Effects of combined test dose and therapeutic drug monitoring strategy in exposure-directed busulfan.

Although exposure-directed busulfan (BU) dosing can improve allogeneic hematopoietic stem cell transplantation outcomes, there is still large variability in BU exposure with test dose alone due to changes in BU clearance caused by drug interactions. We conducted a single-arm phase II trial using the combined test dose and therapeutic drug monitoring strategy (PK-guided group) and compared the outcomes with an external historical cohort receiving a fixed-dose (fixed-dose group). The first eight and second eight doses were adjusted based on the area under the blood concentration-time curve (AUC) of the test and first doses, respectively, targeting a total AUC of 82.1 mg·h/L. All patients received either BU and cyclophosphamide conditioning (BU/CY) or fludarabine (FLU)-containing conditioning. The BU clearance at the first dose decreased more in patients receiving FLU than in those receiving BU/CY; however, BU clearance also declined over time in patients who received BU/CY. The simulated total AUC (sAUC) with test dose only was significantly higher in patients who received FLU than in those who received BU/CY, but sAUC with the combined strategy was comparable. The 100-day progression-free survival was 85.5% (95% confidence interval [CI]: 71.9-92.8%), and was not inferior to that in the fixed-dose group. For the FLU-containing regimens, the PK-guided group showed decreased relapse (0.0% vs. 26.9%, p = 0.03), and favorable overall survival (75.1% vs. 57.0%, p = 0.07) at 1 year. The combined strategy effectively controlled the BU exposure close to the target levels, potentially improving efficacy, especially in patients receiving the FLU-containing regimen. Clinical evaluation of efficacy of dose-modified intravenous busulfan in allogeneic hematopoietic stem cell transplantation for hematological malignancy (#UMIN000014077, June 15th, 2014).

Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy.

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.

Improved outcomes of single-unit cord blood transplantation for acute myeloid leukemia by killer immunoglobulin-like receptor 2DL1-ligand mismatch.

The impact of the killer immunoglobulin-like receptor (KIR)-ligand mismatch between donor and recipient in hematopoietic stem cell transplantation is controversial. Recently, it has been suggested that their effect on cord blood transplantation (CBT) differs among types of mismatched KIR-ligand and graft-versus-host disease (GVHD) prophylaxis. To investigate their role in acute myeloid leukemia (AML), mismatch of KIR2DL1, KIR3DL1, and KIR3DL2-ligand (HLA-C2, Bw4, and A3/11) were retrospectively assessed in patients undergoing CBT with GVHD prophylaxis comprising a calcineurin inhibitor plus methotrexate (CNI/MTX) or mycophenolate mofetil (CNI/MMF). In patients who received CNI/MTX, a favorable effect of KIR-ligand mismatch on relapse was noted in HLA-C2 mismatched cases (24.8% at 3 years post-CBT [no HLA-C2 mismatch, n = 1602] vs. 15.4% [HLA-C2 mismatch, n = 161], P = 0.0116). In this group, overall survival (OS) was also superior (68.2%, P = 0.0083) compared to the other group (55.0%). Multivariate analysis results supported these findings (hazard ratio [HR] 0.61 for relapse, P = 0.017 and HR 0.72 for OS, P = 0.016). However, the KIR-ligand mismatch effect was not observed in patients with KIR-ligand mismatch types other than HLA-C2 and those using CNI/MMF for GVHD prophylaxis. These results suggest that HLA-C2 mismatch in CBT using CNI/MTX as GVHD prophylaxis may improve the outcomes of patients with AML.

Coexistence of HLA and KIR ligand mismatches as a risk factor for viral infection early after cord blood transplantation.

Viral infection is one of the lethal adverse events after cord blood transplantation (CBT). Human leukocyte antigen (HLA) and killer immunoglobulin-like receptor (KIR) ligand divergences can increase the risk of viral infection due to conflicting interactions between virus-infected cells and immune cells. However, the relationship between these disparities and the frequency of viral infection after CBT remains to be evaluated. Herein, we have conducted a retrospective multicenter study to assess the effect of HLA and KIR ligand mismatches on viral infections after CBT. The study included 429 patients, among which 126 viral infections occurred before day 100. Viral infection was significantly associated with poorer overall survival (OS; hazard ratio [HR] 1.74, p < 0.01). Patients harboring ≥3 mismatches in the HLA allele and inhibitory KIR ligand mismatches (HLA & KIR mismatches) had a significantly greater prevalence of viral infection (HR 1.66, p = 0.04). Thus, patients with HLA & KIR mismatches had poorer outcomes in terms of non-relapse mortality (HR 1.61, p = 0.05). Our study demonstrates the unfavorable impacts of HLA & KIR mismatches on viral infections and non-relapse mortality after CBT. Evaluating the viral infection risk and performance of an appropriate and early intervention in high-risk patients and optimizing the graft selection algorithm could improve the outcome of CBTs.

