Procalcitonin elevation in febrile recipients during pre-transplant conditioning with anti-thymocyte globulin.

Infection is a major contributor to non-relapse mortality in allogeneic hematopoietic stem cell transplantation (allo-HSCT). Detecting infectious diseases in febrile patients during pretransplant conditioning is crucial for subsequent transplant success. Procalcitonin (PCT) is an auxiliary diagnostic marker of severe bacterial infections and has been proposed as a useful predictor of infection in patients undergoing allo-HSCT. Pre-transplant use of anti-thymocyte globulin (ATG) can cause side effects, such as fever and hypotension, which must be distinguished from infectious diseases. Although ATG administration may increase PCT levels, data on PCT levels in febrile patients after ATG administration are limited. Furthermore, no studies have compared PCT levels during allo-HSCT conditioning using ATG or non-ATG regimens. To investigate whether ATG increases PCT levels during febrile episodes in pre-transplant conditioning and whether PCT could be used to discriminate infections during this period, we analyzed 17 ATG and 59 non-ATG patients with fever and who underwent PCT level measurements during pre-transplant conditioning. Our findings revealed that ATG administration was the only significant factor that increased PCT positivity during fever (p = 0.01). In contrast, infectious diseases did not affect PCT positivity in the ATG group (p = 0.24). Furthermore, bloodstream infection was a significant risk factor for PCT positivity in patients who received non-ATG regimens (p < 0.01). Incorporating PCT levels into the diagnostic workup for infectious diseases requires careful consideration, particularly for patients receiving ATG regimens.

Prognostic impact of HLA supertype mismatch in single-unit cord blood transplantation.

The "human leukocyte antigen (HLA) supertype" is a functional classification of HLA alleles, which was defined by structural features and peptide specificities, and has been reportedly associated with the clinical outcomes of viral infections and autoimmune diseases. Although the disparity in each HLA locus was reported to have no clinical significance in single-unit cord blood transplantation (sCBT), the clinical significance of the HLA supertype in sCBT remains unknown. Therefore, we retrospectively analyzed clinical data of 1603 patients who received sCBT in eight institutes in Japan between 2000 and 2017. Each HLA allele was categorized into 19 supertypes, and the prognostic effect of disparities was then assessed. An HLA-B supertype mismatch was identified as a poor prognostic factor (PFS: hazard ratio [HR] = 1.23, p = 0.00044) and was associated with a higher cumulative incidence (CI) of relapse (HR = 1.24, p = 0.013). However, an HLA-B supertype mismatch was not associated with the CI of acute and chronic graft-versus-host-disease. The multivariate analysis for relapse and PFS showed the significance of an HLA-B supertype mismatch independent of allelic mismatches, and other previously reported prognostic factors. HLA-B supertype-matched grafts should be selected in sCBT.

Impact of a third dose of anti-SARS-CoV-2 vaccine in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

This prospective observational study aimed to assess the serological response and safety after the third booster shot of SARS-CoV-2 mRNA vaccines in 292 hematopoietic cell transplant (HCT) recipients. In our patients, mild systemic reactions were present in 10-40% and GVHD aggravation in 1.1%. Overall, clinically relevant response (>250 U/mL) was observed in 93.1% of allogeneic (allo)-HCT recipients and 70.6% of autologous (auto)-HCT recipients, respectively. Of note, detectable antibody response with any titer following the first two doses was a powerful predictor for adequate response after booster shot in both cohorts. For such patients, 98.8% of allo- and 92.3% of auto-HCT recipients obtained clinically relevant response after dose 3. In addition, continued systemic steroid and/or calcineurin inhibitors at the booster shot significantly correlated with serological response. These findings highlighted that booster vaccination efficiently improved serological response without safety concerns and thus recommended for the majority of HCT recipients.

[Maintenance therapy after allogeneic hematopoietic stem cell transplantation].

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival for patients with hematological malignancy, especially for those highly at risk of relapse. However, disease relapse after allo-HSCT remains the most common cause of treatment failure and death, even with conventional chemotherapy and donor lymphocyte infusion. Disease relapse in allo-HSCT can be reduced via pre-emptive treatment based on measurable residual disease and maintenance therapy for patients at high risk of relapse as promising treatment strategies. Recently, the development of novel agents and cellular therapies with high antitumor activity and less toxicity, which can be used in the post-transplant setting, has increased their clinical applications in the therapeutic approach. This review examines the current landscape and future strategies for maintenance therapy, mainly for AML and ALL after allo-HSCT.

Predictors of impaired antibody response after SARS-CoV-2 mRNA vaccination in hematopoietic cell transplant recipients: A Japanese multicenter observational study.

