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Some allogeneic stem cell transplantation (allo-SCT) recipients develop therapy-related myeloid neoplasms (t-MNs) of recipient origin with features including karyotypically abnormal hematopoiesis without cell dysplasia and myeloblast increase. However, due to their rarity their clinical course remains unclear. We report six cases of t-MN in patients with chromosomal abnormalities (CAs) after autologous recovery following allo-SCT for acute leukemia. CAs were first detected at a median interval of 422 (range 30-1941) days from allo-SCT. The fraction of CA-bearing cells of recipient origin increased with time, and cytogenetic relapse of underlying disease was not observed. Continuous emergence of identical autologous CAs was observed in one patient who did not receive total body irradiation (TBI). The other five patients received TBI, and complex karyotypes with the appearance of different types of CAs were the most dominant feature. Despite the persistence of complex abnormalities in the irradiated patients, no patient developed therapy-related acute myeloid leukemia (t-AML). TBI appears to be the major cause of t-MN of recipient origin with different types of CAs. Although t-MNs in patients receiving TBI do not initially seem to evolve to overt t-AML, they were associated with higher risk of underlying disease and greater oncogenic potential of irradiation.

Primary graft failure (PGF) is a lethal complication that occurs early after allogeneic stem cell transplantation (allo-SCT). Cord blood transplantation (CBT) is a potential re-transplantation option. Total body irradiation (TBI) is often incorporated into the pre-salvage CBT conditioning regimen following PGF; however, patients experiencing PGF are not always amenable to TBI, and non-TBI regimens for salvage CBT should be established. Here, we report five patients with hematologic malignancies who received salvage CBT for PGF following a non-TBI regimen using fludarabine (Flu), melphalan (Mel), and low-dose anti-thymocyte globulin (ATG). The median intervals between the failed allo-SCT and salvage CBT, as well as between the diagnosis of PGF and salvage CBT, were 37 days and 8 days, respectively. The median neutrophil recovery period was 21 days (range 18-21 days). Four of five patients achieved neutrophil engraftment following salvage CBT; all four exhibited sustained engraftment with complete donor chimerism. Three of the five patients were alive after a median follow-up time of 907 days (range 315-909 days) post-salvage CBT; two patients died of causes unrelated to recurrence. These data suggest that CBT following the non-TBI regimen described here is feasible in patients with PGF.

Given the poor prognosis of patients with relapsed/refractory acute myeloid leukemia (AML), better therapy is needed. Fludarabine enhances the efficacy of Ara-C (cytarabine) by increasing intracellular Ara-C-triphosphate. The FLAG (fludarabine, high-dose Ara-C, supported with granulocyte colony-stimulating factor) regimen has been tested for use in AML patients by other investigators. In the phase II study reported here, we evaluated the efficacy and toxicity of FLAGM therapy (FLAG with mitoxantrone), further intensified by adding mitoxantrone, based on the results of a phase I study by our group. The major endpoints were complete remission (CR) rate and early death. From June 2004 to February 2008, 41 patients (median age 52 years; range 18-64 years) were enrolled. Thirty (73% 95% CI 58-84%) patients achieved CR, which met the primary endpoint; there was a single case of early death from pneumonia. Two-year overall survival was 39.4% (95% CI 25.2-55.6%). Of those who achieved CR, 27 underwent allogeneic stem cell transplantation (SCT), and 12 SCT recipients showed long-term survival. Grade 3/4 non-hematological adverse events included infection (59%), nausea/vomiting (15%), diarrhea (7%), and elevated liver enzymes (7%). In conclusion, FLAGM is an effective and safe salvage therapy for patients with relapsed/refractory AML, and facilitated SCT for a large proportion of patients.

De novo acute basophilic leukemia (ABL) is a rare form of myeloid leukemia. The low prevalence of ABL makes it difficult to define its clinical characteristics and to establish an effective therapeutic protocol. We present here a case of de novo ABL in a 64-year-old Japanese man. The diagnosis of ABL depended on the following: (1) metachromasia with toluidine blue stain, (2) intracytoplasmic theta granules identified by electron microscopy, and (3) findings obtained from extensive immunophenotypic analysis. Although blast cells lacked basophil-specific antigens such as CDw17, CD88, and FcepsilonRI, an expression profile of cytokine receptors including CD116 (GM-CSF receptor), CD117 (c-kit), and CD123 (IL-3 receptor alpha) helped to define the cellular lineage in our case. The patient achieved complete remission with intensive chemotherapy composed of idarubicin and cytosine arabinoside and was disease free during the following 30 months. We propose that immunophenotyping, especially focusing on cytokine receptors, is useful in diagnosing ABL.

