[Recent findings and advances in treatment of chronic myeloid leukemia].

Imatinib, the first ABL-tyrosine kinase inhibitor (TKI), was approved in 2000 for the treatment of chronic myeloid leukemia (CML). Second- and third-generation TKIs, as well as asciminib, which targets a different site of BCR-ABL1 (the myristoyl pocket), were later approved in 2022. Currently, six drugs are approved for the treatment of CML. Revisions to the clinical guidelines for hematopoietic tumors in 2023 provided new guidance on the utility of new agents as well as TKI dose reduction and treatment discontinuation. This article outlines recently reported predictions regarding TKI treatment response, the role of asciminib in the treatment of CML, and development of new agents, as well as the latest findings regarding the current state of TKI treatment discontinuation.

Bosutinib-induced late-onset severe liver injury preceded by eosinophilia.

Tyrosine kinase inhibitors (TKIs) have dramatically changed the way chronic myeloid leukemia (CML) is treated. Although TKI therapy improves the overall survival of patients with CML, the management of various adverse events (AEs) from the therapy has become a major barrier to its adherence. Bosutinib is a second-generation TKI and an effective first-line treatment for CML. The most frequent AE is diarrhea; however, liver toxicity is also a major complication. In general, drug-induced hepatic enzyme elevation occurs within 1-2 weeks after treatment initiation. However, we noticed that, in a certain number of patients, liver injury appeared late (4-7 weeks) and was accompanied by eosinophilia. Herein, we retrospectively analyzed patients with CML treated with bosutinib at the Juntendo University School of Medicine and observed five patients with CML who developed late-onset liver injury with an elevation of the eosinophil count. In all cases, the liver enzyme level was within the normal range or grade 1 during the first 3 weeks of the bosutinib treatment and then elevated steeply thereafter. The pattern of hepatic toxicity was hepatocellular injury. In addition, all cases of eosinophilia tended to precede or coincide with an elevated liver enzyme level. Thus, the elevation of the eosinophil count may be a predictor for bosutinib-induced liver injury. Careful attention should be paid to delayed-onset hepatic injury, especially at 4-6 weeks after bosutinib initiation.

A pilot study examining the efficacy of hochuekkito for improving quality of life in patients with myeloproliferative neoplasms.

BACKGROUND: The prognosis of Philadelphia chromosome-negative myeloproliferative neoplasms is relatively favorable, but the quality of life can be severely affected by myeloproliferative neoplasm-related symptoms such as fatigue, pruritus, night sweats, bone pain, fever and weight loss. In this study, we administered hochuekkito, a traditional herbal medicine, to patients with myeloproliferative neoplasms and investigated whether there was a reduction in myeloproliferative neoplasm-related symptoms. METHODS: We conducted a randomized parallel-group pilot study. Patients were assigned to a hochuekkito administration or non-hochuekkito administration group. Myeloproliferative neoplasm-related symptoms based on Myeloproliferative Neoplasm Symptom Assessment Form total symptom score and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 were examined before hochuekkito administration and 4 and 8 weeks after administration. RESULTS: Among the 42 patients included in the analysis, 21 were assigned to the hochuekkito group and 21 were assigned to the control group. After administering hochuekkito, the median values of Myeloproliferative Neoplasms Symptom Assessment Form total symptom score at 4 and 8 weeks in the hochuekkito group demonstrated a decreasing trend; however, the difference between the two groups was not significant. CONCLUSIONS: In this study, we were unable to demonstrate significant differences between the hochuekkito and control groups in terms of the efficacy of hochuekkito in treating myeloproliferative neoplasm-related symptoms. However, there were cases that presented prominent improvement in symptoms in the hochuekkito group. The only reported adverse event was grade 1 impaired hepatic function. Therefore, hochuekkito might be a therapeutic option for patients with severely affected quality of life due to myeloproliferative neoplasm-related symptoms.

[Systemic chemotherapy combined with thrombopoietin receptor agonist for the treatment of diffuse large B-cell lymphoma complicated with aplastic anemia].

