A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study).

Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age ≥50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age ≥50. Poor performance status (PS ≥2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis.

Prognostic factors and outcomes of unrelated bone marrow transplantation for Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) pre-treated with tyrosine kinase inhibitors.

BACKGROUND: The treatment and prognosis of Acute Lymphoblastic Leukemia (ALL), including Philadelphia chromosome positive ALL (Ph+ALL), a poor prognostic factor, has changed with the introduction of tyrosine kinase inhibitors (TKIs). Nevertheless, allogeneic hematopoietic cell transplantation (allo-HCT) is still recommended as the first-line curative treatment. To date, no study has investigated the prognostic factors and outcomes of unrelated bone marrow transplantation (u-BMT) for Ph+ALL following pre-transplant treatment with a TKI-containing regimen. METHODS: We retrospectively evaluated 15 transplantations of 14 patients with Ph+ALL pre-treated with a TKI-containing regimen at our institute. The 14 patients comprised 11 males and 3 females, with a median age of 50 years (range: 19-64). We performed univariate and multivariate analyses of risk factors that contributed to overall survival (OS) or leukemia-free survival (LFS). RESULTS: Three-year OS of the patients with molecular complete remission (MCR) and with non-MCR at transplantation were 89% and 40% (p = 0.006), respectively, and three-year LFS rates were 79% and 0% (p = 0.001), respectively. Univariate analysis revealed that first hematological complete remission (HCR1) and MCR at transplant were significantly related to better OS and LFS. Multivariate analysis showed that MCR at transplant was significantly associated with better OS and LFS. CONCLUSIONS: In agreement with a previous study that included other stem cell sources, u-BMT was deemed feasible for the treatment of Ph+ALL. Analysis of a larger cohort is required to clarify the prognostic factors that affect transplant outcome in Ph+ALL since the introduction of TKIs.

[Angioimmunoblastic T cell lymphoma complicated with endocapillary proliferative glomerulonephritis].

A 30-year-old female developed fever and multiple lymphadenopathy in September 2011. Her symptoms improved with antibiotic treatment. However, she again presented with fever and multiple lymphadenopathy in December 2011. In addition, she suffered from nephrotic syndrome with severe edema. She was therefore hospitalized to undergo detailed examinations. Renal biopsy revealed endocapillary proliferative glomerulonephritis. Since her renal function deteriorated rapidly, she was given steroid pulse therapy with methylprednisolone, followed by maintenance therapy with prednisolone. After treatment, her renal function improved but multiple lymphadenopathy persisted. Biopsy of a left axillary lymph node was then performed and revealed angioimmunoblastic T-cell lymphoma (AITL). She received CHOP therapy but showed no response. Therefore, she was given ESHAP therapy. A partial response was achieved and the nephrotic syndrome also resolved completely. We report this extremely rare case of renal dysfunction due to endocapillary proliferative glomerulonephritis complicated by AITL.

[Acute transverse myelitis after allogeneic bone marrow transplantation for acute lymphoblastic leukemia--a case report].

Transverse myelitis is an inflammatory disorder of the spinal cord that results in motor, sensory, and autonomic dysfunction. Herein, we describe a 40-year-old Japanese female who developed acute transverse myelitis (ATM) after an unrelated bone marrow transplantation for Philadelphia-positive acute lymphoblastic leukemia in molecular complete remission. Approximately 90 days after transplantation, she suffered from paresthesias, sphincter dysfunction, and lower extremity weakness. Spinal cord magnetic resonance imaging scan demonstrated findings consistent with ATM. The symptoms were resolved with the administration of steroids, followed by intravenous immunoglobulin therapy for a few sequelae. To the best of our knowledge, the presentation of ATM after hematopoietic stem cell transplantation is relatively rare. As the functional prognosis of ATM depends on prompt diagnosis and treatment, we consider that ATM should be included in the differential diagnosis of post-transplant myelopathies.

[Complication of pernicious anemia during interferon-ß treatment for type C chronic hepatitis].

A 62-year-old man with chronic hepatitis C underwent interferon (IFN)-ß therapy. After treatment for a period comprising 29 months and 2 weeks, hematological results showed a decrease in white blood cell, hemoglobin, and platelet counts (WBC 2,300/µl, Hb 7.2 g/dl, PLT 4.7×10(4)/µl), and IFN therapy was stopped. Despite therapy discontinuation, the pancytopenia continued to progress with elevation of LDH (LDH 4,898 IU/l), and the patient was admitted to our hospital with suspected hematological disease. The patient underwent clinical screening, and pernicious anemia caused by vitamin B12 deficiency was diagnosed. The anemia rapidly improved with vitamin B12 treatment. Interferon is the mainstay of treatment for patients with viral hepatitis. While the adverse effects of interferon therapy are widely recognized, only a few reports have documented pernicious anemia developing during IFN-therapy. We recommend that particular attention be paid to such clinical and laboratory conditions as megaloblastic anemia when administering IFN. We also recommend checking the vitamin B12 level, as a deficiency of this vitamin may lead to the development of megaloblastic anemia.

