Development of progressive multifocal leukoencephalopathy after cord blood transplantation in a patient with refractory angioimmunoblastic T-cell lymphoma.

A patient undergoing cord blood transplantation for refractory angioimmunoblastic T-cell lymphoma was subsequently managed with long-term immunosuppressants for chronic graft-versus-host disease (GVHD). On day 591 post-transplant, she exhibited disorientation and cognitive dysfunction. Magnetic resonance imaging (MRI) of the brain revealed two hyperintense foci in the white matter, suggestive of progressive multifocal leukoencephalopathy (PML). However, we did not include PML in the differential diagnosis at that time. Unfortunately, she developed progressive cognitive impairment, and repeated brain MRIs showed a progression in lesion size. She was still taking immunosuppressants to control her GVHD, therefore we suspected PML. The diagnosis of PML was confirmed through the detection of a John Cunningham (JC) virus in the cerebrospinal fluid on day 640 post-transplant. This report highlights the critical need to consider PML in differential diagnoses for post-allogeneic transplant patients, especially those who exhibit progressive neurological symptoms while on prolonged immunosuppressant therapy.

Donor Lymphocyte Infusion for Relapsed Acute Leukemia or Myelodysplastic Syndrome after Hematopoietic Stem Cell Transplantation: A Single-Institute Retrospective Analysis.

Objective The prognosis of the patients who relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is poor, and therapeutic options are limited. In the present study, we investigated the efficacy and factors associated with the survival in patients with acute leukemia or myelodysplastic syndrome (MDS) who relapsed following allo-HSCT and were treated with donor lymphocyte infusion (DLI) in real-world practice. Patients Twenty-nine patients with acute myeloid leukemia21, acute lymphoid leukemia4 or MDS4 were enrolled. Eleven patients were diagnosed with hematological relapse, and 18 were diagnosed with molecular or cytogenetic relapse. Results The median injection number and median total number of infused CD3+ T cells were 2 and 5.0×107/kg, respectively. The cumulative incidence of acute graft-versus-host disease (aGVHD) of grade ≥II at 4 months after the initiation of DLI was 31.0%. Extensive chronic graft-versus-host disease (cGVHD) occurred in 3 (10.3%) patients. The overall response rate was 51.7%, including 3 cases of hematological complete remission (CR) and 12 cases of molecular/cytogenetic CR. Cumulative relapse rates at 24 and 60 months following DLI in patients who achieved CR were 21.4% and 30.0%, respectively. The overall survival rates at 1, 2 and 3 years after DLI were 41.4%, 37.9% and 30.3%, respectively. Molecular/cytogenetic relapse, a longer interval from HSCT to relapse, and concomitant chemotherapy with 5-azacytidine (Aza) were significantly associated with a relatively long survival following DLI. Conclusion These results indicated that DLI was beneficial for patients with acute leukemia or MDS who relapsed after allo-HSCT and suggested that DLI in combination with Aza for molecular or cytogenetic relapse might result in favorable outcomes.

Wilms' tumor 1 -targeting cancer vaccine: Recent advancements and future perspectives.

This mini-review explores recent advancements in cancer vaccines that target Wilms' tumor (WT1). Phase I/II trials of WT1 peptide vaccines have demonstrated their safety and efficacy against various cancers. Early trials employing HLA class I peptides evolved through their combination with HLA class II peptides, resulting in improved clinical outcomes. Additionally, WT1-targeted dendritic cell vaccines have exhibited favorable results. Studies focusing on hematological malignancies have revealed promising outcomes, including long-term remission and extended survival times. The combination of vaccines with immune checkpoint inhibitors has shown synergistic effects. Current preclinical developments are focused on enhancing the effectiveness of WT1 vaccines, underscoring the necessity for future large-scale Phase III trials to further elucidate their efficacy.

A case of Hodgkin lymphoma-type Richter syndrome presenting as small-intestinal perforation.

