Kazuo Hatanaka

Prognostic factors and outcomes of adult patients with acute myeloid leukemia after first relapse

Background Patients with acute myeloid leukemia who are treated with conventional chemotherapy still have a substantial risk of relapse; the prognostic factors and optimal treatments after relapse have not been fully established. We, therefore, retrospectively analyzed data from patients with acute myeloid leukemia who had achieved first complete remission to assess their prognosis after first relapse. Design and Methods Clinical data were collected from 70 institutions across the country on adult patients who were diagnosed with acute myeloid leukemia and who had achieved a first complete remission after one or two courses of induction chemotherapy. Results Among the 1,535 patients who were treated with chemotherapy alone, 1,015 relapsed. Half of them subsequently achieved a second complete remission. The overall survival was 30% at 3 years after relapse. Multivariate analysis showed that achievement of second complete remission, salvage allogeneic hematopoietic cell transplantation, and a relapse-free interval of 1 year or longer were independent prognostic factors. The outcome after allogeneic transplantation in second complete remission was comparable to that after transplantation in first complete remission. Patients with acute myeloid leukemia and cytogenetic risk factors other than inv(16) or t(8;21) had a significantly worse outcome when they did not undergo salvage transplantation even when they achieved second complete remission. Conclusions We found that both the achievement of second complete remission and the application of salvage transplantation were crucial for improving the prognosis of patients with acute myeloid leukemia in first relapse. Our results indicate that the optimal treatment strategy after first relapse may differ according to the cytogenetic risk.

Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors.

The impact of human leucocyte antigen (HLA) incompatibility between donor and recipient on graft‐versus‐host disease (GVHD) and graft failure after reduced‐intensity conditioning stem cell transplantation (RICT) remains to be elucidated. We retrospectively analysed outcome in 341 patients who underwent RICT from related donors for haematological malignancies. The overall cumulative incidence of grade II–IV acute GVHD (aGVHD) was 40% for all subjects; 39% in recipients with HLA‐matched donors, 44% in those with one‐locus‐mismatched donors, and 50% in those with two‐ to three‐loci‐mismatched donors. In a Cox regression model adjusted for potential confounders, the tendency for grade II–IV aGVHD (P = 0·01), chronic GVHD (cGVHD) (P = 0·05) and graft failure (P = 0·033) increased with HLA disparity. Use of peripheral blood grafts instead of marrow was a risk factor for cGVHD. Use of antithymocyte globulin was associated with reduced aGVHD and cGVHD. Overall survival (OS) in recipients of two‐ to three‐loci‐mismatched RICT at 2 years (18%) was significantly worse than that in patients who received one‐locus‐mismatched RICT (51%) and HLA‐matched RICT (48%) (P < 0·0001). A two‐ to three‐loci mismatch was identified as an independent risk factor for OS (P < 0·001), but there was no significant difference in OS between HLA‐matched and one‐locus‐mismatched RICT. HLA incompatibility between the donor and recipient is an important risk factor for graft failure, aGVHD, cGVHD and OS after RICT. RICT from a one‐locus‐mismatched donor may represent an effective alternative approach in patients with high‐risk malignancies who lack HLA‐matched related donors.