[Chronic myelogenous leukemia complicated by drug-induced agranulocytosis].

We describe a patient with chronic myelogenous leukemia (CML) who developed drug-induced agranulocytosis. A 75-year-old female was diagnosed with CML in December 2001. She had been receiving imatinib therapy for more than five years. In August 2007, she was hospitalized due to a severe neutropenia 10 days after colonoscopy. She was diagnosed as having agranulocytosis induced by colonoscopy premedication including scopolamine butylbromide and flumazenil. Severe neutropenia was resolved by G-CSF treatment without CML progression. Agranulocytosis in patients with CML is rare, but potentially lethal. Here, we report the clinical course in this patient.

[Membranous nephropathy with nephrotic syndrome developed after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia].

A 38-year-old man was diagnosed with acute lymphoblastic leukemia. We performed myeloablative bone marrow transplantation from an unrelated donor during the patient's first complete remission. After engraftment, he developed acute graft-versus-host disease involving the gastrointestinal tract on day 32. Steroids and mycophenolate mofetil were initiated from day 39. His symptoms improved and the dose of immunosuppressants was tapered and then discontinued on day 421. On day 491, he developed nephrotic syndrome (NS). Based on renal biopsy, membranous nephropathy was diagnosed. There were no apparent symptoms or abnormal laboratory data suggestive of chronic graft-versus-host disease (cGVHD). Steroid therapy was initiated from day 518 and proteinuria improved significantly. NS is very rare following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When there is no concomitant cGVHD, as in this case, allo-HSCT-associated NS is difficult to distinguish from idiopathic NS.

Serum cytokine profiles at the onset of severe, diffuse alveolar hemorrhage complicating allogeneic hematopoietic stem cell transplantation, treated successfully with pulse intravenous cyclophosphamide.

A 59-year-old man with lymphoma-type adult T-cell leukemia/lymphoma was admitted to hospital for treatment of a skin relapse on day 398 after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To induce a graft-versus-adult T-cell leukemia/lymphoma effect, we discontinued methylprednisolone and tacrolimus. About a month after the discontinuation, he developed grade II acute graft-versus-host disease (GVHD) with a high fever. Soon after the development of GVHD, all the skin lesions regressed in size and finally vanished. However, he developed diffuse alveolar hemorrhage (DAH), which was resistant to high-dose corticosteroid therapy. He was intubated for respiratory insufficiency on day 451. Cyclophosphamide pulse therapy was administered at a dose of 1 g per day for 2 days and his oxygen saturation then improved, and ventilatory support was released on day 465. On analysis of cytokine profiles at the onset of DAH, we found elevated serum levels of T-helper 2 cytokines as well as T-helper 1 cytokines, suggesting that both T-helper 1 and T-helper 2 cytokines might play a role in the occurrence of DAH following allo-HSCT. Pulse cyclophosphamide treatment might be very effective in suppressing the exaggerated allogeneic immune response in DAH.

[Epstein-Barr virus-associated post-transplant lymphoproliferative disorder diagnosed by the episode of intestinal perforation following allogeneic hematopoietic stem cell transplantation].

A 64-year-old man was diagnosed as having acute myeloid leukemia. We performed sequential treatment with chemotherapy and reduced-intensity stem cell transplantation from an unrelated donor while the patient was in partial remission. After engraftment, he developed acute graft-versus-host disease of the gut on day 42 and steroid therapy was started. Despite transient aggravation of diarrhea, his symptoms slowly improved and the dose of steroid was tapered. On day 159, he complained of acute left lower abdominal pain. A CT scan showed perforation of the digestive tract and ileectomy was performed. At surgery, multiple ulcers of the intestine were found and one of the ulcers was perforated. Pathologically, transmural and diffuse proliferation of atypical cells in the ulcer were confirmed. Since these cells were positive for CD20 and Epstein-Barr-virus (EBV) encoded RNA, we made a diagnosis of EBV-associated post-transplant lymphoproliferative disorder (PTLD). Reduction in the dose of immunosuppressive agents and rituximab led to complete remission of PTLD. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare, and the development of gastrointestinal perforation after allo-HSCT is very rare.

[A modified myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation, consisting of intravenous busulfan, cyclophosphamide and total lymphoid irradiation, in advanced leukemia].