Immunosuppressive therapies, including antithymocyte globulin and cyclosporine (CsA), are used for the treatment of aplastic anemia, but they reportedly cause lymphoproliferative diseases. Here, we report two cases of aplastic anemia in which diffuse large B-cell lymphoma developed during treatment with CsA. In both the cases, CsA was discontinued and combination therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone) plus the thrombopoietin receptor agonist eltrombopag was initiated. Furthermore, supportive care, including blood transfusion and granulocyte colony-stimulating factor, was provided. After six or eight courses of R-CHOP therapy, a complete metabolic response was achieved without serious adverse events. These cases illustrate the safety of combining R-CHOP with eltrombopag therapy in patients at a high risk of severe pancytopenia.

[Management of vascular adverse events during tyrosine kinase inhibitors in patients with chronic myeloid leukemia].

In 2000, imatinib became the first tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myeloid leukemia (CML); this was soon followed by second generation (nilotinib, dasatinib, and bosutinib) and third generation (ponatinib) TKIs, all of which are currently available for the treatment of CML. Their emergence has revolutionized treatment strategies for CML, leading to a new era that has seen the 10-year overall survival rate for CML patients exceed 80%; despite the impact of TKIs on CML prognosis, only 10 to 20% of CML patients maintain treatment-free remission after TKI cessation. Moreover, prolonged treatment produces various adverse effects, such as serious vascular adverse events including stroke, myocardial infarction, and peripheral arterial occlusive disease. The pathophysiological mechanisms underlying those effects remain unclear, and protocols for managing such life-threatening events have not been established. Thus, I conducted a narrative review of the literature to clarify the current state of knowledge. Based on that review and my experiences during daily clinics, I herein present a discussion on the incidence, diagnosis, and management of TKI-induced vascular adverse events.

Clinical Efficacy and Safety of First-Line Dasatinib Therapy and the Relevance of Velocity of BCR-ABL1 Transcript Decline for Achievement of Molecular Responses in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Report from the Juntendo Yamanashi Cooperative Study Group.

OBJECTIVE: The use of tyrosine kinase inhibitors led to an improvement in the prognoses of patients with chronic myeloid leukemia (CML). The aims of this study were to investigate the efficacy and safety of dasatinib in Japanese patients and to explore the factors that affect the achievement of molecular responses. METHODS: The primary endpoint was a major molecular response (MMR) by 12 months. The halving time for BCR-ABL1 transcripts was calculated using transcript levels. RESULTS: Thirty-two patients with chronic-phase CML (CML-CP) were enrolled and 30 received 100 mg dasatinib once daily. At 24 months of follow-up, 21 (72%) and 24 (83%) patients achieved an MMR by 12 and 24 months, respectively; the rates of a deep molecular response (DMR) by 12 and 24 months were 48 and 59%, respectively. A shorter halving time of BCR-ABL1 transcripts (≤10.6 days) accurately predicted both an MMR and a DMR. The incidence of pleural effusion was 50%. Our study reconfirmed the efficacy and safety of dasatinib treatment in Japanese patients with newly diagnosed CML-CP. In addition, the usefulness of the halving time of BCR-ABL1 transcripts was validated. CONCLUSION: These data emphasize the significance of an early treatment response in achieving a DMR during dasatinib therapy.

Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a retrospective study of the CML Cooperative Study Group database.

This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.

Prevalence of Slow-Growth Vancomycin Nonsusceptibility in Methicillin-Resistant Staphylococcus aureus.

We previously reported a novel phenotype of vancomycin-intermediate Staphylococcus aureus (VISA), i.e., "slow VISA," whose colonies appear only after 72 h of incubation. Slow-VISA strains can be difficult to detect because prolonged incubation is required and the phenotype is unstable. To develop a method for detection of slow-VISA isolates, we studied 23 slow-VISA isolates derived from the heterogeneous VISA (hVISA) clinical strain Mu3. We identified single nucleotide polymorphisms (SNPs) in genes involved in various pathways which have been implicated in the stringent response, such as purine/pyrimidine synthesis, cell metabolism, and cell wall peptidoglycan synthesis. We found that mupirocin, which also induces the stringent response, caused stable expression of vancomycin resistance. On the basis of these results, we developed a method for detection of slow-VISA strains by use of 0.032 µg/ml mupirocin (Yuki Katayama, 7 March 2017, patent application PCT/JP2017/008975). Using this method, we detected 53 (15.6%) slow-VISA isolates among clinical methicillin-resistant S. aureus (MRSA) isolates. In contrast, the VISA phenotype was detected in fewer than 1% of isolates. Deep-sequencing analysis showed that slow-VISA clones are present in small numbers among hVISA isolates and proliferate in the presence of vancomycin. This slow-VISA subpopulation may account in part for the recurrence and persistence of MRSA infection.

