Diagnostic utility and prognostic significance of the Ki-67 labeling index in diffuse large B-cell lymphoma transformed from follicular lymphoma: a study of 76 patients.

The diagnosis of histological transformation of follicular lymphoma can be challenging and ambiguous. We investigated the distribution of the Ki-67 labeling index of histological transformation of follicular lymphoma and determined its cutoff value to predict poor outcomes. The diagnostic criteria for histological transformation were a diffuse pattern of proliferation and a proportion of large lymphoma cells ≥20%. Of the 1121 patients with follicular lymphoma, 171 (15%) showed histological transformation to diffuse large B-cell lymphoma. Of these, 76 patients, whose biopsies were obtained from the sites with the highest maximum standardized uptake values, according to the positron emission tomography findings, were included. The Ki-67 index ranged from 16.8% to 98.4% (median, 60.6%). In patients with histological transformation, the most significant differences were found in progression-free survival (p = 0.087, 58% vs. 87% at 2 years) and overall survival (p = 0.024, 53% vs. 85% at 5 years) when a 70% cutoff was used. Additionally, overall survival was significantly shorter in patients with histological transformation with maximum standardized uptake values of ≥20 (p < 0.0001) and absence of a follicular lymphoma component (p = 0.004). A Ki-67 index of ≥70% was a significant adverse factor for overall survival in patients with histological transformation of follicular lymphoma and may predict poor outcomes.

[Successful treatment with preceding low-intensity chemotherapy in a primary mediastinal large B cell lymphoma patient diagnosed at 11 weeks of pregnancy].

At 11 weeks of pregnancy, a 31-year-old woman presented with an anterior chest tumor and dyspnea. A computed tomography (CT) scan revealed a bulky tumor in the mediastinum that compressed the trachea. She underwent a CT-guided needle biopsy and was diagnosed with primary mediastinal large B cell lymphoma. She was initially treated with steroid pulse therapy, followed by vincristine-cyclophosphamide-prednisolone (VCP) therapy, which relieved her dyspnea. She was then treated with 8 cycles of rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) therapy at 13 weeks of pregnancy. The patient delivered her baby at 35 weeks and 6 days of pregnancy. Despite the preterm delivery and other than the low-birth weight, her baby was healthy. A positron emission tomography-CT scan showed that a complete metabolic response was achieved. Our case report suggests that steroid pulse and VCP therapy followed by R-CHOP therapy is safe and effective for patients with malignant lymphoma in their first trimester of pregnancy.

[All-trans retinoic acid/arsenic trioxide combination therapy for a patient with acute promyelocytic leukemia on dialysis].

We report a 55-year-old man who began undergoing hemodialysis for polycystic kidney disease 17 years ago. Because pancytopenia and susceptibility to infection were identified, a bone marrow biopsy was performed, resulting in a diagnosis of acute promyelocytic leukemia (APL). All-trans retinoic acid (ATRA) treatment was initiated, but promyelocytic leukemia/retinoic acid receptor alpha gene fusion without remission was identified by fluorescence in situ hybridization. We administered ATRA/arsenic trioxide (ATO) combination therapy for therapy-resistant APL and confirmed molecular genetic remission. The ATRA/ATO combination therapy was continued, obtaining complete remission 2 years after commencement of treatment. Cystic infections continued during ATRA/ATO combination therapy, similar to infections before APL morbidity, and there were no adverse events leading to treatment discontinuation. ATRA/ATO combination therapy is considered a safe and effective treatment for therapy-resistant APL patients on hemodialysis.

[Outcomes of primary central nervous system lymphoma patients treated with high-dose methotrexate and rituximab].

Primary central nervous system lymphoma (PCNSL) is a rare, aggressive type of non-Hodgkin lymphoma with a poor prognosis and no defined optimal therapeutic strategies. We retrospectively analyzed the survival of six PCNSL patients who were treated with high-dose methotrexate (HDMTX) -based chemotherapy combined with rituximab. The median age at diagnosis was 71 (range, 54-75) years, and the ECOG performance status was ≥3 in four patients. The histopathological findings revealed that all patients had diffuse large B-cell lymphoma. Objective response was obtained in all patients (five, complete response; one, partial response). Three patients had severe non-hematological toxicities: one had pulmonary thromboembolism, one had sepsis, and one developed acute epididymitis. However, each patient recovered and their symptoms could be managed. The median follow-up was 28.8 (range, 13.4-65.5) months. Five patients were still alive and disease-free, and one patient relapsed 62.2 months after the diagnosis. Therefore, the addition of rituximab to HDMTX may improve outcomes. Further clinical investigation is necessary to establish standardized initial therapies for PCNSL, particularly in elderly patients.