In nine patients with advanced acute or chronic leukemia, we performed allogeneic hematopoietic stem cell transplantation (HSCT) following a modified myeloablative conditioning regimen intended to optimize the intensity of conditioning. This regimen consisted of intravenous busulfan 8mg/kg, cyclophosphamide 120mg/kg and total lymphoid irradiation 7.5 Gy. The median age of the patients was 30 years (range 18-59). Stem cell sources were related bone marrow in two, related peripheral blood in one, and unrelated bone marrow in six patients. Prophylaxis against acute graft-versus-host disease (GVHD) was cyclosporine and short-term methotrexate. Acute GVHD appeared in six patients (67%), grade II in all. Extensive chronic GVHD occurred in three of seven evaluable patients. The median follow-up period after HSCT was 813 days (248- 1,702). Of nine patients, five relapsed or progressed after HSCT. However, no patient relapsed or progressed within 100 days after HSCT. During the full follow-up period, transplant-related mortality (TRM) was not observed. The two-year overall survival and event-free survival were 88.9% and 50.0%, respectively. Our results suggested that we might reduce the incidence of TRM and simultaneously control disease by using an optimized conditioning regimen for HSCT.

Cardiac and autonomic nerve function after reduced-intensity stem cell transplantation for hematologic malignancy in patients with pre-transplant cardiac dysfunction.

Recent reports have shown that cardiomyopathy caused by hemochromatosis in severe aplastic anemia is reversible after reduced-intensity allogeneic stem-cell transplantation (RIST). We comprehensively evaluated cardiac and autonomic nerve function to determine whether cardiac dysfunction due to causes other than hemochromatosis is attenuated after RIST. In five patients with cardiac dysfunction before transplant, we analyzed the changes in cardiac and autonomic nerve function after transplant, using electrocardiography (ECG), echocardiography, radionuclide angiography (RNA), serum markers, and heart rate variability (HRV), before and up to 100 days after transplant. There was no significant improvement in cardiac function in any patient and no significant alteration in ECG, echocardiogram, RNA, or serum markers. However, on time-domain analysis of HRV, the SD of normal-to-normal RR intervals (SDNN) and the coefficient of variation of the RR interval (CVRR) decreased significantly 30 and 60 days after transplant (P = 0.04 and 0.01, respectively). Similarly, on frequency-domain analysis of HRV, low and high frequency power (LF and HF) significantly and temporarily decreased (P = 0.003 and 0.03, respectively). Notably, in one patient who had acute heart failure after transplantation, the values of SDNN, CVRR, r-MSSD, LF, and HF at 30 and 60 days after transplantation were the lowest of all the patients. In conclusion, this study suggests that (a) RIST is well-tolerated in patients with cardiac dysfunction, but we cannot expect improvement in cardiac dysfunction due to causes other than hemochromatosis; and (b) monitoring HRV may be useful in predicting cardiac events after RIST.

Cord blood transplantation for adult patients with hematological malignancies.

BACKGROUND: Recently, clinical studies of cord blood transplantation (CBT) in adults after myeloablative or nonmyeloablative conditioning regimens showed cord blood (CB) could effectively restore hematopoiesis and was associated with acceptable levels of graft versus host disease (GVHD). METHODS: This study reports the results of cord blood transplantation in 7 adults with hematological malignancies. RESULTS: Median age was 56 years (range, 43-69 years). HLA match was 4 of 6 in 4 cases and 5 of 6 in 3 cases. Median nucleated cell dose was 2.74 x 10(7) cells/kg (range, 2.13-3.80) and CD34+ cell dose was 1.15 x 10(5) cells/kg (range, 0.44-2.79). Three patients had primary graft failure. There was one early death at day 24 after CBT due to pneumonia. Three patients with engraftment are alive and free of disease at day 390, day 348 and day 164 after CBT. Acute GVHD grade II occurred in 2 cases with engraftment, and chronic GVHD occurred in 1 of 3 evaluable patients. Six patients with and without engraftment received more than 2.0 x 10(7) cells/kg nucleated cells. Three patients without engraftment received CD34+ cell dose less than that of 3 patients with engraftment. CONCLUSIONS: It is considered that graft CD34+ cell dose besides nucleated cell dose is important for engraftment. We believe that adult patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT by the choice of CB including both sufficient nucleated cell dose and CD34+ cell dose.

[Chronic GVHD with polymyositis after non-myeloablative stem cell transplantation].

