Pioneering cord blood transplantation in relapsed/refractory HIV-related lymphoma: A case study with concurrent intramuscular antiretroviral therapy.

A 44-year-old HIV-positive man diagnosed with diffuse large B-cell lymphoma in 2021 achieved complete remission with six cycles of R-CHOP therapy but had a relapse in November 2022. ESHAP therapy failed to induce remission, leading to complete remission with four cycles of Pola-BR therapy. Post-failure of autologous stem cell harvest, cord blood transplantation (CBT) was performed in June 2023. Notably, this case used recently approved intramuscular antiretroviral therapy (ART) with cabotegravir and rilpivirine, addressing gastrointestinal complications during CBT. This innovative use of intramuscular ART in the treatment of malignancy represents a first in the field, offering a pioneering approach to HIV-related lymphoma.

Trisomy X conferring moderate hemophilia A by extremely skewed X-chromosome inactivation.

Background: Hemophilia carriers occasionally present with bleeding tendency due to skewed inactivation of normal F8 carrying X chromosome. Key Clinical Question: Can extreme skewing of X-chromosome inactivation (XCI) with trisomy X cause low factor (F) VIII activity and bleeding in a hemophilia carrier?. Clinical Approach: A young female with low FVIII activity (2 IU/dL), who presented with history of frequent bleeding and F8 variant, NP_000123.1:p.(Arg1800His), was identified. The mother was also confirmed genetically as hemophilia carrier. Karyotype was 47, XXX, multiplex ligation-dependent probe amplification for aneuploidy in the family identified trisomy X only in the index case. Digital polymerase chain reaction using leucocytes, urine, and oral mucosa identified one maternal F8 variant carrying and 2 wild-type F8 carrying X chromosomes, but it detected no somatic mosaicisms. Methylation-sensitive-HpaII-polymerase chain reaction assay showed predominantly activated maternal and 2 fully inactivated paternal X chromosomes. The XCI patterns using tissues of different developmental origins showed extremely skewed XCI. Conclusion: Extreme skewing of XCI can occur even in hemophilia carriers with trisomy X, conferring frequent bleeding and low FVIII activity.

Comprehensive comparison of global coagulation assays to differentiate lupus anticoagulant from acquired hemophilia A in patients with prolonged APTT.

There is no established method for differentiating acquired hemophilia A (AHA) from lupus anticoagulant (LA) positivity because both present with prolonged activated partial thromboplastin time. We compared various parameters of rotational thromboelastometry (ROTEM), thrombin generation assay (TGA), and clot waveform analysis (CWA) in patients with AHA (n = 10) and LA (n = 44). Compared with AHA, possible (n = 12) and definite (n = 32) LA showed significantly shorter clotting time (CT) in NATEM mode of ROTEM (> 3600 vs. 501/533). In TGA, peak height was significantly lower in AHA (16 vs. 242/174 nM). In CWA, CT was significantly longer (81 vs. 36/41 s) and Ad|min1| was lower (2.1 vs. 8.7/6.7) in AHA. Notably, CT by NATEM and peak height in TGA completely discriminated between AHA and LA, whereas Ad|min1| did not discriminate between them in 4 cases of AHA and 1 of LA. Comparison of 3 patients with both AHA and LA against a patient with only LA and markedly low FVIII activity (3.5%) showed that both CT by NATEM and peak height of TGA precisely classified the former 3 cases as AHA and the latter 1 case as LA, whereas Ad|min1| classified all 4 cases as AHA. ROTEM and TGA can comparably distinguish between AHA and LA.

Young age is a key determinant of body weight gain after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in Japanese people living with HIV.