HCT recipients reportedly have a high mortality rate after developing COVID-19. SARS-CoV-2 vaccination is generally useful to prevent COVID-19. However, its safety and efficacy among HCT recipients remain elusive. This large-scale prospective observational study including 543 HCT recipients with 37-months interval from transplant demonstrated high safety profiles of mRNA vaccine: only 0.9% of patients avoided the second dose due to adverse event or GVHD aggravation following the first dose. Regarding the efficacy, serological response with a clinically relevant titer (≥250 BAU/mL) was obtained in 397 (73.1%) patients. We classified the remaining 146 patients as impaired responders and compared the clinical and immunological parameters between two groups. In allogeneic HCT recipients, multivariable analysis revealed the risk factors for impaired serological response as follows: age (≥60, 1 points), HLA-mismatched donor (1 points), use of systemic steroids (1 points), absolute lymphocyte counts (<1000/µL, 1 points), absolute B-cell counts (<100/µL, 1 points), and serum IgG level (<500 mg/dL, 2 points). Notably, the incidence of impaired serological response increased along with the risk scores: patients with 0, 1-3, and 4-7 points were 3.9%, 21.8%, and 74.6%, respectively. In autologous HCT recipients, a shorter interval from transplant to vaccination was the only risk factor for impaired serological response. Our findings indicate that two doses of SARS-CoV-2 vaccine are safe but insufficient for a part of HCT recipients with higher risk scores. To improve this situation, we should consider additional treatment options, including booster vaccination and prophylactic neutralizing antibodies during the SARS-CoV-2 pandemic.

Successful pseudo-autologous stem cell transplantation for donor-derived Burkitt lymphoma occurring 9 years after allogeneic transplantation.

Donor-derived hematological malignancies have been recognized as rare but serious late complications in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Most cases in the literature were diagnosed as myelodysplastic syndrome or acute leukemia, with very few malignant lymphoma reported. We herein present another case of donor-derived Burkitt lymphoma that occurred 9 years after allo-HSCT under continued administration of immunosuppressants for chronic graft-versus-host disease (GVHD). The patient achieved a partial response after rituximab-combined intensive chemotherapy. To reduce the risk of relapse and to avoid organ toxicities due to repeated chemotherapies, we performed upfront high-dose chemotherapy followed by stem cell rescue using donor-derived CD34+ cells, called pseudo-autologous HSCT (pASCT), and adjusted immunosuppressants appropriately. The patient remained disease-free for 23 months after pASCT without exacerbation of cGVHD. Although the observation period has been relatively short and longer follow-up is needed, pASCT may be a feasible option for donor-derived lymphoma even in patients with active cGVHD.

Prognostic value of pre-transplantation total metabolic tumor volume on 18fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography in relapsed and refractory aggressive lymphoma.

Relapsed and refractory aggressive lymphoma have a poor prognosis. High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is effective in chemosensitive patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is among the few options for non-chemosensitive patients. 18Fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18FDG-PET/CT) is the standard tool for evaluating response to chemotherapy and residual tumor volume. However, accurate assessment of residual tumor volume is not currently being achieved in clinical practice, and its value in prognostic and therapeutic stratification remains unclear. To answer this question, we investigated the efficacy of quantitative indicators, including total metabolic tumor volume (TMTV), in predicting prognosis after auto-HSCT and allo-HSCT. We retrospectively analyzed 39 patients who received auto-HSCT and 28 who received allo-HSCT. In the auto-HSCT group, patients with a higher TMTV had a poor prognosis due to greater risk of relapse. In the allo-HSCT group, patients with a higher TMTV had a lower progression-free survival rate and a significantly higher relapse rate. Neither Deauville score nor other clinical parameters were associated with prognosis in either group. Therefore, pre-transplant TMTV on PET is effective for prognostic prediction and therapeutic decision-making for relapsed or refractory aggressive lymphoma.

Risk factors for late cytomegalovirus infection after completing letermovir prophylaxis.

