Clinical Significance of Cytomegalovirus Reactivation in Patients With Plasma Cell Dyscrasia Who Were Treated With Anti-CD38 Monoclonal Antibody: A Retrospective Analysis in a Single Institution.

INTRODUCTION: Anti-CD38 monoclonal antibodies (mAbs) have improved the prognosis of patients with plasma cell dyscrasia (PCD), but are also associated with increased infectious adverse events. Cytomegalovirus (CMV) is a common latent pathogen that is reactivated in immunocompromised individuals. Although CMV reactivation has mostly been reported after high-dose chemotherapy followed by stem cell transplantation in patients with PCD, cases of reactivation during anti-CD38 mAb therapy have been reported recently. Due to limited studies, we aimed to determine the frequency and impact of CMV reactivation during anti-CD38 mAb therapy. PATIENTS AND METHODS: This retrospective analysis included 154 consecutive patients with PCD who were treated with anti-CD38 mAbs at a single institution. RESULTS: Seventy-six patients were evaluated for CMV reactivation by CMV pp65 antigen testing, and 29 (38%) patients, including nine with newly diagnosed PCD, showed positive results. Patients who tested positive for the CMV pp65 antigen had substantially lower serum albumin levels than those who tested negative. However, the two groups showed no marked difference in the concurrent anti-PCD medications or baseline absolute lymphocyte count. Although most patients showing positive results in the CMV pp65 antigen test had mild or no symptoms, with fever being the most common symptom, some patients developed CMV end-organ disease. In addition, CMV reactivation interfered with the course of anti-PCD treatment in most patients, necessitating dose reductions, delays, and discontinuation of chemotherapy. CONCLUSION: This study provides an overview of the clinical impact of CMV reactivation in patients with PCD treated with anti-CD38 mAb-containing regimens.

Nomogram for predicting survival of patients with diffuse large B-cell lymphoma.

The international prognostic index (IPI) system has been widely used to predict prognosis in diffuse large B-cell lymphoma (DLBCL). However, this system categorizes DLBCL patients into four risk groups, and cannot optimize individualized prognosis. In addition, other clinicopathological factors, such as molecular aberrations, are not incorporated into the system. To partly overcome these weak points, we developed nomograms to predict individual patient survival. We also incorporated MYD88L265P and CD79BY196 mutations into the nomograms since these mutations are associated with a worse prognosis and their signaling pathways have been highlighted as a therapeutic target. We analyzed 302 DLBCL cases for which multivariate analysis by Cox proportional hazard regression was performed. Nomograms for progression-free survival (PFS) and overall survival (OS) were constructed and assessed by a concordance index (C-index). The nomograms were also evaluated using an open external dataset (n = 187). The MYD88L265P and/or CD79BY196 (MYD88/CD79B) mutation was detected in 62/302 patients. The nomograms incorporating IPI factors exhibited a C-index of 0.738 for PFS and a C-index of 0.765 for OS. The nomograms incorporating IPI factors and the MYD88/CD79B mutation showed a C-index of 0.745 for PFS and a C-index of 0.769 for OS. The nomograms we created were evaluated using an external dataset and were well validated. The present nomograms incorporating IPI factors and the MYD88/CD79B mutation have sufficient discrimination ability, and may effectively predict prognosis in DLBCL patients. The prognostic models we have presented here may help clinicians personalize prognostic assessments and clinical decisions.

Low-dose fluconazole as a useful and safe prophylactic option in patients receiving allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Invasive fungal infections (IFIs) represent a potentially fatal complication in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) if the initiation of therapy is delayed. Some guidelines recommend antifungal prophylaxis or preemptive therapy for these patients depending on the risk of IFIs following allogeneic HSCT. This retrospective study aimed to identify the group of patients who safely undergo allogeneic HSCT with low-dose fluconazole (FLCZ) prophylaxis (100 mg/day). METHODS: We retrospectively reviewed 107 patients who underwent their first allogeneic HSCT at Nagoya City University Hospital from January 1, 2010, to December 31, 2019. We analyzed the efficacy of low-dose FLCZ prophylaxis and investigated the relationship between major risk factors and antifungal prophylaxis failure (APF) within 100 days post-transplant. RESULTS: Of the 107 patients, 70 received low-dose FLCZ prophylaxis, showing a cumulative incidence of APF of 37.1% and a proven/probable IFI rate of 4.3%. There were no fungal infection-related deaths, including Aspergillus infections, in the FLCZ prophylaxis group. In a multivariable analysis, cord blood transplantation (CBT) (subdistribution hazard ratio (SHR), 3.55; 95% confidence interval (CI), 1.44-8.77; p = 0.006) and abnormal findings on lung CT before transplantation (SHR, 2.24; 95% CI, 1.02-4.92; p = 0.044) were independent risk factors for APF in the FLCZ prophylaxis group. CONCLUSION: Low-dose FLCZ prophylaxis is a useful and safe option for patients receiving allogeneic HSCT, except in those undergoing CBT or having any fungal risk features including history of fungal infections, positive fungal markers, and abnormal findings on lung CT before transplantation.