Hodgkin lymphoma type of Richter syndrome (HL-type RS) is a rare disease that arises in patients with chronic lymphocytic leukemia (CLL). HL-type RS lesions can manifest in various sites and are often accompanied by related symptoms. This is the first case report to describe diagnosis of HL-type RS after emergency surgery for gastrointestinal perforation caused by the development of a HL-type RS lesion. A 47-year-old man diagnosed with CLL three years prior began treatment with ibrutinib due to worsening anemia and splenomegaly two months prior to the emergency department presentation. Although splenomegaly improved, lymphocytopenia, anemia, and a newly arising mesenteric lymphadenopathy continued to worsen. He presented to the emergency department with abdominal pain, and subsequent surgery revealed small intestinal perforation and mesenteric lymphadenopathy with HL-type RS confirmed by histopathological examination of the resected small intestine. He subsequently received brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD), which effectively managed the HL-type RS. If CLL clinical presentation deviates from the typical course, an early tissue biopsy should be considered to evaluate for HL-type RS. Given the adoption of the A + AVD regimen as the standard treatment for Hodgkin lymphoma, further research is needed to evaluate its efficacy in HL-type RS.

Wilms' tumor 1 peptide-loaded dendritic cell vaccination in patients with relapsed or refractory acute leukemia.

INTRODUCTION: The prognosis of patients with relapsed or refractory acute leukemia is poor. In the present pilot study, we treated relapsed or refractory acute leukemia patients with Wilms' tumor 1 (WT1) peptide-loaded dendritic cells (DCs) and examined safety, clinical and immunological responses. METHODS: Eleven eligible patients were enrolled. DCs were administered every 2-3 weeks with OK-432 adjuvant. RESULTS: The treatment was well tolerated. The reduction of leukemia cells or the expression of WT1 mRNA was observed in four patients which was maintained for a significant period of time. All the responding patients manifested immune responses against WT1 which might be related to clinical outcome. Decreases in the absolute number of regulatory T cells were observed following vaccination, indicating that DC vaccinations may contribute to the reversal of immunosuppression. CONCLUSION: These results indicate that DC-based immunotherapy is safe and feasible for patients with acute leukemia.

New-onset Evans syndrome associated with systemic lupus erythematosus after BNT162b2 mRNA COVID-19 vaccination.

Evans syndrome presents as concurrent autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP). Systemic lupus erythematosus (SLE) is the most frequent autoimmune disorder associated with Evans syndrome. We herein report a case of new-onset Evans syndrome associated with SLE after BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccination in a 53-year-old woman. Blood examination at diagnosis showed hemolytic anemia with a positive Coombs test and thrombocytopenia. Hypocomplementemia and the presence of lupus anticoagulant indicated a strong association with SLE. Prednisolone administration rapidly restored hemoglobin level and platelet count. This case suggests that mRNA COVID-19 vaccination may cause an autoimmune disorder. Physicians should be aware of this adverse reaction by mRNA COVID-19 vaccination and should consider the benefits and risks of vaccination for each recipient.

Baseline immunity predicts prognosis of pancreatic cancer patients treated with WT1 and/or MUC1 peptide-loaded dendritic cell vaccination and a standard chemotherapy.

The prognosis of patients with advanced pancreatic cancer is poor despite the recent introduction of immune checkpoint inhibitors. Therefore, the development of new therapeutic approaches is urgently required. In the present phase I/II study, we have evaluated the safety, the efficacy and the prognostic factors of Wilms' tumor 1 (WT1) and/or mucin 1 (MUC1) peptide-loaded dendritic cell (DC) vaccination in combination with a chemotherapy employing gemcitabine plus nab-paclitaxel or a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Forty-eight eligible patients were enrolled and received the vaccinations approximately every 2-4 weeks at least seven times. No severe adverse events related to the vaccinations were observed. Median progression free survival and overall survival were 8.1 months and 15.1 months, respectively. DC vaccinations augmented tumor specific immunity which might be related to clinical outcome. The multivariate analyses demonstrated that WT1 or MUC1-specific interferonɤ enzyme-linked immunospot number prior to DC vaccination was an independent prognostic factor related to overall survival. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and has clinical benefits for patients in advanced stage of PDAC. The precise evaluation of the baseline antitumor specific immunity is critical to predict clinical outcome.