A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study).

Hypoplastic myelodysplastic syndrome (hMDS) is a distinct entity with bone marrow (BM) hypocellularity and the risk of death from BM failure (BMF). To elucidate the characteristics of hMDS, the data of 129 patients diagnosed between April 2003 and March 2012 were collected from 20 institutions and the central review team of the National Research Group on Idiopathic Bone Marrow Failure Syndromes, and compared with 115 non-hMDS patients. More RA and fewer CMMoL and RAEB-t in French-American-British (FAB) and more RCUD and MDS-U and fewer RCMD in World Health Organization (WHO) classifications were found in hMDS than non-hMDS with significant differences. The overall survival (OS) and AML progression-free survival (AML-PFS) of hMDS were higher than those of non-hMDS, especially in patients at age ≥50 and of lower risk in Revised International Prognostic Scoring System (IPSS-R). In competing risks analysis, hMDS exhibited decreased risk of AML-progression in lower IPSS or IPSS-R risk patients, and higher risk of death from BMF in patients at age ≥50. Poor performance status (PS ≥2) and high karyotype risks in IPSS-R (high and very high) were significant risk factors of death and AML-progression in Cox proportional hazards analysis.

[Chronic myeloid leukemia complicated by pulmonary hypertension during dasatinib therapy: a single-center retrospective study].

Pulmonary artery hypertension (PAH) has been reported to be a severe adverse event associated with dasatinib therapy. Among the 76 chronic myeloid patients who were treated with dasatinib at our hospital, six patients showed high estimated pulmonary arterial systolic pressure, as observed by echocardiography. PAH was confirmed using right heart catheterization in three (3.9%) patients with increased mean pulmonary artery pressure (mPAP). In one patient, although mPAP was higher than the normal range, it did not fulfill the criteria of pulmonary hypertension. After the discontinuation of dasatinib, BNP and dyspnea were improved in five patients. Therefore, it should be noted that dasatinib can cause PAH at higher rates than those reported previously, and if PAH is confirmed or suspected during dasatinib therapy, then dasatinib should be immediately discontinued.

Acute exacerbation of organizing pneumonia leading to sudden death in a patient with sarcoidosis-lymphoma syndrome.

The subject was an 83-year-old female; she had a history of Propionibacterium acnes-related sarcoidosis at the age of 79 years. At diagnosis, she was treated with clarithromycin and achieved remission. Four years later, during a routine physical check-up, she presented with pulmonary opacities and swelling of multiple lymph nodes. A definitive diagnosis of lymphoma could not be made by inguinal lymph node biopsy. The patient's general condition was good, and we observed her clinical course. Oh the 56th day of her illness, she died suddenly. Autopsy revealed diffuse large B-cell lymphoma (DLBCL). Sarcoidosis-lymphoma syndrome (SLS) was diagnosed after sampling hyalinized nodules from both lungs. The cause of death was organizing pneumonia around an epithelioid granuloma and cor pulmonale. Organization markedly increased around the DLBCL. These findings might be associated with cor pulmonale. Although SLS often appears during chronic active sarcoidosis, sudden death is rare and there are few reports on SLS in Japan. We report this case along with a review of the literature.

Leukocyte concentration and composition in platelet-rich plasma (PRP) influences the growth factor and protease concentrations.

