The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study.

Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3 G) TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3 G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3 G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients or Materials Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3 G TKIs were classified into the Non-TKI, IM, and 2/3 G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3 G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3 G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusions We demonstrated that the pretransplant use of 2/3 G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.

Involvement of the complement system in immune thrombocytopenia: review of the literature.

Immune thrombocytopenia (ITP) is a thrombocytopenic condition induced by autoimmune mechanisms and includes secondary ITP with underlying diseases such as connective tissue diseases (CTD). In recent years, it has been elucidated that the subsets of the ITP are associated with complement abnormalities but much remains unclear. To perform a literature review and identify the characteristics of complement abnormalities in ITP. PUBMED was used to collect the literature published up to June 2022 related to ITP and complement abnormalities. Primary and secondary ITP (CTD-related) were examined. Out of the collected articles, 17 were extracted. Eight articles were related to primary ITP (pITP) and 9 to CTD-related ITP. Analysis of the literature revealed that the ITP severity was inversely correlated with serum C3, C4 levels in both ITP subgroups. In pITP, a wide range of complement abnormalities was reported, including abnormalities of initial proteins, complement regulatory proteins, or the end products. In CTD-related ITP, reported complement abnormalities were limited to the initial proteins. Activation of the early complement system, mainly through activation of C3 and its precursor protein C4, was reported for both ITPs. On the other hand, more extensive complement activation has been reported in pITP.

Dose-finding trial of azacitidine as post-transplant maintenance for high-risk MDS: a KSGCT prospective study.

This 3+3 dose-escalation phase I multicenter study investigated the optimal dose of azacitidine (AZA) for post-hematopoietic stem cell transplantation (HSCT) maintenance, which remains unknown in Japan. Recipients of a first HSCT for high-risk myelodysplastic syndromes (MDS, n = 12) or acute myeloid leukemia (AML) with antecedent MDS (n = 3) received post-HSCT AZA maintenance in 2015-2019. The optimal AZA dose was defined as the dose at which 50-70% of patients can complete four cycles without dose-limiting toxicity (DLT). The initial dose level 1 was set as 30 mg/m2 for 5 days per 28-day cycle, and dose levels 0, 2, and 3 were set as 20, 40, and 50 mg/m2. DLT was defined as any grade 3 non-hematological or grade 4 hematological toxicity. The 15 evaluable patients were 55 (37-64) years old. The median observation of the post-HSCT survivors was 935 (493-1915) days. The median number of days post-HSCT to the start of AZA was 101 (59-176). In the first, second, and third cohorts, five of nine patients completed four cycles at dose level 1. In the final cohort, five of six additional patients completed at the same dose. In total, 10 (67%) patients tolerated AZA 30 mg/m2, which was determined as optimal. DLT occurred in five cases: grade 3 hepatotoxicity, pneumonia, enterocolitis, and grade 4 thrombocytopenia and neutropenia. The 2-year overall survival and disease-free survival rates post-HSCT were 77.0% and 73.3%. Post-HSCT AZA maintenance was well-tolerated and merits further evaluation for patients with MDS or AML with antecedent MDS. Trial registration: UMIN000018791.

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Letermovir has been approved as a novel cytomegalovirus (CMV) prophylactic agent after allogeneic hematopoietic stem cell transplantation (HSCT). However, there are still insufficient data to properly evaluate the real-world role of letermovir, and the risk factors for CMV reactivation under letermovir prophylaxis have not been clarified. METHODS: We performed a single-institution retrospective analysis of patients under prophylaxis with or without letermovir who underwent allogeneic HSCT between March 2012 and December 2019. In August 2018, letermovir was added to the clinical practice at our institution for the prophylaxis of CMV reactivation in allogeneic HSCT recipients. Patients who underwent HSCT without prophylactic letermovir from March 2012 until September 2018 served as a historical control. RESULTS: The cumulative incidence of clinically significant CMV infection (CS-CMVi) was significantly lower in the letermovir group than in the historical control group not receiving letermovir (30.2% vs. 71.6%, p < .05, at 100 days). In addition, the cumulative incidence of non-relapse mortality (NRM) at day 500 was significantly lower in the letermovir group (4.7% vs. 19.8%, p < .05). We then performed a risk factor analysis for developing CS-CMVi in the letermovir group. The only significant factor identified by this multivariable analysis was transplantation from a CMV seronegative donor to a seropositive recipient (Hazard ratio = 2.76, 95% confidence interval 1.14-6.68, p < .05). CONCLUSION: Our study showed that letermovir prophylaxis significantly reduced the incidence of CS-CMVi and NRM in a real-world setting and that the CMV serostatus of the donor remained as a risk factor for CS-CMVi even under letermovir prophylaxis.