Successful treatment of refractory subcutaneous panniculitis-like T-cell lymphoma with allogeneic peripheral blood stem cell transplantation from HLA-mismatched sibling donor.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is an uncommon type of peripheral T-cell lymphoma (PTCL) usually presenting with erythematous, subcutaneous nodules and fever [1]. It is considered as a cytotoxic T-cell neoplasm with cyotoxic granules and can be cytochemically identified using granzyme B, perforin or TIA-1 [2]. Some cases of SPTCL might be indolent for months or years, but SPTL frequently has an aggressive course, and is often complicated by fatal hemophagocytic syndrome (HPS) [3]. Among the cases of SPTCL, resistance to anthracyclin-based therapy generally means a poor prognosis [4]. The use of high-dose therapy (HDT) with autologous stem cell transplantation (SCT) in patients with SPTCL who are refractory to anthracyclins has yielded good results [4]. However, a cure can only be expected if the disease is at least sensitive to HDT [5]. Allogeneic SCT, however, might yield a cure even in chemo-refractory lymphoma patients via a graft-vs.-lymphoma (GVL) effect [6]. We report a case of successful use of an allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HLA-mismatched sibling donor in a patient with SPTCL who was refractory to conventional chemotherapy. In August 2000, a 17-year-old woman presented to our hospital because of an intermittent fever and a painful swelling of her hip and right thigh. A biopsy specimen of cutaneous tissue from her right hip was diagnosed as cytophagic histiocytic panniculitis. She was treated with oral prednisolone, which resolved the skin lesions. Three months later, she once again presented with persistent high fever and multiple subcutaneous indurations. Oral prednisolone and etoposide were administered, but only a temporary effect on the skin lesions and fever was seen. A second incisional biopsy of the subcutaneous tissue of her right thigh was performed on 19 March 2001. The biopsy specimen showed massive neoplastic lymphoid infiltration of the subcutaneous fat compatible with a diagnosis of SPTCL (Figure 1A). Immunohistochemically, the neoplastic cells were positive for CD3 and CD45RO (UCHL-1), positive for granzyme B, partially positive for CD4 and CD56 and negative for CD20. A test for Epstein – Barr virus using EBER-1 in situ hybridization was negative. A full blood count revealed mild pancytopenia (white blood cell of 2.4610/l, hemoglobin of 111 g/l and platelets of 74610/l). Her serum lactate dehydrogenase level was 1304 IU/l (normal range 150 – 460 IU/l). Bone marrow aspiration revealed marked hemophagocytosis by activated macrophages without involvement of lymphoma cells (Figure 1B). Two cycles of CHOP-E (cyclophosphamide, adriamycin, vincristine, prednisolone and etoposide) resolved the skin lesions, fever, and HPS. However, 2 weeks after the second course of CHOP-E chemotherapy, the skin lesion and fever recurred. Several treatments, such as high-dose etoposide (500 mg/m on days 1 – 3), L-asparaginase (6000 U/m on days 1 – 7), L-asparaginase (6000 U/m on day 2) plus cytarabine (Ara-C; 3 g/m every 12 h on days 1 – 2), and high-dose Ara-C (1.5 g/m every 12 h on days

Feasibility of Reduced-Intensity Cord Blood Transplantation as Salvage Therapy for Graft Failure: Results of a Nationwide Survey of Adult Patients

To evaluate whether rescue with cord blood transplantation (CBT) could improve the poor survival after graft failure (GF), we surveyed the data of 80 adult patients (median age, 51 years) who received CBT within 3 months of GF (primary 64, secondary 16), with fludarabine-based reduced-intensity regimens with or without melphalan, busulfan, cyclophosphamide, and/or 2-4 Gy total-body irradiation (TBI). A median number of 2.4 × 10(7)/kg total nucleated cells (TNC) were infused, and among the 61 evaluable patients who survived for more than 28 days, 45 (74%) engrafted. The median follow-up of surviving patients was 325 days, and the 1-year overall survival rate was 33% despite poor performance status (2-4, 60%), carryover organ toxicities (grade 3/4, 14%), and infections (82%) prior to CBT. Day 100 transplantation-related mortality was 45%, with 60% related to infectious complications. Multivariate analysis showed that the infusion of TNC ≥2.5 × 10(7)/kg and an alkylating agent-containing regimen were associated with a higher probability of engraftment, and that high risk-status at the preceding transplantation and grade 3/4 organ toxicities before CBT were associated with an increased risk of mortality. In conclusion, in an older population of patients, our data support the feasibility of CBT with a reduced-intensity conditioning regimen for GF.

Reduced-intensity versus conventional myeloablative conditioning for patients with Philadelphia chromosome–negative acute lymphoblastic leukemia in complete remission

To the editor: We read with interest the results of the comparison between reduced-intensity conditioning (RIC) and conventional myeloablative conditioning (MAC) allogeneic stem cell transplantation (allo-SCT) for patients with acute lymphoblastic leukemia (ALL) in complete remission (CR), reported

Prognosis of patients with core binding factor acute myeloid leukemia after first relapse

Core binding factor acute myeloid leukemia is known to have a favorable prognosis, however, there have been no detailed analyses on prognostic factors after first relapse. Using a nationwide database, we retrospectively analyzed core binding factor acute myeloid leukemia patients who relapsed after being treated with chemotherapy alone during their first complete remission. Of a total of 397 patients who were diagnosed with core binding factor acute myeloid leukemia, 208 experienced a first relapse, and analyses were performed in 139 patients for whom additional data were available. In the entire cohort, the overall survival rate after relapse was 48% at 3 years. By multivariate analysis, younger age at diagnosis, a longer interval before relapse, and inv(16) were shown to be independently associated with better survival after relapse. Although there was no significant difference in survival after relapse between patients who underwent allogeneic hematopoietic cell transplantation and those who did not in the overall series of relapsed patients, we found that transplantation significantly improved survival among patients who had t(8;21) (54% versus 26% at 3 years, P=0.002). In addition, among patients with t(8;21), those who had different cytogenetics at relapse had a significantly improved survival after transplantation, while those who had same cytogenetics did not. We showed that the prognosis differs significantly and optimal treatment strategies may vary between groups of patients with core binding factor acute myeloid leukemia with different cytogenetic profiles at relapse. These findings may help to guide therapeutic decisions after first relapse.