BACKGROUND: Platelet-rich plasma (PRP) therapy has become an increasingly popular treatment for orthopaedics and sports-related injuries, and various clinically available PRP preparation methods exist. However, the differences in PRP quality among numerous preparation methods remain unclear. Specifically, the benefit of including leukocytes in the PRP product remains controversial, and few studies have been conducted to evaluate the effects of the interaction between platelets and leukocytes on the growth factor concentrations. The aim of the present study was to compare the biological characteristics of PRPs focusing on the leukocyte concentration and composition. METHODS: Leucocyte rich (LR)-PRP, leucocyte poor (LP)-PRP, and pure-PRP were prepared from the peripheral blood of 6 healthy male volunteers (mean age: 31.3 years). The concentrations of platelets, leukocytes, erythrocytes, growth factors (transforming growth factor-beta 1: TGF-ß1; fibroblast growth factor-basic: FGF-b; platelet-derived growth factor-BB: PDGF-BB; vascular endothelial growth factor: VEGF) and matrix metalloproteinase-9 (MMP-9) from each of the PRP samples were measured. Considering the interaction between platelets and leukocytes, correlations between platelets/leukocytes and growth factors/MMP-9 were analyzed using partial correlation coefficients. RESULTS: The platelet concentration did not differ among the three PRP preparation methods. Conversely, the leukocyte concentration was dramatically different: 14.9 ± 4.5 (10(3)/µl) in LR-PRP, 2.4 ± 1.3 (10(3)/µl) in LP-PRP, 0.2 ± 0.2 (10(3)/µl) in pure-PRP. The platelet concentration positively correlated with all growth factors. On the other hand, the leukocyte concentration positively correlated with PDGF-BB and the VEGF concentration, while it negatively correlated with FGF-b. Regarding catabolic factors, the MMP-9 concentration strongly correlated with the leukocyte concentration, while there was no correlation between the platelet and MMP-9 concentrations. CONCLUSIONS: These findings demonstrate that leukocytes strongly influence the quality of PRPs. Therefore, modifying the PRP preparation method according to the pathology is essential to achieve better clinical results with PRP therapy.

Congenital haptoglobin deficiency discovered on the occasion of anaphylaxis induced by platelet concentrate transfusion.

A 77-year-old man with myelodysplastic syndrome suffered from duodenal perforation after undergoing endoscopic submucosal dissection (ESD) for treatment of duodenal cancer. He presented with hemorrhagic shock, peritonitis and disseminated intravascular coagulation (DIC), and received transfusions of red blood cells (RBC), fresh frozen plasma (FFP), γ-globulin and albumin (Alb). One month after the last RBC transfusion, prolonged thrombocytopenia was observed, and platelet concentrate (PC) was transfused. However, immediately after starting PC transfusion, he developed dyspnea, hypotension and rash, and was thus diagnosed as being in anaphylactic shock. Analysis of the patient's serum revealed absence of haptoglobin (Hp) and the presence of anti-Hp antibody. Further studies, using PCR detected Hpdel, yielded a diagnosis of congenital Hp deficiency. Thus, the anaphylactic shock was considered to have been induced by Hp in the transfused PC reacting with pre-existing anti-Hp antibodies. Thereafter, transfusions were safely carried out with the use of washed PC. Congenital Hp deficiency is relatively prevalent, and in such cases transfusions should be carried out using washed RBC, washed PC and congenital Hp deficiency donor derived FFP to avoid anaphylactic transfusion reactions. Transfusions would be even safer if production of congenital Hp deficiency donor derived PC were to be made available in the future.

Case report: Ensitrelvir for treatment of persistent COVID-19 in lymphoma patients: a report of two cases.

Persistent COVID-19 is a well recognized issue of concern in patients with hematological malignancies. Such patients are not only at risk of mortality due to the infection itself, but are also at risk of suboptimal malignancy-related outcomes because of delays and terminations of chemotherapy. We report two lymphoma patients with heavily pretreated persistent COVID-19 in which ensitrelvir brought about radical changes in the clinical course leading to rapid remissions. Patient 1 was on ibrutinib treatment for mantle cell lymphoma when he developed COVID-19 pneumonia which was severe and ongoing for 2 months despite therapy with molnupiravir, multiple courses of remdesivir, one course of sotrovimab, tocilizumab, and steroids. Patient 2 was administered R-CHOP therapy for diffuse large B-cell lymphoma when he developed COVID-19 which was ongoing for a month despite treatment with multiple courses of remdesivir and one course of sotrovimab. A 5-day administration of ensitrelvir promptly resolved the persistent COVID-19 accommodated by negative conversions of RT-qPCR tests in both patients within days. Ensitrelvir is a novel COVID-19 therapeutic that accelerates viral clearance through inhibition of the main protease of SARS-CoV-2, 3-chymotrypsin-like protease, which is vital for viral replication. Ensitrelvir is a promising treatment approach for immunocompromised lymphoma patients suffering from persisting and severe COVID-19.