Dendritic cell vaccination combined with a conventional chemotherapy for patients with relapsed or advanced pancreatic ductal adenocarcinoma: a single-center phase I/II trial.

The prognosis of patients with advanced pancreatic cancer is poor. In the present phase I/II study, we have evaluated the safety and the feasibility of Wilms' tumor 1 (WT1) and/or mucin1 (MUC1) peptide-pulsed dendritic cell (DC) vaccination in combination with chemotherapy in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Sixty-five eligible patients were enrolled. No severe adverse events related to the vaccinations were observed. Objective response rate and disease control rate was 12.3% and 50.8%, respectively. Median progression-free survival and overall survival were 4.9 and 9.6 months, respectively. DC vaccinations augmented WT1- and MUC1-specific immunity which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of PDAC.

Immunotherapy employing dendritic cell vaccination for patients with advanced or relapsed esophageal cancer.

The prognosis of patients with advanced esophageal cancer is poor despite the recent introduction of immune checkpoint inhibitors. In the present pilot study, we have evaluated the safety and the feasibility of Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (DC) vaccination in combination with OK-432 in patients with advanced or relapsed esophageal cancer. Fifteen eligible patients were enrolled. No severe adverse events related to the vaccinations were observed. Objective response rate and disease control rate were 20% and 40%, respectively. Median progression free survival and overall survival was 4.1 months and 7.0 months, respectively. WT1 peptide-pulsed DC vaccinations augmented WT1specific immunity, which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of esophageal cancer.

Phase I/II Pilot Study of Wilms' Tumor 1 Peptide-Pulsed Dendritic Cell Vaccination Combined With Conventional Chemotherapy in Patients With Head and Neck Cancer.

The prognosis of metastatic or relapsed head and neck squamous cell carcinoma (HNSCC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with Wilms' tumor 1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with conventional chemotherapy. Eleven eligible patients with metastatic or relapsed HNSCC were enrolled. No severe adverse events related to a vaccination were observed. Five patients had durable stable disease and six other patients had disease progression after DC vaccination. Median progression-free survival and overall survival was 6.4 months and 12.1 months, respectively. DC vaccination augmented Wilms' tumor 1-specific immunity which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of HNSCC.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial).

BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

Vaccination of Urological Cancer Patients With WT1 Peptide-Pulsed Dendritic Cells in Combination With Molecular Targeted Therapy or Conventional Chemotherapy Induces Immunological and Clinical Responses.

The prognosis of metastatic or relapsed renal cell carcinoma (RCC) or bladder cancer (BC) remains poor despite the introduction of immune checkpoint blockade agents. We aimed to investigate the safety and the feasibility of a vaccination with WT1 peptide-loaded dendritic cells (DCs) and OK-432 adjuvant combined with molecular targeted therapy or conventional chemotherapy. Five eligible patients with metastatic or relapsed RCC and five eligible patients with BC were enrolled. No severe adverse events related to a vaccination were observed. Seven patients with RCC or non-muscle invasive BC had durable stable disease and three other patients had disease progression after DC vaccination. DC vaccination augmented WT1 specific immunity and the reduction of regulatory T cells which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a molecular targeted therapy or a conventional chemotherapy is safe and feasible for patients in advanced stage of RCC or BC.

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

Immunological Analysis and Generation of Dendritic Cells From Lavage Fluid Obtained by Cell-Free and Concentrated Ascites Reinfusion Therapy.

Cell-free and concentrated ascites reinfusion therapy (CART) is an effective treatment for patients with refractory ascites. Cellular components such as cancer cells and blood cells are removed and discarded. The aim of this study was to investigate the alteration of immune cells in lavage fluid and the generation of dendritic cells (DCs) from lavage fluid obtained by CART. Flow cytometry analysis showed a trend toward immunosuppression and impairment in innate immunity in lavage fluid. Immature DCs with downregulation of CD14 and increased antigen-uptake were generated by culturing monocytes obtained from lavage fluid with GM-CSF and IL4. Following the culture with proinflammatory mediators, mature DCs with upregulation of CD83 and potent ability of T cell activation were induced. There were no significant phenotypical or functional differences between these DCs and DCs derived from peripheral blood, indicating lavage fluid might be employed for an alternative cellular source for the generation of DCs.