Prophylactic use of letermovir (LMV) markedly reduces the incidence of early clinically significant cytomegalovirus (csCMV) infection within the first 100 days after allogeneic hematopoietic cell transplantation (allo-HCT), which improves transplant outcomes. However, some patients eventually develop late-csCMV infection (beyond day 100) after completing LMV prophylaxis. To assess the incidence of late-csCMV infection as well as its risk factors and impacts on transplant outcome, a total of 81 allo-HCT recipients who had not developed early csCMV infection during LMV prophylaxis were retrospectively analyzed. Among them, 23 (28.4%) patients developed late-csCMV infection (until day 180) at a median time of 131 days after transplantation and 30 days after LMV discontinuation, respectively. Late-csCMV infection was correlated with apparent delayed immune reconstitution: patients transplanted from HLA-mismatched donors (hazard ratio [HR] = 13.0, p = 0.011) or CMV-IgG-negative donors (HR = 2.39, p = 0.043) had a significantly higher risk. In this study, transplant outcomes did not differ between patients with and without late-csCMV infection. This suggests a need to clarify the efficacy of extended administration of LMV for preventing late-csCMV infection in a larger number of allo-HCT recipients, especially those with "high-risk" donors.

Early-onset cardiac dysfunction following allogeneic haematopoietic stem cell transplantation.

OBJECTIVE: Heart failure following allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a serious complication that requires early detection; however, the clinical implications of early-onset cancer therapy-related cardiac dysfunction (CTRCD) following allo-HSCT remain unclear. We investigated the determinants and prognostic impact of early-onset CTRCD in allo-HSCT recipients. METHODS: The records of 136 patients with haematological malignancies who underwent allo-HSCT at our institute were retrospectively reviewed. Early-onset CTRCD was defined as a decrease in left ventricular ejection fraction (LVEF) of ≥10% and an LVEF of ≤53% within 100 days after HSCT. RESULTS: Early-onset CTRCD was diagnosed in 23 out of 136 included patients (17%), and the median duration from HSCT to CTRCD diagnosis was 24 (9-35) days. Patients were followed up for 347 (132-1268) days. In multivariate logistic regression analysis, cumulative doxorubicin dosage (each 10 mg/m2) and severity of acute graft-versus-host disease (GVHD/grade) were independent indicators of early-onset CTRCD (OR (95% CI) 1.04 (1.00 to 1.07); p=0.032; OR (95% CI) 1.87 (1.19 to 2.95), p=0.004, respectively). The overall and primary disease death rates were significantly higher in allo-HSCT recipients with early-onset CTRCD than in those without early-onset CTRCD (HR (95% CI) 1.98 (1.11 to 3.52), p=0.016; HR (95% CI) 2.96 (1.40 to 6.29), p=0.005, respectively), independent of primary disease type, remission status and transplantation type. CONCLUSIONS: Severe acute GVHD and higher cumulative anthracycline are two significant determinants of early-onset CTRCD. Early-onset CTRCD following allo-HSCT regulates survival in patients with haematological malignancies.

Development and Validation of an LC-MS/MS Method to Quantify Gilteritinib and Its Clinical Application in Patients With FLT3 Mutation-Positive Acute Myelogenous Leukemia.

BACKGROUND: Gilteritinib, a novel oral tyrosine kinase inhibitor, is used to treat acute myeloid leukemia (AML) with FMS-like tyrosine kinase-3 (FLT3) mutations. Therapeutic drug monitoring (TDM) of gilteritinib is important for improving clinical outcomes and ensuring safety. Therefore, this study aimed to develop a simplified method for quantifying gilteritinib in human plasma using liquid chromatography-tandem mass spectrometry. METHODS: Liquid chromatography was performed by using an Acquity BEH C18 column (50 mm × 2.1 mm, 1.7 µm) and a gradient elution with 0.1% formic acid in water (A) and acetonitrile (B). Detection was performed by using a Shimadzu tandem mass spectrometer through multiple reaction monitoring in the positive-ion mode. RESULTS: The developed method enabled quantification of gilteritinib in 4 minutes and was validated by evaluating selectivity, calibration curve (10-1000 ng/mL, r 2 > 0.99), a lower limit of quantification (LLOQ), accuracy (overall bias -4.2% to 1.9%), precision (intraday CV ≤ 7.9%; interday CV ≤ 13.6%), carryover, recovery, matrix effect, dilution integrity, and stability according to the US Food and Drug Administration (FDA) guidelines. This method was successfully applied to the TDM of gilteritinib trough concentrations in 3 patients with AML. CONCLUSIONS: The developed method fulfilled the FDA guideline criteria and can easily be implemented to facilitate TDM in patients receiving gilteritinib in a clinical setting.

Incidence of refractory cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation.