[Spontaneous remission of relapsed skin lesions of ALK-positive anaplastic large cell lymphoma after autologous stem cell transplantation].

A 44-year-old woman was diagnosed with anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) with clinical stage IVA (nodal and bladder involvement). Complete response (CR) was achieved after the CHOP chemotherapy; however, 12 months after the last course of chemotherapy, ALCL relapsed in the form of skin lesions without nodal involvement. After achieving a second CR with chemotherapy, autologous stem cell transplantation was performed. Two months after transplantation, the disease again relapsed as multiple skin lesions. Electron beam irradiation was performed; however, other skin lesions appeared thereafter and spontaneously disappeared. At present, 3.4 years after the transplantation, the patient is free from disease. ALK-positive ALCL relapsing as skin lesions may behave differently from the nodal relapse. An accumulation of cases is required to elucidate ALCL characteristics relapsing as skin lesions.

Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening.

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21-118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6-4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

[Chronic active Epstein-Barr virus infection with multiple vascular lesions successfully treated by cord blood transplantation].

An 18-year-old woman presented with fever and liver dysfunction. Computed tomography showed lymphadenopathy, hepatosplenomegaly, and vascular lesions such as aneurysms and irregularities at multiple arteries, including coronary arteries. Based on the high copy number of Epstein-Barr virus (EBV)-DNA in the peripheral blood, EBV-infected CD4+T cells, and the proliferation of EBER-positive cells in the bone marrow, chronic active EBV infection (CAEBV) was diagnosed. Although the fever and liver dysfunction improved as a result of the initial immunosuppressive therapy and multiagent chemotherapy, EBV-DNA remained high. Moreover, she experienced repeated episodes of angina pectoris due to coronary arterial lesions. Therefore, cord blood transplantation was performed after reduced-intensity conditioning. EBV-DNA decreased quickly after initiating the conditioning and became undetectable at day 7 after the transplant. Vascular lesions did not progress after the transplant, and the patient's angina pectoris resolved. At 2.5 years after the transplant, she is alive without disease recurrence. The prognosis of CAEBV with vascular lesions is especially poor. Although the indication for allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to determine in such cases, the clinical course of our case suggests that allogenic HSCT could be safely performed under appropriate management and could successfully control not only CAEBV but also vascular lesions.

[Efficacy of photocatalytic air purifiers in reducing dimethyl sulfide malodor following cryopreserved peripheral blood stem cell infusion].

Dimethyl sulfoxide (DMSO) is used as a cryoprotectant for peripheral blood stem cells (PBSC) preservation. Dimethyl sulfide (DMS) is a metabolite of DMSO secreted through patients' breath after PBSC infusion. It possesses malodor causing an unpleasant environment. We evaluated the efficacy of a photocatalyst environment purifier, which has the potential to lyse toxic substances, in reducing DMS malodor. High DMS concentration in the air after PBSC infusion rapidly decreased after operating the device. Our results suggest that photocatalytic reaction has the potential to reduce the DMS odor associated with PBSC infusion.

Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention.

After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13-31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17-61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200-100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

Histological transformation in duodenal-type follicular lymphoma: a case report and review of the literature.

Duodenal-type follicular lymphoma (DFL) is a rare variant of follicular lymphoma (FL) characterized by distinctive clinical features such as localization and favorable prognosis. We herein report a case of DFL in which histological transformation into diffuse large B-cell lymphoma developed 7 years after diagnosis. The transformed lymphoma was refractory to chemotherapy, and the patient passed away due to disease progression. To date, there have been only a limited number of reported cases of histological transformation of DFL, and the clinical outcomes of those cases except our present case have been favorable, with good responses to chemotherapy. Although the histological transformation of DFL is a rare event, the clinical course of the present case suggested that it would be a fatal event and underscore the importance of the life-long management of DFL. Further accumulation of cases is required to elucidate its incidence, characteristics, and prognosis.

