rα, G-CSFR, c-fms, c-mpl, c-kit, FLT3, and GP130 in leukemia cells from 767 adult patients with AML by flow cytometry and determined their prevalence and clinical significance. All cytokine receptors examined were expressed at varying levels, whereas the levels of IL-3Rα, GM-CSFRα, IL-2Rα, γc, c-kit, and G-CSFR exhibited a wide spectrum of ≥10,000 sites/cell. In terms of their French-American-British classification types, GM-CSFRα and c-fms were preferentially expressed in M4/M5 patients, G-CSF in M3 patients, and IL-2Rα in non-M3 patients. Elevated levels of IL-3Rα, GM-CSFRα, and IL-2Rα correlated with leukocytosis. In patients ≤60 years old, higher levels of these 3 receptors correlated with poor responses to conventional chemotherapy, but only IL-2Rα was associated with a shorter overall survival. By incorporating IL-2Rα status into cytogenetic risk stratification, we could sort out a significantly adverse-risk cohort from the cytogenetically intermediate-risk group. Analyses with various phenotypical risk markers revealed the expression of IL-2Rα as an independent prognostic indicator in patients with intermediate-risk cytogenetics. These findings were not observed in patients >60 years old. Our results indicate that several cytokine receptors were associated with certain cellular and clinical features, but IL-2Rα alone had prognostic value that provides an additional marker to improve current risk evaluation in AML patients ≤60 years old.

PC-SPES decreases proliferation and induces differentiation and apoptosis of human acute myeloid leukemia cells.

PC-SPES is an eight herbal mixture which has been shown to be active against prostate cancer cells in vitro as well as in patients. In this study, we discovered that it has anti-leukemia activity. HL-60, NB4, U937 and THP-1 human acute myeloid leukemia cells were cultured in the presence of various concentrations of PC-SPES (0.06-0.5 micro l/ml) for 4 days, and cell numbers were counted by Trypan blue exclusion. PC-SPES inhibited proliferation of these cells with an ED50 of 0.17, 0.09, 0.18, 0.32 micro l/ml, respectively. In clonogenic assay, PC-SPES inhibited growth of HL-60 cells (ED50, 0.043 micro l/ml). On the other hand, PC-SPES (0.1 micro l/ml) stimulated growth of normal myeloid committed stem cells (CFU-GM) by 1.4-fold of control (p=0.03). Anti-leukemia effects also occurred against freshly isolated leukemia cells from acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. Interestingly, when PC-SPES was combined with ATRA, the antiproliferative effect was markedly enhanced. For example, PC-SPES (0.125 micro l/ml) or ATRA (10(-8) mol/l) inhibited growth of HL-60 cells after 4 days of culture, by approximately 40 and 30%, respectively; simultaneous treatment with both, suppressed growth by 80%. In addition, PC-SPES induced differentiation of HL-60 and NB4 cells, as measured by expression of CD11b and reduction of NBT. ATRA synergistically enhanced this activity. For example, either PC-SPES (0.5 micro l/ml) or ATRA (10(-8) mol/l) induced 23 and 18% of HL-60 cells, respectively to express CD11b on day 2 of culture; and when both were combined, 60% of HL-60 cells were stimulated to express CD11b antigen. Furthermore, PC-SPES (0.5 micro l/ml) produced apoptosis of HL-60 and NB4 cells, as measured by TUNEL assay, with 17% of HL-60 cells and 52% of NB4 cells becoming apoptotic on their third day of culture. Importantly, PC-SPES stimulated expression of the novel myeloid specific transcription factor C/EBPepsilon in HL-60 and NB4 cells. Taken together, PC-SPES inhibits growth and induces differentiation and apoptosis of myeloid leukemia cells, and enhances the antiproliferative and prodifferentiative effects of ATRA on these cells. PC-SPES might be useful with ATRA for treatment of patients with acute promyelocytic leukemia (APL), and it could have a role in other types of cancers including MDS.

Clinical significance of breakthrough fungemia caused by azole-resistant Candida tropicalis in patients with hematologic malignancies.

A 5-year retrospective analysis of fungemia in patients with hematologic malignancies revealed that four patients, who received fluconazole and itraconazole during neutropenia, developed breakthrough candidemia due to azole-resistant Candida tropicalis isolates. This observation suggests that causative organisms of candidemia in neutropenic patients receiving azoles should be suspected of being azole-resistant.

Resveratrol, a natural product derived from grapes, is a new inducer of differentiation in human myeloid leukemias.