BACKGROUND: Treatment with tenofovir alafenamide fumarate (TAF) is associated with body weight gain. However, little or no information is available on this issue in Asian populations. METHODS: This single-center retrospective study included Japanese people living with HIV (PLWH) who satisfied the following criteria; 1) switching from TDF to TAF after HIV-suppression, 2) follow-up for ≥2 years while on TDF and TAF, and 3) no switching of the third antiretroviral agent. Changes in annual body weight and lipid profiles were compared between the TDF and TAF periods. RESULTS: Of 328 patients, dolutegravir (DTG) was used in 118 PLWH. Overall, no significant difference in weight gain was observed between TDF and TAF (0.76 vs. 0.9 kg/year, p = 0.331). In TAF-period, younger (<50 years of age) group showed significantly greater weight gain than older group (1.03 vs. 0.12 kg/year, p = 0.037). In DTG group, weight gain was larger in TAF-period (0.74 vs. 1.31 kg/year, p = 0.046), especially in younger subgroup (1.43 kg/year) compared with older one (-0.12 kg/year). Multivariate regression analysis showed that TAF was not associated with weight gain (estimates 0.201, p = 0.170) except for DTG group, whereas young age was associated with weight gain in all subjects (estimates -0.033/1 year older, p < 0.001), DTG, RAL, and EFV groups. CONCLUSION: In Japanese PLWH, annual body weight change was comparable in TDF- and TAF-period, while TAF plus DTG correlated with weight gain. Since young age was a key determinant of weight change, careful interpretation is needed for TAF-associated weight gain.

The safety of the combination therapy of recombinant factor VIIa and plasma-derived factor VIIa and factor X for refractory hemorrhage in acquired hemophilia A.

Acquired hemophilia A (AHA) is a rare, life-threatening hemorrhagic disease caused by autoantibodies against factor VIII (FVIII), and bypassing agents (BPA) are used to control bleeding. However, some cases need a change of BPA or BPAs given sequentially or in combination for refractory bleeding. A 71-year-old man was admitted with subcutaneous hemorrhage. Laboratory investigations showed prolongation of activated partial thromboplastin time (APTT) and low-coagulation FVIII activity and FVIII inhibitor; we, therefore, diagnosed AHA. He was treated with recombinant factor VIIa (rFVIIa) BPA and prednisolone. However, his symptoms did not improve sufficiently, thus we switched BPA to activated prothrombin complex concentrate. Unfortunately, this was not effective and he suffered hemorrhagic shock. Therefore, we selected rFVIIa, with plasma-derived FVIIa and factor X (pd-FVIIa/FX) as combination therapy, and hemostasis was achieved without thrombosis. This case suggests that the combination of rFVIIa and pd-FVIIa/FX short-term can be well tolerated for refractory hemorrhage in AHA.

Real-World Use of Albutrepenonacog Alfa, A Recombinant Coagulation Factor IX Albumin Fusion Protein, for Personalized Prophylaxis in Japanese Individuals With Hemophilia B: A Case Series.

Currently, the mainstay of disease management for hemophilia B, a hemorrhagic disease caused by a congenital deficiency or molecular abnormalities of blood coagulation factor IX (FIX), is prophylaxis using FIX concentrate. On-demand injections of FIX concentrate may also be required, even during prophylaxis, when a patient with hemophilia B is bleeding. Albutrepenonacog alfa (rFIX-FP) is a human albumin fusion gene recombinant FIX, which is administered once every seven, 14, or 21 days, depending on patient preferences and symptoms. Studies have demonstrated its efficacy and safety in a range of patients; however, to date, reports of real-world experiences of the use of rFIX-FP in Japan are limited. We present a case series of three Japanese individuals with moderately severe (FIX activity 1 to <2%) or severe (FIX activity <1%) hemophilia B who benefited from prophylaxis using rFIX-FP in our clinical practice setting. We highlighted the good effectiveness of rFIX-FP in a patient with moderately severe hemophilia B who required prophylaxis due to joint bleeding, which was causing deterioration of his left ankle joint, as well as in a patient with severe hemophilia B and atherothrombotic cerebral infarction, whose trough level had to be ≥5% for concomitant use of an antiplatelet drug, and in a patient with severe hemophilia B who was working in nursing care, which involved heavy labor and night shifts, and who had previously been treated with on-demand FIX concentrate. In all three cases, rFIX-FP improved disease symptoms, and the patients were able to maintain steady states of therapy due to the treatment characteristics of rFIX-FP, which stabilizes FIX at high trough levels.

In vitro validation of chromogenic substrate assay for evaluation of surrogate FVIII-activity of emicizumab.