Laryngeal edema as a symptom of local cytokine release syndrome after BCMA-targeting CAR-T therapy for relapsed and refractory multiple myeloma.

Cytokine release syndrome (CRS) can be a major side effect of chimeric antigen receptor T-cell (CAR-T) therapy, and may occasionally become life-threatening in patients with factors such as high tumor burden or poor performance status. Among the many CRS events observed in B-cell maturation antigen (BCMA)-targeting CAR-T therapy, local symptoms (also called local CRS) are poorly understood due to their low frequency. Here, we present the case of a 54-year-old woman with refractory multiple myeloma exhibiting laryngeal edema as a local CRS. Before CAR-T therapy, she was diagnosed with progressive disease indicated by a left thyroid mass. After local irradiation, she received the BCMA-targeting CAR-T agent idecabtagene vicleucel (ide-cel). On day 2, the patient developed CRS, which resolved on treatment with tocilizumab. However, on day 4, laryngeal edema worsened, and was judged to be a local CRS. Intravenous dexamethasone rapidly reduced this edema. In conclusion, laryngeal edema rarely occurs as a local CRS, and to the best of our knowledge, has never been reported after ide-cel infusion. Dexamethasone was effective for reducing the local reaction that persisted after treatment of systemic symptoms with tocilizumab.

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

BACKGROUND: The recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). METHODS: We retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL). RESULTS: Although active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3. CONCLUSIONS: This study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response.

Case report: Genomic analysis of a therapy-related chronic myelomonocytic leukemia with KMT2A rearrangement that progressed to acute myeloid leukemia with acute promyelocytic leukemia-like features.

We report a 69-year-old female who was a human T-cell leukemia virus type 1 carrier and exhibited a unique clinical course of developing three hematological malignancies within a short period: diffuse large B-cell lymphoma (DLBCL), chronic myelomonocytic leukemia (CMMoL), and acute myeloid leukemia (AML). Although the blast cells in AML showed typical morphological and immunophenotypical features of acute promyelocytic leukemia (APL), it did not harbor RARα gene fusion and thus initially diagnosed as APL-like leukemia (APLL). The patient developed heart failure with a fulminant clinical course and died soon after the diagnosis of APLL. Retrospective analysis with whole-genome sequencing detected a chromosomal rearrangement between KMT2A and ACTN4 gene loci both in CMMoL and APLL samples, but not in the DLBCL sample. Therefore, CMMoL and APLL were considered to be derived from the same clone with KMT2A translocation associated with prior immunochemotherapy. However, KMT2A rearrangement is rarely found in CMMoL in general and ACTN4 is also a rare partner of KMT2A translocation. Thus, this case did not follow typical transformational process of CMMoL or KMT2A-rearranged leukemia. Importantly, additional genetic alterations, including NRAS G12 mutation, were found in APLL, but not in CMMoL samples, suggesting that they might contribute to leukemic transformation. This report highlights the diverse effects of KMT2A translocation and NRAS mutation on the transformation of hematological cells as well as the importance of upfront sequencing analysis to detect genetic backgrounds for a better understanding of therapy-related leukemia.

Two cases of transplant-acquired food allergy who developed resensitization after a negative oral food challenge.

BACKGROUND: Cases of food allergy after hematopoietic stem cell and solid organ transplantation in previously nonallergic transplant recipients were reported as transplant-acquired food allergy (TAFA), but information about its long-term outcome is still limited. A phenomenon where patients reacquire food allergy by resuming daily consumption after a negative oral food challenge has not yet been reported. CASE PRESENTATION: We report two cases of TAFA after liver transplantation and cord blood transplantation. In each case, the threshold of daily consumption to cause allergic symptoms decreased when a negative oral food challenge was obtained. CONCLUSIONS: Our cases show an importance of gastrointestinal tract as a route of food sensitization because thresholds that caused allergic reactions decreased during their resuming process. We need to be careful with possible resensitization once a negative substantial dose was confirmed.

A comprehensive evaluation of humoral immune response to second and third SARS-CoV-2 mRNA vaccination in patients with malignant lymphoma.