Human Herpesvirus 6 Reactivation Evaluated by Digital Polymerase Chain Reaction and Its Association With Dynamics of CD134-Positive T Cells After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) causes life-threatening central nervous system disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent studies implicated CD134 as a specific receptor of HHV-6B and demonstrated that its expression levels in CD4-positive T cells after allo-HSCT could be related to the reactivation of HHV-6. We prospectively evaluated the relationship between HHV-6 reactivation and CD134+ T cells in the recipients of allo-HSCT. METHODS: HHV-6 viral load in plasma was quantitatively measured weekly after allo-HSCT by digital polymerase chain reaction in 34 patients. The ratio of CD134 in CD4+ T cells (CD134/CD4 ratio) was serially measured by flow cytometry before and after transplantation. RESULTS: HHV-6 reactivation was detected in 23 patients (68%). The CD134/CD4 ratio before conditioning was significantly higher in patients with HHV-6 reactivation than in those without (median, 3.8% vs 1.5%, P < .01). In multivariate analysis, a higher CD134/CD4 ratio before conditioning was significantly associated with the incidence of HHV-6 reactivation (odds ratio, 10.5 [95% confidence interval, 1.3-85.1], P = .03). CONCLUSIONS: A higher CD134/CD4 ratio before conditioning was associated with a higher risk of HHV-6 reactivation, suggesting that the rate may be a promising marker for predicting HHV-6 reactivation after allo-HSCT.

[Bacteriocidal effects of introducing copper products on highly touched areas in hematology ward].

Nosocomial infection via the hospital environment is a serious problem, and highly touched surfaces are the main route of transmission. Copper has been reported to possess bacteriocidal effects, and the introduction of copper-impregnated products is receiving attention as a potential component of hospital infection control. In this study, copper-impregnated door handles as highly touched areas were introduced in a hematology ward, and their bacteriocidal effects were evaluated in comparison with conventional products. All 12 samples obtained from conventional door handles were positive for bacterial cultures, whereas only 5 of 18 samples from copper-impregnated handles were positive (P<0.0001). The mean number of bacterial colonies per milliliter of sample was 300 (range: 40-1.1×106) in samples from conventional handles, but it was significantly lower in samples from copper-impregnated handles (0; range: 0-220, P<0.0001). While various types of bacteria grew on conventional handles, most of the bacteria on copper-impregnated handles were Bacillus subtilis. These results suggest that the introduction of copper-impregnated products would be useful for hospital infection control by reducing the bacterial burden on highly touched areas. However, the efficacy of this approach against spore-forming bacteria should be further investigated.

Renal dysfunction and anemia associated with long-term imatinib treatment in patients with chronic myelogenous leukemia.

Knowledge of the toxicity profile of long-term treatment with imatinib is limited. In the present study, we sought to evaluate renal function and hemoglobin levels during long-term imatinib treatment. Eighty-two patients with chronic myelogenous leukemia in chronic phase who had been on imatinib for over 5 years were retrospectively analyzed. The mean estimated glomerular filtration rate (eGFR) was significantly decreased over 5 years (77 ± 17 to 62 ± 14 ml/min/1.73m², P < 0.001). Higher age and lower eGFR value at initiation of imatinib were significantly associated with development of renal dysfunction by multivariate analyses. Mean hemoglobin levels also significantly decreased over the 5-year period (12.9 ± 1.7 to 12.4 ± 1.3 g/dl, P < 0.01). The rate of decrease in eGFR correlated significantly with hemoglobin levels (correlation coefficient = - 0.249, P < 0.05). Serum erythropoietin (EPO) levels did not increase in 16 patients with both renal dysfunction and anemia (median, 31.9 mIU/ml). In patients who participated in a clinical trial of imatinib discontinuation, mean eGFR (50.0 ± 6.5 to 56.0 ± 10.2 ml/min/1.73m², P < 0.05) and hemoglobin levels (12.0 ± 1.7 to 14.0 ± 1.6 g/dl, P < 0.01) improved significantly at 1 year after discontinuation. These findings suggest that long-term imatinib results in a partially reversible continuous decline in renal function and decreased hemoglobin levels.