[Introduction] Emicizumab, a bispecific antibody mimicking activated factor VIII (FVIII), is increasingly used in prophylaxis against bleeding in hemophilia A. Human factor-based chromogenic substrate assay (hCSA) shows concentration-dependency between emicizumab and reported FVIII activity. However, the assay measurement settings have not been optimized for emicizumab, and the reported FVIII activity cannot be directly referred as surrogate FVIII activity. [Materials and Methods] For in vitro validation of hCSA-reported surrogate FVIII activity, we compared the equation curves for emicizumab concentration with surrogate FVIII activity using spiked plasma in the thrombin generation assay (TGA), hCSA, and clot waveform analysis (CWA). Then, we generated conversion equations for hCSA-reported surrogate FVIII value to that of TGA. We also assessed the additive effect of rFVIII onto 340 nM (i.e., 50 µg/mL) emicizumab using the same assays. [Results] With 1:20 diluted plasma, halving hCSA-reported surrogate FVIII activity can be approximated to that in TGA triggered by the extrinsic pathway reagent (27.3 IU/dL vs. 13.9 IU/dL) under therapeutic emicizumab concentration. Both in TGA and hCSA, the additive effect of added FVIII on therapeutic emicizumab concentration (340 nM) was maintained at low levels of FVIII but gradually decreased at higher levels. [Conclusions] Surrogate FVIII activity can be estimated simply by halving hCSA-reported FVIII value, and the additive effect of FVIII on emicizumab diminishes at high concentrations. Based on our in vitro study, a clinical study is currently being conducted to compare individual variation of surrogate FVIII activity in hCSA and TGA.

Combination therapy with von Willebrand factor concentrate plus recombinant factor VIII during cesarean section in a patient with type 3 von Willebrand disease and a low inhibitor titer: a case report.

Type 3 von Willebrand disease (VWD), a rare and severe subtype, can produce inhibitors in roughly 5% to 10% of cases. We present a case of type 3 VWD with inhibitors in late pregnancy, which was successfully managed with a combination of neutralization and factor (F)VIII replacement during cesarean delivery. The patient, a 30-year-old woman, had no history of inhibitors despite over 100 exposures to VWF/FVIII. She developed inhibitors after 28 weeks of weekly pd VWF/FVIII prophylaxis for recurrent urolithiasis-associated hematuria during pregnancy. Genetic analysis detected two novel frameshift mutations: VWF Exon7 c.777_784dup and Exon14 c.1625_1646del. Titers of inhibitors to factors VIII and VWF using the Bethesda assay were 1.2 and 1.1 BU/mL, respectively. Pharmacokinetics revealed significantly low in vivo recovery of FVIII:C and VWF:Rcof and shortened half-life. During cesarean delivery, a combination of bolus pd VWF/FVIII once daily for neutralizing inhibitors plus continuous infusion of recombinant FVIII Fc fusion protein resulted in minimal bleeding without allergic reactions. Both VWF:Rcof and FVIII:C levels increased transiently during the 7-h of combination therapy without thrombotic events. In conclusion, combination therapy with neutralization and continuous FVIII replacement was effective for hemostasis with a low VWD inhibitor titer, though further optimization is required.

A Case of Acquired Factor V Inhibitor Following Nivolumab Administration.

Acquired factor V inhibitor (AFVI) is a very rare disease. We presented herein a case of hypopharyngeal cancer in which AFVI developed after nivolumab administration. Blood test findings two weeks after the first dose of nivolumab showed a significant prolongation of prothrombin time (PT) and activated partial thromboplastin time (APTT), indicating a marked abnormality in the coagulation function. Factor V activity had decreased significantly and was below the detection limit (<3%), and the factor V inhibitor level was as high as 16 Bethesda units (BU)/mL. His underlying illness was a malignant tumor, but we considered that nivolumab administration was the cause of AFVI, considering the time when coagulation abnormality developed. No significant bleeding tendency was observed in the subsequent course, and the AFVI was followed up without treatment. To the best of our knowledge, the present study is the first to report AFVI occurrence after immune checkpoint inhibitor administration.

Genetic analysis of carrier status in female members of Japanese hemophilia families.