A 57-year-old man underwent an autologous hematopoietic stem cell transplant for mantle cell lymphoma in August 1999. Anemia and thrombocytopenia appeared in November 2001. He was diagnosed with further hematological examination as having acute myeloid leukemia with multilineage dysplasia following secondary myelodysplastic syndrome. He received the allogeneic hematopoietic stem cell transplant from his HLA DRB1 locus mismatched brother in May 2002. The nonmyeloablative preparative regimen consisted of fludarabine 30mg/m2 for 6 days and busulfan 4mg/kg for 2 days. Eosinophilia, decrease of lacrimal fluid and liver dysfunction appeared on Day 104. We diagnosed this as chronic GVHD and treated the patient with prednisolone 10 mg/day. Thereafter, his chronic GVHD gradually improved. He had fever and myalgia in the extremities and lumbar region with elevated serum CPK and aldolase in January 2003. Histological examination led to a diagnosis of polymyositis simultaneously with chronic GVHD. Prednisolone 50 mg/day as an initial dose was started for the polymyositis following which the prednisolone dose was gradually tapered off. The polymyositis improved promptly after the administration of prednisolone and remains in remission with a current maintenance program of prednisolone 5 mg/day.

[Acute myelomonocytic leukemia complicated with multiple lower intestinal ulcers induced by nonsteroidal anti-inflammatory drugs].

We report an 18-year-old woman with acute myelomonocytic leukemia, who developed massive lower intestinal bleeding following induction chemotherapy. Colonoscopy revealed multiple circular ulcers but no infectious colitis or infiltration of leukemia. The biopsy specimen showed mild non-specific inflammatory changes and scattered apoptosis bodies. She took nonsteroidal anti-inflammatory drugs (NASIDs) for pyrexia and pharyngalgia for a long time. We concluded these were signs of ulcers induced by NSAIDs. Despite discontinuance of NSAIDs, melena did not improve. Transarterial embolization therapy using microcoils was tried with unsatisfactory results. Finally, colonoscopic clipping therapy and continuous arterial injection of vasopressin were performed. Subsequently, her condition improved markedly. In conclusion, NSAID-induced intestinal bleeding is not limited to the upper GI tract but may occur in the lower GI tract after long-term NSAID use. The possibility of lower GI tract complications from NSAID should be kept in mind.

[Autologous hematopoietic stem cell transplantation for aggressive B-cell non-Hodgkin's lymphoma].

To evaluate the results of high-dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with diffuse B-cell aggressive non-Hodgkin's lymphoma(NHL). Between 1991 and 2004, 25 patients who did not achieve complete remission and 26 in complete remission from conventional chemotherapy received HDC-ASCT. Of 25 patients with refractory NHL,14 were chemotherapy-sensitive before HDT-ASCT and 11 were chemotherapy-resistant. CR was achieved after HDC-ASCT in 50% of 14 chemotherapy sensitive patients and in none of 11 chemotherapy-resistant patients. The 5-year probability of event-free survival for chemotherapy-sensitive and chemotherapy-resistant patients was 51.3% and 20.8%, respectively (p<0.05, log-rank test). Moreover, the 5-year probability of event-free survival for patients in the low-risk group with International Prognostic Index (IPI) and in the high-risk group with IPI was 75.0% and 16.3%, respectively (p<0.05, log-rank test). HDT-ASCT should be considered for patients with refractory aggressive NHL who are chemotherapy-sensitive rather than chemotherapy-resistant. Twenty-six patients in complete remission received consolidation therapy with HDT-ASCT. The 5-year probability of disease-free survival for patients in the low-risk group and in the high-risk group was 68.8% and 60.0%,respectively (p = 0.9 6). HDT-ASCT should be considered for patients at high risk who achieve complete remission after induction treatment. In future, HDT-ASCT combined with rituximab as induction therapy or as consolidation therapy is needed for patients with aggressive NHL in the high-risk group.

Infliximab for the treatment of severe steroid refractory acute graft-versus-host disease in three patients after allogeneic hematopoietic transplantation.

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated three patients with severe aGVHD refractory to steroids with infliximab. Patients (MDS 1, NHL 1, ALL 1) developed grade II-IV GVHD at a median of 13 days (range 9-17) after non-myeloablative PBSCT (HLA mismatched). All patients had received treatment with high-dose steroids for a median of 7 days (range 7-10) in addition to mycophenolate mofetil (MMF) (one). Infliximab was given in 3 weekly doses of 5 mg/kg. In one of three patients a partial resolution of diarrhea and minor improvement of skin were observed. One patient died with refractory GVHD. Infliximab is apparently an effective drug for the treatment of aGVHD, but can be more effective at doses of 5 mg/kg or higher and/or by administering it repeatedly every week.