The presence of pre-transplant anti-HLA antibodies in recipients of cord blood transplantation (CBT) is associated with failed engraftment. However, only a small number of studies have reported that recipient-derived anti-HLA antibodies persist after CBT and have potential impact on the outcome. Of 61 patients who underwent HLA-mismatched CBT at Saiseikai Maebashi Hospital, three patients were identified as having anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB. All patients achieved successful engraftment. However, the three patients with the pre-transplant anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB continued to produce these antibodies even after engraftment; the persistence of these antibodies served as a sensitive minimal residual disease (MRD) marker. In contrast, donor HLA-specific and newly produced third party antibodies were not detectable even after relapse. The persistence of anti-HLA antibodies even after engraftment may be a potential marker for MRD, but is not a significant factor in secondary humoral engraftment failure.

Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is caused by reactivation of Epstein–Barr virus (EBV). A successful approach, monitoring EBV-DNA load in peripheral blood (PB) accompanied by preemptive rituximab therapy, has recently been reported. Here, we describe a 29-year-old woman who developed isolated central nervous system (CNS) PTLD. She received HSCT against acute myelogenous leukemia from a related human leukocyte antigen-haploidentical donor, following a conditioning regimen that included antithymocyte globulin. Tacrolimus and methylprednisolone were given as prophylaxis for graft-versus-host disease. On day +172, the patient’s consciousness deteriorated. Magnetic resonance imaging showed six ring-enhanced lesions in the cerebral hemispheres. These tumors were diagnosed, via a craniotomy and tumorectomy, as PTLD. EBV-DNA load was elevated in the cerebrospinal fluid (CSF) but not detected in PB. She was treated with whole-brain irradiation and rituximab, and achieved partial remission of the tumors. This case serves as a reminder that vigilance is required regarding the development of isolated CNS PTLD; it is worth examining EBV-DNA replication in CSF for diagnosis even when the EBV-DNA load is negative in PB.

The standard therapy for patients affected by acute promyelocytic leukemia (APL) is the administration of all-trans-retinoic acid (ATRA). ATRA therapy is usually well-tolerated, but it also has the potential to induce toxicity. The most severe side effect of ATRA is retinoic acid syndrome; the next is acute pancreatitis, which is a rare but serious adverse event mostly due to hypertriglyceridemia. We herein report a patient who developed ATRA-induced acute pancreatitis without hypertriglyceridemia. A 17-year-old female presented to our hospital complaining of a 3-week history of dyspnea. Her peripheral blood counts were: Hb: 4.5 g/dL, WBC: 0.96 9 10/L with 9% blasts, and platelets: 48 9 10/L. The biochemistry findings were significant only regarding the serum lactate dehydrogenase level of 276 IU/L. A bone marrow examination revealed an abnormal cellularity, thus indicating APL, while a cytogenetic study showed the presence of t(15;17) (q22;q21). The patient was treated with ATRA for the purpose of remission induction. On the second day of ATRA treatment, she suffered acute epigastric and upper left quadrant pain, and laboratory tests showed an elevation of amylase to 7,600 IU/L (normal range: 49–136 IU/L) and lipase to 1,680 IU/L (normal range: 11–53 IU/L), with no marked increases in triglyceride (TG). Computed tomography of the abdomen revealed no abnormal findings in either the biliary ducts or pancreas. With the cessation of ATRA, the symptoms rapidly disappeared and the pancreas-derived enzyme level thereafter decreased to the normal range. The peak level of TG was only 145 mg/dL (normal range: 30–149 mg/dL) throughout the entire course. The patient was then treated with arsenic trioxide therapy without experiencing any subsequent complications, and she has since remained in complete remission for 8 months after starting the induction treatment. Four cases of acute pancreatitis associated with the use of ATRA have been described [1–4], but only one of these presented without hypertriglyceridemia, which is one of the common side effects of ATRA [4, 5]. Our case is the second such case. The pathogenesis of ATRA-induced acute pancreatitis without hypertriglyceridemia is not clear. Cytokines, such as IL-8, IL-1beta, and TNF-alpha, have been shown to be intimately involved in the inflammatory response to acute pancreatitis in general [6]. Teng et al. suggested that the increased expression of these cytokines in APL cells induced by ATRA may also play a role in the pathogenesis of ATRA-induced acute pancreatitis [4, 7]. As far as the case of Teng et al. is concerned, however, this suggestion remains controversial because of the recurrence of an elevated lipase level with a second ATRA treatment even after achieving complete remission in his case. His case rather suggests that either allergic or autoimmune mechanisms might play critical roles in the development of ATRA-induced acute pancreatitis. On the other hand, the activation of pancreatic stellate cells (PSCs) is known to be implicated in the production of pancreatic fibrosis and associated with the loss of retinol-containing fat droplets, which are stored in quiescent PSCs. Recent studies have demonstrated that retinol and its ATRA metabolites induce quiescence in activated PSCs and decreased collagen synthesis [8]. Pancreatic fibrosis, which is the process of repair after pancreatic injury, is prevented by ATRA, and then proinflammatory cytokines might be upregulated and lead to ATRA-induced acute pancreatitis. T. Hoshino (&) N. Hatsumi S. Takada T. Sakura S. Miyawaki Leukemia Research Center, Saiseikai Maebashi Hospital, Kamishinden-machi, 564-1, Maebashi, Gunma 371-0821, Japan e-mail: takumihoshino4249@yahoo.co.jp