Changes in chronic myeloid leukemia treatment modalities and outcomes after introduction of second-generation tyrosine kinase inhibitors as first-line therapy: a multi-institutional retrospective study by the CML Cooperative Study Group.

This study investigated changes in treatment modalities and outcomes of chronic myeloid leukemia in the chronic phase (CP-CML) after the approval of second-generation tyrosine kinase inhibitors (2G-TKIs) for first-line therapy. Patients were grouped into those who underwent TKI therapy up to December 2010 (imatinib era group, n = 185) and after January 2011 (2G-TKI era group, n = 425). All patients in the imatinib era group were initially treated with imatinib, whereas patients in the 2G-TKI era group were mostly treated with dasatinib (55%) or nilotinib (36%). However, outcomes including progression-free survival, overall survival, and CML-related death (CRD) did not differ significantly between groups. When stratified by risk scores, the prognostic performance of the ELTS score was superior to that of the Sokal score. Even though both scoring systems predicted CRD in the imatinib era, only the ELTS score predicted CRD in the 2G-TKI era. Notably, the outcome of patients classified as high-risk by ELTS score was more favorable in the 2G-TKI era group than in the imatinib era group. Thus, expanding treatment options may have improved patient outcomes in CP-CML, particularly in patients classified as high-risk by ELTS score.

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Subcutaneous panniculitis-like T-cell lymphoma post-mRNA-1273 COVID-19 vaccination.

This is a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) was diagnosed by skin biopsy in a patient who presented with fever and erythema nodosum in the umbilicum following mRNA-1273 COVID-19 vaccination. COVID-19 vaccines may cause SPTCL and skin biopsy may help in the diagnosis of erythema nodosum.

Endothelial function measured by peripheral arterial tonometry in patients with chronic myeloid leukemia on tyrosine kinase inhibitor therapy: a pilot study.

BACKGROUND: Arterial occlusive events are an emerging problem in patients with chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor (TKI) therapy. Endothelial cell damage is thought to play an important role in the development of vascular events. Measurement of the peripheral vasodilator response by peripheral arterial tonometry (PAT) has reportedly been useful in the non-invasive assessment of endothelial dysfunction. To date, no studies have assessed endothelial function using PAT in patients with CML receiving TKIs. METHOD: We measured the reactive hyperemia index (RHI) using PAT in young patients with CML (men aged ≤ 55 years and women aged ≤ 65 years) receiving TKIs. RESULTS: Thirty patients with CML were examined (mean age, 43.5 ± 9.8 years; men, 57%). The median RHI was 1.81. Among these patients, 16.7% and 83.3% were taking imatinib and second- or third-generation TKIs, respectively. There were no differences in the baseline characteristics between the low RHI (< 1.67, n = 10), borderline RHI (≥ 1.67 and < 2.10, n = 14), and normal RHI (≥ 2.10, n = 6) groups. Serum uric acid (UA) levels and the RHI were significantly negatively correlated (r = -0.40, p = 0.029). CONCLUSION: One-third of young patients with CML receiving TKI therapy were classified as having a low RHI. The RHI was negatively correlated with serum UA level. Larger prospective studies are necessary to examine whether the RHI predicts cardiovascular events in such patients.

Clinical management of second-generation tyrosine kinase inhibitor therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase, focusing on age and dose effects.

ABL1-tyrosine kinase inhibitors (TKIs) are an established treatment choice for patients with chronic myeloid leukemia in the chronic phase (CML-CP). However, effects of TKI dose modification have not been well investigated. In this study, we retrospectively analyzed 178 patients with newly diagnosed CML-CP who were treated with dasatinib or nilotinib, focusing on age and dose effects. Efficacy as measured by cumulative major molecular response (MMR) and molecular response 4.5 rates did not differ significantly between the younger group and elderly group. Elderly patients who started nilotinib at a reduced dose had similar or better efficacy outcomes (including cumulative MMR and continuation ratios) than other groups, and elderly patients who started dasatinib at a reduced dose had the lowest MMR ratio and longest MMR duration. Effects of dose modification based on age and TKI selection can be attributed to flexible management of TKI therapy in real-world practice, but further studies are required to validate the findings of this study.