BACKGROUND: Genetic characteristics and genetic carrier diagnosis in Japanese hemophilia female carriers have not been evaluated. OBJECTIVES: To provide genetic information on Japanese hemophilia female carriers and demonstrate the advantages of genetic testing in carrier diagnosis. METHODS: DNA sequencing combined with long polymerase chain reaction for inversion and multiplex ligation-dependent probe amplification for large mutations. RESULTS: Genetic analysis was performed in 69 male hemophiliac patients (48 hemophilia A [HA] and 21 hemophilia B [HB]) and 112 female family members (FFM) (80 from 50 families with HA and 32 from 22 families with HB). In 72 hemophiliac families, the identified F8 mutations were inversion (42%), missense (26%), and other variations (32%), while 74% of F9 mutations were point mutations. Among the 112 FFM, 53/80 (66%) with HA and 21/32 (66%) with HB were diagnosed genetically as carriers based on detection of heterozygous mutations. Low factor VIII activity (FVIII:C) levels (<50 IU/dL) were detected in only 10% of gene-confirmed carriers, suggesting that FVIII:C is not suitable for HA carrier prediction. Low FVIII/von Willebrand factor ratio (<0.9) was observed in 67% of gene-confirmed carriers. Half of the gene-confirmed HB carriers had low FIX:C (<60 IU/dL). Importantly, 32 mothers of 37 sporadic cases (86%) (24/27 [89%] HA and 8/10 [80%] HB) showed the relevant mutations, suggesting low incidence of de novo mutations in males. CONCLUSIONS: This study is the first to provide genetic information on Japanese hemophilia female carriers. Gene analysis is the gold standard for carrier diagnosis as it well identifies undetected female carriers based on pedigree information and hemostatic measurements.

Long-term administration of pegylated liposomal doxorubicin at almost twice the recommended lifetime dose in 10 years without cardiotoxicity in a Japanese patient with HIV-associated Kaposi sarcoma.

We report a Japanese patient with HIV-associated Kaposi sarcoma (KS) who had many cutaneous KS lesions with extensive bilateral groin edema. As the KS was refractory to antiretroviral therapy and pegylated liposomal doxorubicin (PLD), he was administered PLD up to a cumulative dose of 940 mg/m2 in 10 years, which exceeded the recommended lifetime dose (550 mg/m2). However, the patient showed no major adverse events, including cardiotoxicity, and he eventually died of pancreatic cancer.

[Undetectable anti-platelet factor 4/heparin antibodies with IgG-specific chemiluminescent immunoassays in a heparin-induced thrombocytopenia patient].

A 51-year-old man with a 9-month history of narrowing of visual fields and papilledema was admitted to the Department of Neurosurgery. Upon admission, glycerol was intravenously administered and heparin flushes were initiated to maintain intravenous access. Brain MRI revealed right transverse and sigmoid sinus thrombosis on hospital day 2, and the patient was treated with unfractionated heparin. On hospital day 9, the patient had a seizure and impaired mental status. Moreover, on hospital day 10, the platelet count decreased to less than half compared with that documented upon admission. The patient was then switched from heparin to argatroban because thrombosis exacerbation due to heparin-induced thrombocytopenia (HIT) was suspected. Despite negative IgG-specific chemiluminescent immunoassay for anti-platelet factor 4 (PF4) /heparin antibodies, positive functional assay led to the diagnosis of HIT. Warfarin was initiated and the platelet count was restored. Because maintaining the patient's PT-INR within the therapeutic range was difficult probably due to concomitant antimicrobial administration for complicating pneumonia, anticoagulation was switched to rivaroxaban. No bleeding or thrombotic complications developed. Thus, the presentation and clinical course should be considered for an accurate diagnosis of HIT. This is particularly important when the immunological assay is negative for anti-PF4/heparin antibodies. Furthermore, anticoagulation with rivaroxaban can be useful in the management of the subacute phase of HIT.

[Investigation of the Pathophysiology and Diagnostic Methods Through a Case of Acute HIV Infection in which the Western Blot Method Remained Negative Over the Long Term and the 4th Generation Screening Assay Became Negative for a Certain Period of Time after Initiating Antiretroviral Therapy].