Post-transplant cytomegalovirus (CMV) disease can be almost completely avoided by current infection control procedures. However, CMV reactivation occurs in more than half of patients, and some patients can develop clinically resistant CMV infections. Whether resistance is due to the host's immune status or a viral resistance mutation is challenging to confirm. Therefore, a prospective observational analysis of refractory CMV infection was conducted in 199 consecutive patients who received allogeneic hematopoietic stem cell transplantation at a single institution. Among them, 143 (72%) patients received anti-CMV drugs due to CMV reactivation, and only 17 (8.5%) exhibited refractory CMV infection. These patients had clinically refractory infection. However, viral genome analysis revealed that only one patient exhibited a mutation associated with the anti-CMV drug resistance. Clinical resistance was mainly correlated with host immune factors, and the incidence of resistance caused by gene mutations was low at the early stage after a transplantation.

[Stratified treatment of fit and unfit acute myeloid leukemia].

The etiology and pathogenesis of acute myeloid leukemia (AML) have been elucidated at chromosomal and genetic levels. The classification and prognosis for its treatment has clearly involved specific chromosomal aberrations and genetic mutations. The recent comprehensive genomic analysis represented by next-generation sequencers has led to discovering new genetic mutations in AML. These findings have not only been applied clinically as prognostic factors and MRD markers but also contributed to the development of new molecular-targeting drugs. Many new drugs have already been approved in the USA and Europe, and new stratified treatments have tried to incorporate them. With the advent of venetoclax, treatment strategies, especially for patients with poor prognosis and who are unfit, have been substantially revised, and the maintenance therapy for AML is also being reevaluated in accordance to the National Comprehensive Cancer Network guidelines. This article will review the current status of AML treatment in Japan and according to Western guidelines.

Azacitidine for the treatment of patients with relapsed acute myeloid leukemia after allogeneic stem cell transplantation.

We retrospectively analyzed 38 patients with AML who received azacitidine (AZA) to treat disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with objective response (OR) (n = 20) after AZA had significantly higher 2-year overall survival (OS) (45.0% vs 5.6%; p = 0.004) than progressive disease. The 2-year OS was significantly higher in the retransplant group (n = 23) than in the nonretransplant group (n = 15) (34.8% vs 13.3%; p = 0.034). We analyzed 167 patients who underwent the second allo-HSCT to clarify the impact of pretransplant AZA after the second allo-HSCT. Patients in the AZA group (n = 21) had significantly higher 2-year disease-free survival (DFS) (32.7% vs 14.5%; p = 0.012) and OS (38.1% vs 17.5%; p = 0.044) than those in the SOC group (n = 146). Our data demonstrate that AZA is an effective and well-tolerated bridging therapy to the second allo-HSCT.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

Low-dose anti-thymocyte globulin for GVHD prophylaxis in HLA-matched allogeneic peripheral blood stem cell transplantation.

Allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with an increased risk of severe acute and chronic graft-versus-host disease (GVHD) compared to bone marrow transplantation. Anti-thymocyte globulin (ATG) can reduce severe acute and chronic GVHD in PBSCT; however, an optimal dose of ATG remains undefined. We conducted a multicenter phase II study to investigate safety and efficacy of low-dose ATG (a total of 2 mg/kg Thymoglobulin) in patients undergoing HLA-matched PBSCT after myeloablative conditioning. The primary endpoint was grades III-IV GVHD at 100 days. Seventy-seven patients were enrolled and 72 patients with a median age of 46.5 years were eligible for analysis. The primary endpoint, cumulative incidence of grades III-IV acute GVHD at 100 days was 1.4% (95% CI, 0.1-6.7%), which was greatly less than our pre-defined statistical threshold value (18.0%). The incidence of chronic GVHD at 1 year was also low (all-grade; 15.3%, moderate to severe; 5.6%). Non-relapse mortality, relapse, overall survival, disease-free survival, and GVHD-free, relapse-free survival at 1 year were 4.2%, 20.8%, 84.7%, 75.0%, and 69.4%, respectively. Low dose thymoglobulin is promising to reduce severe acute and chronic GVHD in HLA-matched PBSCT following myeloablative conditioning.

Efficacy of prophylactic letermovir for cytomegalovirus reactivation in hematopoietic cell transplantation: a multicenter real-world data.

A novel anti-cytomegalovirus (CMV) agent, letermovir (LMV), could reportedly improve the outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) recipients because of its high potential to prevent CMV reactivation. Therefore, 685 Japanese allo-HCT recipients, of whom ~80% had a high risk of CMV reactivation, were retrospectively analyzed to assess the impacts of prophylactic LMV on the incidence of clinically significant CMV (csCMV) infection as well as their transplant outcome. By comparing 114 patients who received LMV prophylaxis for a median 92 days to 571 patients without prophylaxis, we observed that prophylactic LMV could significantly (1) reduce the 180-day cumulative incidence of csCMV infection (44.7 vs. 72.4%, p < 0.001), (2) delay the median time until initiation of CMV antigenemia-guided preemptive therapy (90 vs. 36 days, p < 0.001), (3) shorten the duration of anti-CMV preemptive treatment (21 vs. 25 days, p = 0.006), and (4) improve the overall survival rate at 180 days after transplant (80.4 vs. 73.0%, p = 0.033) with a trend of lower non-relapse mortality (8.9 vs. 14.9%, p = 0.052). Our findings demonstrate that prophylactic LMV treatment is highly effective in preventing the development of csCMV infection and ultimately reduces transplant-related mortality.