Feasibility of ovarian stimulation for fertility preservation during and after blinatumomab treatment for Ph-negative B-cell acute lymphoblastic leukemia.

It is challenging to preserve the fertility of female patients with B-cell acute lymphoblastic leukemia (B-ALL) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) while maintaining treatment intensity. We report two cases of female patients with Philadelphia chromosome-negative (Ph -) B-ALL whose oocytes were retrieved after controlled ovarian stimulation during and after blinatumomab treatment. The first patient was a 30-year-old woman with relapsed Ph-B-ALL who received prednisolone (PSL) and cytoreductive chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone, followed by three courses of blinatumomab bridging to allo-HSCT. Ovarian stimulation was performed twice during blinatumomab administration, and two oocytes were retrieved during each course. The second patient was a 26-year-old woman with newly diagnosed Ph-B-ALL who received PSL, one course of conventional chemotherapy, and one course of high-dose methotrexate and cytarabine followed by two courses of blinatumomab bridging to allo-HSCT. Immediately after completion of the first course of blinatumomab, ovarian stimulation was performed, and three oocytes were retrieved. Use of a 2-week rest period enabled ovarian stimulation and oocyte retrieval to be performed without delaying treatment. Blinatumomab may be an option for preserving fertility while maintaining treatment intensity.

Impact of HLA class I allele-level mismatch on viral infection within 100 days after cord blood transplantation.

Viral infection is more frequently reported in cord blood transplantation (CBT) than in transplantation of other stem cell sources, but its precise mechanism related to antiviral host defenses has not been elucidated yet. To evaluate the effect of human leukocyte antigen (HLA) class I allele-level incompatibility on viral infection in CBT, we conducted a single-center retrospective study. Total 94 patients were included, and viral infections were detected in 32 patients (34%) within 100 days after CBT. HLA-C mismatches in graft-versus-host direction showed a significantly higher incidence of viral infection (hazard ratio (HR), 3.67; p = 0.01), while mismatches in HLA-A, -B, or -DRB1 were not significant. Overall HLA class I mismatch was also a significant risk factor and the predictor of post-CBT viral infection (≥ 3 mismatches, HR 2.38, p = 0.02), probably due to the insufficient cytotoxic T cell recognition and dendritic cell priming. Patients with viral infection had significantly worse overall survival (52.7% vs. 72.1%; p = 0.02), and higher non-relapse mortality (29.3% vs. 9.8%; p = 0.01) at 5 years. Our findings suggest that appropriate graft selection as well as prophylaxis and early intervention for viral infection in such high-risk patients with ≥ 3 HLA class I allele-level mismatches, including HLA-C, may improve CBT outcomes.

Successful granulocyte apheresis using medium molecular weight hydroxyethyl starch.

Granulocyte transfusion (GTX) is a therapeutic option for severe bacterial or fungal infection in patients with sustained neutropenia after chemotherapy or stem cell transplantation. However, high molecular weight hydroxyethyl starch (HES), which has been used for selective sedimentation of red blood cells during apheresis, is not easily available in many countries including Japan. In this study, we evaluated the efficiency of granulocyte collection using medium molecular weight HES (130 kDa) in combination with the Spectra Optia apheresis system. Apheresis was performed for 2 consecutive days from seven donors and the mean total neutrophil yield from the first and second apheresis was 5.27 ± 3.10 × 1010 and 2.91 ± 2.92 × 1010, respectively. Infusion of concentrates from the first apheresis resulted in a significant neutrophil count increase and concentrates from the second apheresis were enough for maintenance of the neutrophil counts in all the recipients. Although the number of cases is limited, our results clearly show that sufficient number of granulocytes can be harvested by using medium molecular weight HES and this strategy is a safe and effective clinical practice in countries where high molecular weight HES is not available.

NK-cell post-transplant lymphoproliferative disease with chronic active Epstein-Barr virus infection-like clinical findings.

A 69-year-old man who underwent cord blood transplantation seven years ago was admitted because of fever, elevated liver enzymes and thrombocytopenia. Bone marrow aspirate revealed hemophagocytic lymphohistiocytosis. Viral capsid antigen (VCA)-immunoglobulin (Ig) G, VCA-IgM, VCA-IgA, Epstein-Barr virus nuclear antigen-IgG, early antigen-diffuse-type and restricted-type (EA-DR) IgG, and EA-DR IgA titers were 2560, <10, 10, 40, 40, and <10, respectively. Real-time polymerase chain reaction assay of peripheral whole blood for Epstein-Barr virus-deoxyribonucleic acid (EBV-DNA) revealed 240,000 copies/µg DNA. Flow cytometric in situ hybridization assay confirmed that EBV-infected cells were NK-cells. Clonality evaluation by Southern blot assay of EBV-DNA terminal repeats proved to be bi-clonal. Accordingly, we made a diagnosis of NK-cell post-transplant lymphoproliferative disease with chronic active EBV infection-like clinical findings (CAEBV-like NK-cell PTLD). Although CAEBV-like PTLD is extremely rare, its prognosis seems to be very poor. The disease should be considered in such patients who present persistent or recurrent infectious mononucleosis-like symptoms after transplantation.