QT dispersion correlates with systolic rather than diastolic parameters in patients receiving anthracycline treatment.

OBJECTIVE: The aim of this study was to investigate the relation of QT dispersion to left ventricular (LV) systolic and diastolic function in patients undergoing anthracycline therapy. METHODS: We used echocardiography to evaluate LV systolic and diastolic function and electrocardiography to evaluate QT dispersion and corrected QT dispersion (QTcD) in patients with hematological diseases, who received anthracycline therapy. PATIENTS: Seventy-two patients with hematological diseases who were receiving anthracycline treatment were enrolled in the present study. RESULTS: LV end-diastolic diameter or LV end-systolic diameter had a significant positive correlation to QTcD (r = 0.35, p < 0.01, r = 0.43, p < 0.01). Also left ventricular ejection fraction of (LVEF) or fractional shortening had a significant negative correlation to QTcD (r = -0.46, p < 0.001, r = -0.27, p = 0.02). The highest QTcD group had a significantly larger LV end-diastolic diameter or LV end-systolic diameter than the lowest QTcD [48.5 +/- 5.7 vs. 44.4 +/- 4.5 (mm), p < 0.001, 34.1 +/- 6.4 vs. 28.8 +/- 4.3 (mm), p < 0.001] and the highest QTcD group had a significantly lower LVEF than the lowest QTcD [57.5 +/- 8.0 vs. 65.5 +/- 6.4 (%), p < 0.001]. On the other hand, none of the diastolic function markers were significantly correlated with QTcD. CONCLUSION: We concluded that increased QTcD is correlated with LV dilation and systolic dysfunction induced by anthracycline therapy, and does not reflect a dispersion of ventricular repolarization or asynchronous motion.

[A case of amelanotic melanoma of the nasal cavity].

A 68-year-old male visited Hospital A for treatment of epistaxis, his chief complaint. He was told that he had an easily-bleeding tumor in the nasal cavity. Based of biopsy, a diagnosis of amelanotic melanoma was made. Operation was performed for removal of the tumor. About 8 months after discharge, he visited Hospital B with complaints of lumbar pain and epistaxis. After biopsy at Hospital B, malignant lymphoma (diffuse large cell) was diagnosed, and the patient was referred to our hospital. On bone marrow puncture and biopsy, tumor cell infiltration was observed. Flow cytometric surface marker analysis revealed that these tumor cells were negative for CD45. Results of HE staining of the nasal cavity tumor were insufficient for diagnosis, and staining by immunohistochemistry was necessary to confirm the diagnosis. On immunohistochemical staining of the nasal cavity tumor tissue and bone marrow biopsy tissue, LCA, L26 and UCHL-1 were negative, and S-100 and HMB-45 positive. Recurrence of amelanotic melanoma accompanied by bone marrow infiltration was therefore diagnosed. The incidence of amelanotic melanoma with primary lesions in the nasal cavity is low. However, in making the diagnosis of a nasal cavity lesion, the possibility of such a melanoma should be kept in mind. In many cases, it is difficult to diagnose amelanotic melanoma with HE staining alone, and immunohistochemistry must be used.

[Primary malignant lymphoma arising from the nipple and areolar area of the breast].

A 56-year-old woman noticed soreness and swelling in the right nipple. Two weeks later, she noticed a mass in the outer lower region of the right areolar area, which was excised and the pathology of which was consistent with diffuse large B cell lymphoma (DLBCL). She was admitted when the right nipple mass was noted to be increasing, and was diagnosed as having stage I lymphoma. Her nipple mass was excised, and the pathology was consistent with DLBCL. CHOP therapy was administered three times and she was judged as having complete remission. Malignant lymphoma accounts for 0.15-0.17% of primary breast malignancies. Though the nipple and areolar area seem to be a rare primary site, this should be recognized as a sentinel zone for malignant lymphoma.

[Successful treatment with foscarnet for disseminated varicella-zoster infection after reduced intensity stem cell transplantation in a case of relapsed refractory central nervous system lymphoma].

Visceral disseminated varicella-zoster virus (VZV) infection occurred with acute graft-versus-host disease in a 33-year-old Japanese male with non-Hodgkin lymphoma who had undergone allogeneic stem cell transplantation from an HLA-identical sibling after reduced intensity conditioning chemotherapy. Although ganciclovir and acyclovir treatment was effective temporarily, the number of VZV-DNA copies in the blood remained at a high level, and the hepatitis was prolonged. The patient was treated with foscarnet, which led to improvement of the VZV viremia and the hepatic dysfunction. Foscarnet therapy should be considered for acyclovir-resistant VZV infection in the setting of allogeneic hematopoietic stem cell transplantation.