A natural product, resveratrol (3,4,40-trihydroxy-trans-stilbene), a phytoalexin found in grapes and other food products, is known as a cancer chemopreventive agent. We studied the in vitro biological activity of this compound by examining its effect on proliferation and differentiation in myeloid leukemia cell lines (HL-60, NB4, U937,THP-1, ML-1, Kasumi-1) and fresh samples from 17 patients with acute myeloid leukemia. Resveratrol (20 microM, 4 days) alone inhibited the growth in liquid culture of each of the 6 cell lines. Resveratrol (10 microM) enhanced the expression of adhesion molecules (CD11a, CD11b, CD18, CD54) in each of the cell lines except for Kasumi-1. Moreover, resveratrol (25 microM, 4 days) induced 37% of U937 cells to produce superoxide as measured by the ability to reduce nitroblue tetrazolium (NBT). The combination of resveratrol (10 microM) and all-trans-retinoic acid (ATRA) (50 nM, 4 days) induced 95% of the NB4 cells to become NBT-positive, whereas <1% and 12% of the cells became positive for NBT after a similar exposure to either resveratrol or ATRA alone, respectively. In U937 cells exposed to resveratrol (25 microM, 3 days), the binding activity of nuclear factor-kappaB (NFkappaB) protein was suppressed. Eight of 19 samples of fresh acute leukemia cells reduced NBT after exposure to resveratrol (20 microM, 4 days). Taken together, these findings show that resveratrol inhibits proliferation and induces differentiation of myeloid leukemia cells.

Effect of interferon-alpha on chromosome abnormalities in treated chronic myelogenous leukemia patients.

To investigate the relationship of chromosomal aberrations at blastic crisis (BC) in chronic myelogenous leukemia (CML), with previous therapies and with atomic bomb (AB) exposure, we studied 114 CML patients who developed BC, including 23 AB survivors in Hiroshima. In total, only 45.6% showed major-route abnormalities, which figure was far lower than those previously reported, implying possibility of geographical difference. Occurrence of major-route abnormality was not associated with either duration of chronic phase or survival time after BC. Patients treated with interferon-alpha (IFNalpha) showed lower frequency of major-route abnormalities and lower number of abnormal chromosomes than did patients treated with busulfan (Bu). The frequency of trisomy 8 was lower and monosomy 7 was higher in IFNalpha-treated than in Bu-treated patients. The frequency of unusual abnormalities at BC in IFNalpha-treated patients was indistinguishable from those in Bu-treated patients and, notably, a more common (40%) feature in IFNalpha-treated patients was no change in the cytogenetic picture. Thus, we conclude that IFNalpha action on chromosome aberration is basically quite neutral and that IFNalpha does not induce any specific aberrations, including unusual ones at BC, with an exception of deletion of chromosome 7. Atomic bomb exposure status did not make any difference in secondary abnormalities at BC.

Itraconazole prophylaxis for invasive gingival aspergillosis in neutropenic patients with acute leukemia.

BACKGROUND: Due to an increasing number of leukemic patients with invasive gingival aspergillosis during neutropenia (neutrophils <500 cells/microl for >10 days), we evaluated the efficacy of oral itraconazole prophylaxis for preventing this invasive infection at our hospital. METHODS: This was a retrospective, non-randomized study to analyze the onset of identified invasive gingival aspergillosis among 536 patients with acute leukemia at risk due to the presence of neutropenia from 1991 to 1998. Patients received itraconazole capsules 100 mg/day prophylactically between April 1994 and December 1996, and 200 mg/day between January 1997 and December 1998. Itraconazole serum levels at day 10 were measured in some patients. RESULTS: In the 39 months prior to April 1994 without itraconazole prophylaxis, 15 cases of invasive gingival aspergillosis were detected in 192 high risk patients with 469 episodes of neutropenia (7.8% of the high risk patients). Between April 1994 and December 1996, using itraconazole prophylaxis at 100 mg/day, there was a dramatic decrease in the infections resulting in 3 of 198 high risk patients with 511 episodes of neutropenia (1.5% of the high risk patients). Furthermore, between January 1997 and December 1998, using itraconazole prophylaxis at 200 mg/day, no cases of the infection were observed in the 146 high risk patients with 380 episodes of neutropenia. The incidence of invasive gingival aspergillosis was significantly lower among patients administered itraconazole than among those without itraconazole (100 mg/day; P = 0.006 and 200 mg/day; P = 0.001). The mean itraconazole serum level in 20 patients receiving 100 mg/day was 71.78 ng/mL and in 16 patients receiving 200 mg/day was 202.67 ng/ml. CONCLUSIONS: These findings suggest that oral itraconazole could be effective for preventing invasive gingival aspergillosis in neutropenic patients with acute leukemia and warrants further randomized investigation.

Five cases of anthracycline-induced cardiomyopathy effectively treated with carvedilol.

Anthracycline, a widely used anti-cancer agent, can elicit irreversible cardiomyopathy called anthracycline-induced cardiomyopathy (ACM). In this report, we describe 5 cases of severe chronic heart failure due to ACM effectively treated with the beta-blocker, carvedilol. Their left ventricular function as well as cardiac symptoms were persistently improved after treatment with carvedilol, suggesting that carvedilol may be an effective therapeutic strategy for ACM as demonstrated in other forms of chronic heart failure.

[Acute myelogenous leukemia associated with severe esophageal stricture after chemotherapy].

A 41-year-old woman with relapsed acute myelogenous leukemia was treated twice with idarubicin hydrochloride and cytarabine. She developed a 6-cm-long stricture in the lower esophagus 12 days after re-induction therapy. Although she had preceding candida infection, it is suspected that her stricture was caused by mucosal damage due to chemotherapeutic agents. This case suggests that the possibility of esophageal stricture should be considered in patients with swallowing disturbance after intensive chemotherapy.