Outcome predictors after retransplantation in relapsed acute lymphoblastic leukemia: a multicenter, retrospective study.

Retransplantation is the only curative treatment option for patients with acute lymphoblastic leukemia (ALL) that has relapsed after allogeneic hematopoietic cell transplantation (allo-HCT); however, data in this setting remain scant. Hence, this multicenter, retrospective study aims to determine outcome predictors after retransplantation in relapsed ALL. We examined 55 recipients who underwent multiple allo-HCTs during 2006-2018. The 2-year overall survival (OS), progression-free survival (PFS), and non-relapse mortality rates were 35.9%, 29.1%, and 23.6%, respectively. We observed a trend of better outcome in Ph + ALL (n = 22) patients compared with non-Ph ALL (n = 33) patients; the 2-year PFS was 40.9% versus 21.2%, indicating a beneficial effect of more potent second- or third-generation tyrosine kinase inhibitors. Univariate analysis revealed that late relapse after the previous transplant was the only significant predictor of better transplant outcome among Ph + ALL patients, whereas factors related to prolonged OS/PFS in non-Ph ALL patients were late relapse after the previous transplant, longer duration from disease relapse/progression to second or more allo-HCT, disease status at the transplantation, and good performance status. Nevertheless, further investigations are warranted to determine whether novel molecular-targeted agents with higher efficacy and fewer toxicities could exceed conventional chemotherapies as a bridging strategy to next allo-HCT and improve the outcomes of non-Ph ALL patients.

Epstein-Barr Virus-Associated Encephalopathy Presenting with Nonconvulsive Status Epilepticus in an Immunosuppressive State.

Epstein-Barr virus (EBV) infection is occasionally accompanied by central nervous system (CNS) complications, particularly in immunosuppressed patients. However, the symptoms and clinical features of EBV infection in the CNS are rather heterogeneous and remain unknown. We herein describe the first reported adult case manifesting nonconvulsive status epilepticus (NCSE), possibly associated with reactivation of EBV in an immunosuppressive state. A 63-year-old man with a history of acute myeloid leukemia and taking immunosuppressants was admitted due to progressively impaired consciousness without any focal neurological signs, including paralysis or convulsions. Arterial spin labeling magnetic resonance imaging (ASL-MRI) and brain perfusion single-photon emission computed tomography showed hyperperfusion in the right temporal region, despite no morphological abnormalities in other MRI sequences. White blood cell counts, EBV viral load, and virus-capsid antigen IgG in cerebrospinal fluid were elevated. We diagnosed him with EBV-associated encephalopathy presenting with NCSE. Administration of levetiracetam, an antiepileptic, improved the consciousness and the abnormal hyperperfusion. This case suggests a new concept of EBV-associated encephalopathy leading to epilepsy, particularly in immunosuppressed patients.

Myeloablative intravenous busulfan-containing regimens for allo-HSCT in AML or MDS patients over 54 years old: combined results of three phase II studies.

An optimal pretransplant conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in older adults has not been established. Three prospective multicenter phase II studies were conducted, in which 142 patients older than 54 years (median age, 61 years; range 55-70 years) with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) received a myeloablative dose of intravenous busulfan (ivBu, 12.8 mg/kg) along with fludarabine (180 mg/m2) ± low dose total body irradiation for allo-HSCT between September 2009 and February 2013. A total of 103 AML and 39 MDS patients including 21 related bone marrow (BM) or peripheral blood (PB), 50 unrelated BM, and 71 unrelated cord blood (UCB) transplantation were enrolled. Grade 3 or greater toxicities were observed in 105 patients. Neutrophil engraftment was achieved in 70 out of the 71 related PB/BM or unrelated BM recipients, and 61 out of the 71 UCB recipients. The cumulative incidence rates of relapse and non-relapse mortality after 2 years were 24.0 and 24.1%, respectively. The overall and event-free survival rates at 2 years were 53.3 and 47.4%, respectively. The myeloablative dose of ivBu was well tolerated without increased toxicity-related mortality in older adults who underwent allo-HSCT with any donor source.