Invasive hepatic mucormycosis: A case report and review of the literature.

Mucormycosis generally develops under immunocompromised conditions, including hematological malignancies and solid organ or hematopoietic stem cell transplantation. Although mucormycosis usually affects the lungs and paranasal sinuses, sporadic cases of invasive mucormycosis of the liver have been reported. We hereby report a patient with myelofibrosis who developed hepatic mucormycosis diagnosed by post-mortem examination. An extensive literature review identified 13 reported cases of hepatic mucormycosis, including ours, without lung involvement. Most of the underlying diseases or conditions were hematological malignancies and solid organ transplantation. Three cases had splenic lesions and four had gastrointestinal lesions, suggesting the possibility of translocation to the liver and/or spleen from the gastrointestinal tracts. Hepatic mucormycosis should be recognized as one of the presentations of invasive mucormycosis, especially when hepatic nodules are found in immunocompromised patients such as those with hematological malignancy or recipients of solid organ transplantation.

[Evans syndrome complicated with multicentric Castleman disease successfully treated with tocilizumab].

A 26-year-old man presented with fever, multiple lymphadenopathies, polyclonal hypergammaglobulinemia, and an elevated serum interleukin-6 (IL-6) level. Multicentric Castleman disease (MCD) was diagnosed by lymph node biopsy. Treatment with prednisolone (PSL) was initiated; however, its efficacy was limited. During PSL tapering, rapidly progressive anemia and thrombocytopenia developed concurrently with increased reticulocyte level, elevated serum LDH level, decreased haptoglobin level, and positive direct Coombs test. Based on these findings, Evans syndrome, which is a concurrent development of autoimmune hemolytic anemia and immune thrombocytopenia, was confirmed. The PSL dose was increased but was ineffective. Therefore, treatment with tocilizumab was initiated, and the clinical findings of both MCD and Evans syndrome improved. The clinical course of this case suggests that tocilizumab could be a treatment option for Evans syndrome complicated with MCD. Three other cases of Evans syndrome complicated with MCD have also been reported; however, this is the first case that shows the efficacy of tocilizumab as treatment for both MCD and Evans syndrome.

[Mixed connective tissue disease with pulmonary hypertension developing in a chronic myeloid leukemia patient on dasatinib treatment].

A 37-year-old woman was diagnosed with chronic phase chronic myeloid leukemia. Nilotinib treatment was initiated; however, it had to be discontinued due to an allergic reaction one month later, and dasatinib treatment was provided. Although favorable response was obtained, she started complaining of shortness of breath 7 months after initiating dasatinib treatment. Chest X-ray and echocardiography indicated pulmonary congestion and hypertension. Further, she was diagnosed with mixed connective tissue disease (MCTD) based on Raynaud phenomenon, swollen fingers, sclerodactyly, pancytopenia, hypocomplementemia, and positive anti-U1-RNP antibody. Consequently, dasatinib treatment was discontinued, and she was administered prednisolone (1 mg/kg/day), which was effective and successfully tapered with concomitant administration of cyclophosphamide. This is the first case of MCTD that developed during dasatinib treatment. However, because the present case was a young woman, the development of MCTD could probably be attributed to autoimmune diatheses or it may be a coincidence. However, the possibility of patients receiving dasatinib treatment developing autoimmune diseases needs to be assessed.

Recurrent bacterial pneumonia due to immunoglobulin G2 subclass deficiency after allogeneic hematopoietic stem cell transplantation: Efficacy of immunoglobulin replacement.

Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria. We encountered a case of recurrent pneumonia due to Streptococcus pneumoniae after allogeneic hematopoietic stem cell transplantation (HSCT). IgG2 subclass level was specifically low, and prophylactic Ig replacement successfully prevented subsequent infections. However, the cessation of Ig replacement resulted in subsequent pneumonia. These findings suggested that IgG2 deficiency could be a cause of recurrent pneumococcal infection after allogeneic HSCT.