Confirmatory tests using Western blot (WB) and HIV-1 nucleic acid testing (HIV-1 RNA) following a positive screening test are required for the diagnosis of HIV-1 infection according to the current Japanese guidelines for HIV-1/2 diagnosis. We report herein on a rare case in a patient who remained negative for WB over 10 months in spite of being positive by fourth-generation immunoassays (4thGIA) and who subsequently seroreverted by 4thGIA for three months after initiating antiretroviral therapy. Case: A man in his early twenties previously visited a hospital because of fever in October 2012. Laboratory data revealed leukocytopenia, thrombocytopenia and increased serum ferritin, suggesting hemophagocytic syndrome (HPS). During that visit, he tested positive for a 4thGIA, but negative for HIV-1 WB and his result of HIV-1 RNA result was detected invalid because of the presence of some inhibitory material in his RNA preparation. Thereafter, he was diagnosed as having cytomegalovirus-associated HPS treatment was for which initiated. In January 2013, he developed Pneumocystis jirovecii pneumonia, and his HIV-1 RNA viral load was 7.7 × 105 copies/mL in February 2013. Acute HIV infection was suspected, because the HIV-1 WB remained negative. He was started on antiretroviral therapy in April 2013. His 4thGIA was converted to negative in May 2013 and was reconverted to positive in August 2013. HIV-1 WB, however, continued to be indeterminant until February 2014, in which it turned positive for the first time according to the CDC criteria. Methods and Results: The genetic analyses of HIV-1 were done on the gag, env, nef and pol region of the HIV-1 gene from the patient. There was no clear element to delay antibody production on the virus side. Preserved specimens of the patient were measured with eight kinds of HIV screening assay. It was thought that the fourth generation assay was positive only by the presence of the antigen until March 2013 because the antibody had not been detected. Discussion: We encountered a case of acute HIV infection in which the WB result was negative for 10 months after the first positive response of the 4thGIA. The 4thGIA is essential for the early diagnosis and early treatment of HIV infection; therefore, the 4thGIA should be strictly recommended to avoid the use of older generations of immunoassay in the diagnostic guidelines. The role of the WB test should be examined closely from various aspects for use as a confirmatory test under recent laboratory situations in which highly sensitive and specific methods, e.g. the 4th GIA, have become available. In addition, unnecessary confusion due to the diversities of antibody formation should be avoided. The antibody detection tests for HIV are still necessary and indispensable for the confirmation of the disease or the diagnosis of the acute infection stage. Therefore development of a newer antibody measuring method which could achieve an easier operation and should have a higher sensitivity and specificity for HIV confirmation is strongly expected.

[Syphilis Testing and High Rate of Infection Among HIV-infected Patients].

Background: The incidence of syphilis has globally increased over the last decade, particularly among men who have sex with men coinfected with the human immunodeficiency virus (HIV). HIV infection may make the clinical symptoms and seroreactivity of syphilis atypical, which requires careful consideration in terms of diagnoses and treatments by clinicians. Syphilis is known as a great imitator, and is often difficult to be diagnosed or it can be overlooked if clinicians depend only on its symptoms or signs. It is also highly contagious and could be transmitted without sexual intercourse, and reinfection is common. Guidelines recommend that all HIV-infected persons be provided with STD screening, including syphilis, at least annually. However, to our knowledge, there are no published data on the actual frequency of testing and instances of syphilis among HIV-infected persons in Japan. Materials and Methods: We collected data from HIV infected male patients who had sex with men (MSM) at Tokyo Medical University Hospital from June 2011 to June 2012. Data from the patients, who had been tested with the rapid plasma reagin assay (RPR) at least once during the study period, were retrospectively obtained from clinical records and were analyzed. Results: Among 1000 patients with HIV infection, 935 patients were MSM. 723 patients (77.4%) were tested using the Treponema pallidum latex agglutination test (TPLA) and RPR more than once during the study period. Out of the 723 patients, 443 patients (61.3%) were reactive for TPLA and 238 patients (32.9%) had reactive tests for RPR. All patients who were reactive for RPR were reactive for TPLA. Among the patients who were reactive for RPR, 93 patients (12.9%) were considered newly diagnosed or with a repeat infection. In this cohort, all patients were MSM with a median age of 37 years, and a median CD4+T-lymphocyte cell count of 465/uL. A total of 76 patients had been prescribed antiretroviral therapy, and 61 patients had a documented HIV-1 RNA viral load of <40 copies/mL at their most recent test. Two patients both developed two episodes of syphilis during the study period. Of the 95 episodes, 44% were symptomatic syphilis and the most common symptom among them was a skin rash at the second stage. Nearly half of the patients (47%) were diagnosed at regular screenings. Two thirds (67%) had syphilis infections before the study period, whereas at least 20% of them were newly diagnosed during the study period. Conclusions: A substantial percentage of the participants were newly or recurrently diagnosed with syphilis during the study period. More public health awareness should be encouraged regarding the current epidemic of syphilis among HIV-infected persons in Japan. It is also important for clinicians to provide HIV-infected persons with periodical syphilis screening, regardless of the apparent clinical signs or symptoms to achieve earlier treatment intervention.