Metronidazole-induced encephalopathy during treatment for refractory diarrhea after cord blood transplantation.

A 56-year-old man underwent cord blood transplantation for angioimmunoblastic T-cell lymphoma. He developed severe diarrhea and abdominal pain that persisted for more than 4 months. We suspected that he might have cord colitis syndrome (CCS), so metronidazole (MNZ) was administered. The patient's abdominal pain and diarrhea showed some improvement after the initiation of MNZ therapy, but they worsened on the cessation of MNZ, which prompted us to resume MNZ treatment. After the patient had taken MNZ (1500-2000 mg/day) for 78 days, he developed somnolence and dysarthria. We diagnosed him with metronidazole-induced encephalopathy (MIE) based on the characteristic magnetic resonance imaging findings and the clinical course. The patient's dysarthria and somnolence improved within a few days after the discontinuation of MNZ. CCS is a recently proposed clinical entity defined as a persistent diarrheal illness that is culture-negative, antibiotic-responsive, and not attributable to any known cause. Patients with CCS often have recurrent diarrhea after the discontinuation of MNZ and may require prolonged treatment for a median of 120 days. When treating CCS with MNZ, physicians should be alert for the development of MIE.

[Essential thrombocythemia accompanied by adrenal infarction].

A 64-year-old man presented to the emergency department with sudden-onset upper abdominal pain and pain in the left chest area. His platelet count was 121.7×104/µl. Computed tomography (CT) showed bilateral adrenal swelling and inflammation of the adjacent tissue. Diffusion-weighted magnetic resonance imaging (MRI) showed hyperintensity in the bilateral adrenal glands. The patient was diagnosed with bilateral adrenal infarction. A bone marrow biopsy yielded a diagnosis of essential thrombocythemia, and a positive JAK2 V617F mutation was detected. He presented with recurrent adrenal infarction and developed aortic mural thrombosis and splenic infarction. We administered aspirin and performed cytoreductive therapy with hydroxyurea and anagrelide; however, the patient then went into heart failure resulting from coronary artery stenosis. We then added prasugrel to the list of medicines administered to manage his condition. Bilateral adrenal infarction is a very rare thrombotic event of essential thrombocythemia. CT and MRI were useful for making the diagnosis; however, we also had to rule out acute coronary syndrome or intestinal ischemia. Our patient presented with strong thrombotic diathesis, which prompted us to use dual antiplatelet therapy; however, further studies are needed to confirm the efficacy and safety of this treatment.

Successful engraftment after cord blood transplantation from an HLA-homozygous donor (homo-to-hetero cord blood transplantation) in a primary myelofibrosis patient with broad HLA antibodies.

BACKGROUND: Donor-specific human leukocyte antigen (HLA) antibodies are a significant risk factor for graft failure in cord blood transplantation (CBT). Although there are several treatments to decrease HLA antibodies, such as platelet transfusion, plasma exchange, rituximab, and bortezomib, their effectiveness has not been established. STUDY DESIGN AND METHODS: We herein report the case of a primary myelofibrosis (PMF) patient with broad HLA antibodies who underwent CBT from an HLA-homozygous donor in which the alleles were matched only in the host-versus-graft direction (homo-to-hetero CBT). RESULTS: The cord blood was killer cell immunoglobulin-like receptor (KIR) ligand matched. She received a reduced-intensity conditioning regimen. We used tacrolimus and mycophenolate mofetil as prophylaxis against graft-versus-host disease (GVHD). The neutrophils engrafted on Day 31. A chimerism analysis with fluorescence in situ hybridization of peripheral blood cells showed 99.9% donor type on Day 33. She developed only mild acute skin GVHD and chronic skin GVHD. CONCLUSION: This case indicates the usefulness of homo-to-hetero CBT in a patient with broad HLA antibodies with a strong mean fluorescence intensity, which is a significant risk factor for graft failure. Further studies are necessary to determine the risk of GVHD and to elucidate the association between KIR ligand incompatibility and graft failure in homo-to-hetero CBT.

Substantial Improvement in a Nerve Conduction Study of Lymphoma-associated Demyelinating Neuropathy Treated by Intravenous Immunoglobulin and Chemotherapy.

A 64-year-old woman with lymphoma-associated demyelinating neuropathy was treated by 6 cycles of R-CHOP with intravenous immunoglobulin in the first 2 cycles. We noted substantial improvement in the findings of a nerve conduction study (NCS) after the first cycle, followed by more protracted improvement during the second to sixth cycles. The improvement of the neurological symptoms paralleled the findings of the NCS. Our case provides important information for understanding the etiology and optimization of treatments for lymphoma-associated demyelinating neuropathy.