Romidepsin-induced durable remission for relapsed nodal peripheral T-cell lymphoma with T follicular helper phenotype after allogeneic hematopoietic cell transplantation.

Patients with recurrent peripheral T-cell lymphoma (PTCL) after allogeneic hematopoietic cell transplantation (HCT) have dismal outcomes. Nodal PTCL with the T follicular helper phenotype (PTCL-TFH) is uniquely sensitive to histone deacetylase inhibitors compared to non-TFH phenotypes. We report the case of a 19-year-old man who experienced recurrence of PTCL-TFH shortly after allogeneic HCT and subsequently achieved durable remission with romidepsin. Before HCT, the patient had refractory disease after CHOP and ESHAP chemotherapies but achieved a partial response after two cycles of romidepsin as salvage treatment. HLA-haploidentical peripheral blood stem cell transplantation was performed using conditioning with fludarabine 180 mg/sqm, melphalan 80 mg/sqm, and total body irradiation 2 Gy, and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide. One month after HCT, disease progression was observed in the lung. Romidepsin was readministered every 2 weeks at a reduced dose of 12 mg/sqm. After two cycles of romidepsin, the patient achieved a complete metabolic response without severe GVHD or other non-hematological toxicities. Romidepsin was discontinued after seven treatment cycles due to prolonged lymphopenia. The patient remains in complete remission 30 months after the last dose of romidepsin. Our experience suggests that romidepsin could be safely administered soon after allogeneic transplantation.

The outcome of watchful waiting in patients with previously treated follicular lymphoma.

Watchful waiting (WW) is one of the standard approaches for newly diagnosed follicular lymphoma (FL) patients with low-tumor burden. However, the impact of WW in FL patients at the first progression, remains unclear. We reviewed 206 FL patients who experienced the first progression after responding to the initial treatment at our institution between 1998 and 2017. Patients were classified into either the WW cohort (132 patients) or the immediate treatment cohort (74 patients). Overall, the median follow-up from the first progression was 79.8 months (range, 2.1-227.0 months). In the WW cohort, the estimated median time to next treatment (TNT) was 19.7 months (95% confidence interval [CI], 13.4-30.2), and 76.5% (95% CI, 68.0-84.1) of the patients subsequently underwent the second-line treatment at 5 years. There was a significant difference in the median time to treatment failure in the WW cohort (72.8 months; 95% CI, 64.6-94.0) compared to the immediate treatment cohort (23.3 months; 95% CI, 13.4-38.8) (HR, 2.13; 95% CI, 1.48-3.06), whereas overall survival and the cumulative incidence of histological transformation were not significantly different between two cohorts. In a multivariate analysis, rituximab refractory status, progression of disease within 24 months from the induction of first-line therapy, and a high Follicular Lymphoma International Prognostic Index score at diagnosis were significantly associated with shorter TNT. Interestingly, 15 patients (11%) of the WW cohort experienced spontaneous tumor regression during WW, and their TNT (median, 82.1 months, 95% CI, 11.7-NA) was longer than that of the remaining patients in the WW cohort (median, 16.5 months, 95% CI, 13.0-25.4), with a significant difference (p = 0.01). The results of the present study suggested that WW could be a safe and reasonable option even at the first progression for the selected FL patients, without a negative impact on clinical outcomes.

Safety considerations with targeted therapy drugs for B-cell non-Hodgkin lymphoma.