Lung adenocarcinoma may be a more susceptive subtype to a dendritic cell-based cancer vaccine than other subtypes of non-small cell lung cancers: a multicenter retrospective analysis.

OBJECTIVE: The J-SICT DC Vaccine Study Group provides dendritic cell (DC) vaccines for compassionate use under unified cell production and patient treatment regimens. We previously reported beneficial effects of DC vaccines on the overall survival of 62 patients with advanced non-small cell lung cancer (NSCLC) in a single-center analysis. Here, we extended analysis to 260 patients with NSCLC who were treated at six centers. METHODS: Of the 337 patients who met the inclusion criteria, we analyzed 260 patients who received ≥5 peptide-pulsed DC vaccinations once every 2 weeks. RESULTS: The mean survival time (MST) from diagnosis was 33.0 months (95 % confidence interval [CI]: 27.9-39.2), and that from time of first vaccination was 13.8 months (95 % CI 11.4-16.8). An erythema reaction at the injection site that was ≥30 mm in diameter was correlated most strongly with overall survival from the first vaccine (≥30 vs. < 30 mm: MST 20.4 vs. 8.8 months, P < 0.001). We reported a similar finding in our previous analysis of patients with advanced pancreatic cancer. Interestingly, although such findings were common between patients with adenocarcinoma and those with other subtypes, the former group experienced significantly prolonged overall survival and a higher response rate for erythema (56.3 vs. 37.3 %, respectively, P = 0.014). CONCLUSIONS: This is the first multicenter study that suggests a possible clinical benefit of DC vaccines for patients with advanced NSCLC, especially those with adenocarcinoma. These findings suggest a specific potential responder population for DC vaccines and warrant further investigation in well-controlled prospective randomized trials.

Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.

BACKGROUND: First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response. METHODS: The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130. FINDINGS: 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months. INTERPRETATION: Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible. FUNDING: Epidemiological and Clinical Research Information Network (ECRIN).

[Serum ALP elevation early after treatment is a predictor for response in myeloma patients treated with bortezomib].

Several studies have shown the predictive value of elevated serum alkaline phosphatase (ALP) level in multiple myeloma (MM) patients treated with bortezomib (BTZ). We assessed the relationship between changes in ALP levels during treatment and response. Thirty patients treated with BTZ in our hospital were analyzed retrospectively. Of the patients analyzed, 12 were male, median age was 62 years (42-86), and 11 had a history of prior chemotherapy. Eighteen patients were treated with BTZ alone or in combination with dexamethasone, while the others were treated with a combination regimen employing an alkylating agent. Seven patients had undergone autologous stem cell transplantation following BTZ therapy. Ten of 28 patients showed ALP elevation of 25% or more from the baseline at 3 weeks, and 14 of the 28 had this finding at 6 weeks. Four of 5 patients who had achieved VGPR or more showed ALP elevation of 25% or more at 3 weeks, and all five had this finding by 6 weeks. No patient without ALP elevation achieved VGPR or a better response. ALP elevation exceeding 25% from the baseline by day 42 is significantly associated with a treatment response better than VGPR (p=0.019). In conclusion, ALP elevation during BTZ treatment is a valuable prognostic marker.

Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis.

OBJECTIVE: Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. METHODS: Of 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed. RESULTS: The mean survival time from diagnosis was 16.5 months (95 % CI 14.4-18.5) and that from the first vaccination was 9.9 months (95 % CI 8.0-12.9). Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and the prognostic nutrition index, were also representative. Importantly, we found that erythema reaction after vaccination was an independent and treatment-related prognostic factor for better survival and that OK-432 might be a good adjuvant enhancing the antitumor immunity during DC vaccination. CONCLUSIONS: This is the first report of a multicenter clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy. These findings need to be addressed in well-controlled prospective randomized trials.