Cefozopran, meropenem, or imipenem–cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem-cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem-cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem-cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem-cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem-cilastatin compared with cefepime were -5.9% (95% confidence interval (CI): -20.1-8.4), -0.7% (95% CI: -14.6-13.3), and 5.7% (95% CI: -8.1-19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3-5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤ 100 × 10(6)/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3-5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem-cilastatin compared with cefepime (clinical trial number: UMIN000000462).

Acute Leukemia Showing t(8;22)(p11;q11), Myelodysplasia, CD13/CD33/CD19 Expression and Immunoglobulin Heavy Chain Gene Rearrangement

t(8;22)(p11;q11) is a rare but recurrent chromosome translocation that has been reported in 11 cases of myeloproliferative neoplasm or B-acute lymphoblastic leukemia. This translocation results in an in-frame fusion of FGFR1 on 8p11 and BCR on 22q11, and causes constitutive activation of the tyrosine kinase of the BCR/FGFR1 chimera protein. Here, we report the twelfth case of hematological tumor bearing t(8;22)(p11;q11). The bone marrow showed hypoplastic and tri-lineage dysplasia with 24.4% abnormal cells. The abnormal cells were not defined as myeloid or lymphoid morphologically, lacking a myeloperoxidase reaction. Flow cytometric analysis of the bone marrow cells revealed that the abnormal cells expressed CD13, CD33, CD34, and CD19, and that a fraction of the abnormal cells was positive for CD10. Southern blot analysis of the bone marrow cells showed rearrangement of the immunoglobulin heavy chain gene, a genetic hallmark of B-cell differentiation. Previously reported cases with t(8;22)(p11;q11) suggested an association between myeloid and B-lymphoid tumors, whereas other chromosome translocations involving FGFR1 on 8p11 showed a link between myeloid and T-lymphoid tumors. Our observation supports that t(8;22)(p11;q11) might define a dual myeloid and B-lymphoid disorder.

Outcome after first relapse in adult patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia.

To analyse the outcome of adult patients who developed a first relapse of acute lymphoblastic leukaemia (ALL), we collected the clinical data of 332 patients with Philadelphia‐chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first complete remission (CR1) between 1998 and 2008 in 69 institutions all over Japan, including 58 patients who relapsed after allogeneic haematopoietic stem cell transplantation (Allo‐HSCT) in CR1. The overall survival (OS) was 43·4% at 1 year, and 16·3% at 5 years from relapse in patients who received chemotherapy alone in CR1. Among patients who relapsed after chemotherapy alone in CR1, 123 (52·5%) achieved a second remission (CR2) following salvage chemotherapy, of whom 62 subsequently underwent Allo‐HSCT during CR2. Allo‐HSCT in CR2 was significantly associated with better OS. Moreover, the type of salvage chemotherapy influenced OS from relapse. A doxorubicin, vincristine, and predonisone‐based (AdVP‐type) regimen was related to better OS in patients with longer CR1 (more than 1 year), but was related to worse OS in patients with shorter CR1. In conclusion, the prognosis of patients with relapsed Ph‐negative ALL is poor. Allo‐HSCT after a first relapse could improve the prognosis. Selection of the optimal salvage chemotherapy might depend on the duration of CR1.

Successful Treatment of Tacrolimus (FK506)-Related Leukoencephalopathy with Cerebral Hemorrhage in a Patient Who Underwent Nonmyeloablative Stem Cell Transplantation

A 46-year-old woman with Hodgkin’s disease who underwent nonmyeloablative allogeneic stem cell transplantation developed cortical blindness, seizures, and left hemiparesis on day 100 while receiving tacrolimus (FK506) and prednisone for the treatment of graft-versus-host disease (GVHD). Magnetic resonance imaging revealed multiple changes, mainly in the bilateral occipital lobes, suggesting FK506-related leukoencephalopathy. These abnormalities improved after discontinuation of FK506. However, 3 days after the episode, cerebral hemorrhage in the left occipital lobe with perforation to the left subdural space occurred.Although FK506-induced leukoencephalopathy with cerebral hemorrhage is considered the more severe form of such leukoencephalopathy, the patient’s neurological symptoms almost completely resolved and radiographic findings improved after discontinuation of FK506, tapering of methylprednisolone, and initiation of mycophenolate mofetil. FK506-related leukoencephalopathy is a rare complication after allogeneic stem cell transplantation. Although the symptoms usually subside after discontinuation of FK506, therapeutic intervention in many cases may result in severe complications, including GVHD and vascular disease.We consider it important to use immunosuppressive agents without vascular endothelial toxicity for preventing the development of fatal GVHD after discontinuation of FK506.