More information is needed regarding the efficacy of SARS-CoV-2 mRNA vaccines in immunocompromised populations, including patients with malignant lymphoma. This study aimed to evaluate humoral responses to the second and third mRNA vaccine doses in 165 lymphoma patients by retrospective analysis of serum SARS-CoV-2 spike protein antibody (S-IgG) titers. Patients with S-IgG titers ≥ 300, 10-300, and ≤ 10 binding antibody units (BAU)/mL were defined as adequate responders, low responders, and non-responders, respectively. S-IgG titers > 10 BAU/mL were considered to indicate seroconversion. After the second dose, 56%, 16%, and 28% of patients were adequate responders, low responders and non-responders, respectively. Multivariate analysis revealed that being an adequate responder after the second dose was associated with receiving the vaccine > 12 months after last chemotherapy, total peripheral lymphocyte count of ≥ 1000/µL, estimated glomerular filtration rate of ≥ 50 mL/min/1.73 m2, and vaccine type (mRNA-1273). After the third dose, patients had significantly higher S-IgG titers and a greater proportion achieved seroconversion. With this third dose, 26% of second-dose non-responders achieved seroconversion and 68% of second-dose low responders became adequate responders. Subsequent SARS-CoV-2 mRNA vaccinations may elicit an immune response in immunocompromised patients who do not initially respond to vaccination.

Aberrant tryptophan metabolism leads to unfavorable outcomes in lenalidomide-treated myeloma patients.

Indoleamine 2,3-dioxygenase 1 (IDO), an enzyme that metabolizes tryptophan (Trp) to kynurenine (Kyn), is an important microenvironmental factor suppressing antitumor immunity. Here, we investigated the clinical impact of aberrant Trp metabolism in patients with multiple myeloma (MM) treated with lenalidomide (Len) and evaluated its effects on T cell immunity ex vivo. Kyn and Trp concentrations were quantified in sera from 72 patients with relapsed or refractory MM prior to the initiation of therapy with Len plus dexamethasone (Ld). Associations of the Kyn/Trp ratio with progression-free survival (PFS) and overall survival (OS) were analyzed. The expressions of IDO in tumor and stromal cells were evaluated during co-culture, and the effects of culture medium containing low Trp and high Kyn concentrations on T cells in the presence of Len were investigated. Patients with high serum Kyn/Trp ratios (≥46.0, n = 22) had significantly shorter PFS and OS than those with low ratios (4.9 vs. 12.6 months, and 15.5 vs. 45.7 months, respectively). MM cells promoted IDO expression in stromal cells during co-culture in both a direct contact and an indirect manner. Incubation in medium with a high Kyn/Trp ratio significantly inhibited T cell cytokine production and upregulated the expression of inhibitory immune receptors. These effects were sustained even in the presence of Len. In conclusion, a high serum Kyn/Trp ratio is associated with poor prognosis in patients with MM. We propose that aberrant Trp metabolism reduces anti-tumor immunity and the efficacy of Len therapy.

Recent advances in the management of older adults with newly diagnosed multiple myeloma in Japan.

Multiple myeloma is a cancer of plasma cells; the incidence rate of multiple myeloma is high among older adults. Although significant advances have been made in the clinical management of multiple myeloma driven by the introduction of novel drugs, such as proteasome inhibitors, immuno- modulators and antibodies, multiple myeloma remains incurable. Hence, the current therapeutic goal for multiple myeloma is to achieve long-term survival while maintaining a good quality of life. In this context, personalized treatment to balance the efficacy and safety of therapies is important, especially for older adults as they display diverse physical, cognitive or organ functioning. Furthermore, old age is also often associated with frailty. Several tools for evaluating frailty in older adults with multiple myeloma are now available, and frail patients defined by these tools have shown a poor prognosis and more treatment-related toxicities. In addition, it is important to evaluate other factors, such as the International Staging System, high-risk chromosomal abnormalities and treatment response, to predict the clinical course of patients. Further investigations are required to determine how these factors can optimize the treatment for multiple myeloma. In this review, we present a detailed account on the developments and issues related to the current treatment approaches for older adults with newly diagnosed multiple myeloma. We also discuss the ongoing phase III clinical study conducted by the lymphoma study group of the Japan Clinical Oncology Group, which targeted older adults with newly diagnosed multiple myeloma.

Acute Promyelocytic Leukemia in a Patient With Chronic Continuous Type of Crohn's Disease.