Posterior reversible encephalopathy syndrome following acute pancreatitis during chemotherapy for acute monocytic leukemia.

We describe an 18-year-old man with acute leukemia who presented with posterior reversible encephalopathy syndrome (PRES) shortly after developing acute pancreatitis. On day 15 after the third consolidation course with high-dose cytarabine, treatment with broad-spectrum antibiotics was initiated for febrile neutropenia. On day 16, he developed septic shock, and subsequently, acute respiratory distress syndrome (ARDS). After adding vancomycin, micafungin and high-dose methylprednisolone (mPSL) to his treatment regimen, these manifestations subsided. On day 22, he received hemodialysis for drug-induced acute renal failure. On day 24, he developed acute pancreatitis possibly due to mPSL; the following day he had generalized seizures, and was intubated. Cerebrospinal fluid findings were normal. Brain MRI revealed hyperintense signals on FLAIR images and increased apparent diffusion coefficient values in the sub-cortical and deep white matter areas of the bilateral temporal and occipital lobes, indicative of vasogenic edema. Thus, we diagnosed PRES. Blood pressure, seizures and volume status were controlled, with MRI findings showing improvement by day 42. He was extubated on day 32 and discharged on day 49 without complications. Although little is known about PRES following acute pancreatitis, clinicians should be aware that this condition may develop.

[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.

Prolonged sinus tachycardia caused by human herpesvirus 6 (HHV6) encephalomyelitis after allogeneic bone marrow transplantation.

A 19-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia received an allogeneic hematopoietic cell transplant with unrelated bone marrow. On day 20, the patient developed impaired consciousness and disorientation. Examination of the cerebrospinal fluid showed 2×10(4) copies/mL of HHV6B. HHV6 encephalitis was diagnosed, as had HHV6 myelitis based on symptoms that included lancinating pain/pruritus in the lower limbs and dysuria/dyschezia. Concurrently, he showed sinus tachycardia. Even after clearance of the HHV6 genome from the plasma and CSF was achieved by treatment with foscarnet, sinus tachycardia persisted for another 100 days. We suspected prolonged sinus tachycardia due to dysautonomia caused by HHV6 encephalomyelitis.

Eosinophilia, regardless of degree, is related to better outcomes after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Several recent studies report that, after allogeneic hematopoietic cell transplantation (allo-HCT), eosinophilia is a favorable factor for transplant outcomes. However, whether the degree of eosinophilia influences transplant outcomes is yet to be established. METHODS: We studied 144 patients with hematological malignancy who received allo-HCT at our institution. The stem cell sources were bone marrow in 84 patients, peripheral blood stem cells in 32 patients, and cord blood in 28 patients. One hundred and twelve patients underwent myeloablative conditioning and 49 patients had high-risk disease. We performed semi-landmark analysis to examine the influence of eosinophilia. RESULTS: Eosinophilia developed at a median of 47 days after transplantation in 63 patients (44%). The patients with eosinophilia showed significantly better overall survival (OS) and a lower relapse rate at three years, compared to those without eosinophilia (66% vs 55%, p=0.04 and 30% vs 50%, p=0.002). On analysis following division into groups with mild (500-1,500×10(6)/L) and hyper- (>1,500×10(6)/L) eosinophilia, three-year OS and relapse rates were 68% and 65% (p=0.92), and 31% and 28% (p=0.90), respectively. On multivariate analysis, eosinophilia was significantly associated with lower relapse rates [HR: 0.5 (95% CI: 0.3-0.9), p=0.01] and the same trend was preserved in the analysis of the mild and hyper-eosinophilic groups. CONCLUSION: The results suggest that eosinophilia after allo-HCT was associated with better OS and a lower relapse rate, regardless of the levels. The mechanism of this effect is still unclear, and requires study of the pathophysiological process to clarify the relationship between the higher levels of eosinophilia after allo-HCT and organ infiltration.

Factors that contribute to long-term survival in patients with leukemia not in remission at allogeneic hematopoietic cell transplantation.

BACKGROUND: There has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation. METHOD: We retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%). RESULTS: Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively. CONCLUSION: Graft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.