INTRODUCTION: B-cell non-Hodgkin lymphomas (B-NHLs) are the most frequent hematologic malignant cancers. Molecular targeted therapy is an important aspect of B-NHL treatment alongside cytotoxic chemotherapy, radiotherapy, and immunotherapy. AREAS COVERED: Molecular targeted therapies have changed the landscape of treatment strategies for B-NHLs since the approval of rituximab, an anti-CD20 monoclonal antibody, by the US Food and Drug Administration in 1997. Currently, several targeted therapies have been approved or are in the later-phase of clinical trials including naked antibodies, antibody-drug conjugates, and small molecules, such as Bruton's tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3 K) inhibitors, enhancer of zeste homolog 2 (EZH2) inhibitors, and B-cell lymphoma 2 (Bcl-2) inhibitors. These drugs have various toxicities because of their unique mechanisms of action. In this review, the available toxicity data of the targeted therapies for B-NHLs have been summarized. EXPERT OPINION: Recent clinical developments of targeted therapies for B-NHLs have provided several useful effective therapeutic options for patients. However, there are unique toxicities that need to be resolved. It is necessary to find out the toxicity mechanism; optimal treatment strategy for these toxicities; and novel targeted therapies that might potentially overcome the toxicities of previously approved targeted therapies.

Non-diffuse large B-cell lymphoma transformation from follicular lymphoma: a single-institution study of 19 cases.

Diffuse large B-cell lymphoma (DLBCL) is the most common histological transformation (HT) of follicular lymphoma (FL). Other types of HT are very rare, and their incidence, histopathology, and patient outcomes have not been sufficiently described. Here, we assessed the clinicopathological characteristics of 19 cases of non-DLBCL HT of FL in a single institution in Japan to advance the understanding of the disease. Among 889 consecutive patients diagnosed with FL between 2000 and 2018, 191 suffered HT (21%). The median follow-up period was 94 months (range = 3-225). A total of 172 patients (90%) had DLBCL transformation, whereas the remaining 19 patients (10%) exhibited non-DLBCL transformation. In the latter cases, the following diagnoses were made based on morphology, immunohistochemistry, flow cytometry, and fluorescence in situ hybridization analyses: classic Hodgkin lymphoma (7 patients; 4%); high-grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements (4 patients; 2%); HGBL, not otherwise specified (4 patients; 2%); B-cell lymphoblastic leukemia/lymphoma (2 patients; 1%); anaplastic large-cell lymphoma-like lymphoma (1 patient; 0.5%); and plasmablastic lymphoma (1 patient; 0.5%). Epstein-Barr virus-encoded RNA-1 did not associate with HT in any of the cases tested (n = 8). Patients with non-DLBCL transformation showed poor outcomes, with a median overall survival of 13 months (range = 2 days-107 months); 10 of the patients (53%) died of HT. In conclusions, non-DLBCL transformation was observed in 10% of patients with HT from FL. Our data show that timely, accurate, and comprehensive histopathological diagnosis is needed to ensure optimal treatment and improve the outcome of these patients.

COVID-19 pneumonia in a patient with adult T-cell leukemia-lymphoma.

Although some patients with COVID-19 develop only mild symptoms, fatal complications have been observed among those with comorbidities. As patients with cancer are immunocompromised, they are thought to have a high risk of severe illness associated with COVID-19. We report a COVID-19 patient with adult T-cell leukemia-lymphoma (ATL) who was treated using favipiravir. A 69-year-old woman with lymphoma-type ATL was treated using cyclophosphamide, doxorubicin, vincristine, prednisolone and mogamulizumab (M-CHOP) with substantial efficacy. However, in cycle 4 of M-CHOP therapy, she developed fever with mild cough. The patient was admitted to the hospital and CT revealed bilateral ground-glass opacities. SARS-CoV-2 was detected by RT-PCR and the patient was diagnosed with COVID-19. Considering severe immunosuppression caused by ATL, we initiated favipiravir therapy. Subsequently, the fever improved without antipyretics and her C-reactive protein level decreased rapidly. SARS-CoV-2 PCR tests were negative on days 17 and 18 of favipiravir therapy, and the patient was discharged without residual disease on the final CT. This is the first documented case of COVID-19 in a patient with ATL. Although severe immunosuppression caused by ATL was present, severe COVID-19 pneumonia did not develop. The immunosuppressed condition caused by hematological malignancy may not always be a risk factor for severe illness associated with COVID-19. Further accumulation of data regarding COVID-19 in patients with hematological malignancies is warranted to clarify the risk factors for severe illness, the best-in-class antiviral agent, and the optimal treatment strategy in this population.