Chronic inflammation can induce leukemogenic mutations in hematopoietic stem cells (HSCs). We report a case of acute promyelocytic leukemia (APL) in a patient with chronic continuous type of Crohn's disease. The patient had been diagnosed with Crohn's disease at the age of 28 years and had received conventional treatments with biologics, but not azathioprine. At the age of 51, he was diagnosed with APL with ider(17). Long-term exposure to chronic continuous inflammation from Crohn's disease might be a factor inducing genomic instability in HSCs, which lead to the subsequent development of APL. APL is a rare hematological manifestation that required attention in Crohn's disease patients.

Clinicopathological analysis of primary refractory diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone chemoimmunotherapy.

BACKGROUND: Approximately 15% of patients with diffuse large B-cell lymphoma (DLBCL) experience refractory or early relapsed disease after initial rituximab-containing chemoimmunotherapy is regarded as a primary refractory disease. Although the standard treatment for relapsed DLBCL is high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT), the efficacy of this approach for primary refractory DLBCL is not well understood. We aimed to investigate the clinicopathological characteristics and outcomes of patients with primary refractory DLBCL. METHODS: Sixty-nine consecutive patients with primary refractory DLBCL who were treated at our institution were categorized as partial responders (partial response to rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone [R-CHOP] or relapse within 6 months of R-CHOP) (n = 41) or primary progressors (no response to R-CHOP) (n = 28). Survival curves were constructed using the Kaplan-Meier method and compared using the log-rank test. RESULTS: At initial diagnosis, 70% of patients had Ann Arbor stage III/IV disease, 56% had non-germinal center B-cell-like type DLBCL, and 42% had double-expressor lymphoma (MYC and BCL2 expression). The 3-year overall survival rate was significantly poorer in the primary progressors group than in the partial responders' group (15% vs. 48%, p < 0.001). Four of 17 patients treated with HDC-ASCT were primary progressors; only one patient survived without relapse. Although double-expressor lymphoma status did not significantly impact overall survival among all patients (p = 0.794), it was identified as an independent poor prognostic factor in HDC-ASCT-treated patients (p = 0.002). CONCLUSIONS: We identified a subgroup of patients with primary refractory DLBCL who may not benefit from current treatment strategies. Further treatment development is needed to improve the outcomes of these patients.

Clinicopathological factors and tumor microenvironment markers predicting watch-and-wait discontinuation in 82 patients with follicular lymphoma.

OBJECTIVES: In this study, we aimed to determine the clinicopathological factors influencing the treatment-free period in patients with follicular lymphoma (FL) using a watch-and-wait (WW) strategy. METHODS: We retrospectively assessed histopathological parameters of 82 patients with FL. RESULTS: The median time from diagnosis to WW discontinuation was 62 months (range, 3-138), and median follow-up was 86 months (range, 3-183). Intermediate or high-risk Follicular Lymphoma International Prognostic Index score (P = .012), non-duodenal-type (P = .011), higher numbers of interfollicular CD4+ (P = .038) and intrafollicular FOXP3+ cells (P = .024) in the tumor microenvironment, and Ki-67 index ≥10% (P = .031) were significant adverse factors for WW discontinuation in univariate analyses. CONCLUSION: Patients with adverse factors for WW discontinuation should be carefully observed during follow-up.

Volunteer unrelated donor cell-derived acute myeloid leukemia with RUNX1-RUNX1T1.

A 15-year-old male was diagnosed with acute myeloid leukemia with t(6;9)(p23;q34), a chimeric DEK-NUP214 fusion gene. He underwent allogeneic bone marrow transplantation (allo-BMT) from an unrelated volunteer donor at first molecular remission. Approximately 5 years after allo-BMT, multiple bone marrow aspirations showed increased blasts to 63%, which were positive for myeloperoxidase, CD13, CD33, CD56, and CD34. Surprisingly, t(8;21)(q22;q22.1), a chimeric RUNX1-RUNX1T1 (not DEK-NUP214) fusion gene, was detected with full donor chimerism. To our best knowledge, this is the first case of a volunteer unrelated donor cell-derived acute myeloid leukemia harboring a chimeric RUNX1-RUNX1T1 fusion gene.

The role of local radiotherapy following rituximab-containing chemotherapy in patients with transformed indolent B-cell lymphoma.

OBJECTIVES: This study aimed to evaluate the outcomes of local radiotherapy (LRT) in patients with histologic transformation (HT) following rituximab-containing chemotherapy. METHODS: We retrospectively analysed 92 patients with biopsy-confirmed HT undergoing rituximab-containing chemotherapy at our institution between 2003 and 2015. RESULTS: Of the 36 patients with limited-stage disease at diagnosis of HT, 29 (78%) received LRT. The estimated 5-year progression-free survival (PFS) rate was significantly better in patients who underwent LRT than in those who did not (93% and 42%, respectively; P < 0.05). Multivariate analyses employing age, sex, performance status, LRT and treatment response demonstrated that LRT was an independent prognostic factor for PFS (hazard ratio [HR]: 11.8; 95% confidence interval [CI]: 1.28-108.1; P < 0.05). Of the 32 patients who underwent LRT for HT lesion treatment, 31 (97%) did not show disease progression within radiation fields; among them, 27 patients (84%) survived without disease progression during the follow-up period. One patient developed hypothyroidism due to LRT; the others had no acute or late-onset complications of LRT. CONCLUSIONS: Our data support the recommendation of LRT for HT lesion treatment following rituximab-containing chemotherapy in select patients with localised HT, as a rational treatment approach with potentially limited toxicity.

[Treatment strategy for untreated transplantation-ineligible multiple myeloma patients].

Novel drugs, such as proteasome inhibitors, immunomodulators, and antibody drugs, have been consistently developed, and several standard treatment regimens were approved for elderly patients with multiple myeloma who are ineligible for autologous transplantation. Meanwhile, the clinical characteristics of elderly patients are more diverse than those of younger patients in terms of various factors, such as cognitive, mental, or social functions as well as physical or organ functions. Therefore, it is difficult to implement a standard treatment regimen to all elderly patients with a one-size-fits-all approach. Furthermore, it is important to evaluate the diversity of elderly patients as objectively as possible by evaluating organ functions and frailty in accordance with geriatric assessment, which helps determine the treatment plan. In addition, it is also ideal to select the treatment after considering the factors associated with tumors, such as the presence or absence of unfavorable chromosomal abnormalities.

Transformation Scoring System (TSS): A new assessment index for clinical transformation of follicular lymphoma.

Although histologic analysis is the gold standard for diagnosing follicular lymphoma (FL) transformation, many patients are diagnosed with transformation by clinical factors as biopsy specimens often cannot be obtained. Despite the frequency of clinical diagnosis, no clinical assessment tool has yet been established for FL transformation in the rituximab era. We derived and validated a transformation scoring system (TSS) based on retrospective analyses of 126 patients with biopsy-proven FL and histologic transformation (HT) at two hospitals of the National Cancer Center of Japan. In the derivation set (76 patients), the detailed analyses of the clinical characteristics at disease progression showed that lactate dehydrogenase (LDH) elevation, focal lymph nodal (LN) enlargement, hemoglobin <12 g/dl, and poor performance status (PS) (2-4) were associated with HT. The weights of these variables were decided based on the regression coefficients. Next, we constructed a TSS encompassing the above four factors: LDH, (> upper limit of normal [ULN], ≤ULN ×2) (1 point), (≥ULN ×2) (2 points); focal LN enlargement, (≥3 cm, <7 cm) (1 point), (≥7 cm) (2 points); hemoglobin <12 g/dl (1 point); poor PS (2 points). We identified a high positive predictive value (PPV) (96.4%) and negative predictive value (NPV) (85.4%) for diagnosing HT when a cutoff score of 2 was selected for our TSS. In an external validation set (50 patients), the probability of HT was high with scores ≥2 (PPV, 93.3%; NPV, 82.9%). We developed a TSS that offers a simple, yet, valuable tool, for diagnosing HT, especially in patients who cannot undergo biopsy.

Hepatitis B virus reactivation in a myeloma patient with resolved infection who received daratumumab-containing salvage chemotherapy.

A 72-year-old female complaining of back pain was diagnosed with IgG-κ multiple myeloma. After osteosynthesis for fracture of the left femoral shaft due to myeloma, she received bortezomib, melphalan, and prednisolone as an initial regimen for multiple myeloma, but discontinued it after three courses due to progressive disease. The patient subsequently received lenalidomide and dexamethasone as a second-line regimen for 2.5 years, and pomalidomide and dexamethasone as a third-line regimen for only 2 months. An anti-CD38 monoclonal antibody, daratumumab (DARA), and bortezomib and dexamethasone (DVd) as a fourth-line regimen were administered for refractory myeloma. However, hepatitis B virus (HBV) reactivation occurred on day 15 of the third course of DVd. The HBV DNA level in peripheral blood suddenly increased to 2.2 log IU/mL. An anti-HBV nucleotide analog, entecavir, was subsequently administered when the HBV DNA level increased to 2.6 log IU/mL. No HBV-related hepatitis was observed during follow-up. DARA can improve the prognosis of patients with multiple myeloma, but also potentially increase the risk of HBV reactivation. Host and viral risk factors need to be identified in such patients in order to implement a more cost-effective strategy against HBV reactivation.