Systemic inflammatory autoimmune disease before allogeneic hematopoietic stem cell transplantation is a risk factor for death in patients with myelodysplastic syndrome or chronic myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34-8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT.

Impacts of Posttransplant Cyclophosphamide Dose on Graft-versus-leukemia Effects via HLA-B Leader in HLA-haploidentical Peripheral Blood Stem Cell Transplantation.

INTRODUCTION: The graft-versus-leukemia effect of HLA-B leader dimorphism, i.e. methionine (M) or threonine (T) at position -21 of the leader sequence, has been observed in HLA-haploidentical hematopoietic cell transplantation with posttransplant cyclophosphamide (PTCy-haplo). However, the biological mechanism has been unclear, and the contributions of HLA-B leader genotype to risk reduction of relapse might be dependent on posttransplant cyclophosphamide (PTCy) doses. METHODS: To investigate whether the effect of HLA-B leader dimorphism was modified by the PTCy dose, we retrospectively analyzed 99 patients who received PTCy-haplo. RESULTS: In the low-dose PTCy group, the patient M+ HLA-B leader genotype did not significantly affect the cumulative incidence of relapse (CIR) but negatively impacted the overall survival (OS) compared to the M- genotype. In contrast, in the high-dose PTCy group, patients with the M+ genotype had a decreased CIR, but no significant difference in the OS was observed between patients with the M+ and M- genotypes. Regardless of PTCy doses, the patient M+ genotype had detrimental effects on nonrelapse mortality. CONCLUSION: Our findings suggest that the effect of the patient HLA-B leader genotype is modified by the PTCy dose, providing immunological insight into the PTCy dosage and supporting further studies to investigate the underlying mechanisms.

Efficacy of elotuzumab for multiple myeloma deteriorates after daratumumab: a multicenter retrospective study.

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.

Autotaxin is a potential predictive marker for the development of veno-occlusive disease/sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT), and stratification of the high-risk group before transplantation is significant. Serum autotaxin (ATX) levels have been reported to increase in patients with liver fibrosis caused by metabolic inhibition from liver sinusoidal endothelial cells. Considering that the pathophysiology of VOD/SOS begins with liver sinusoidal endothelial cell injury, an increase in serum ATX levels may precede the onset of VOD/SOS. A retrospective study with 252 patients, including 12 patients with VOD/SOS, who had received allo-HCT was performed. The cumulative incidence of VOD/SOS was higher in the group with serum ATX levels before conditioning (baseline ATX) above the upper reference limit (high ATX group, p < 0.001), and 1-year cumulative incidences were 22.7% (95% confidence interval [95%CI], 3.1-42.4%) and 3.5% (95%CI, 1.1-5.8%), respectively. In the multivariate analysis, elevated baseline ATX was identified as an independent risk factor for VOD/SOS development and showed an additive effect on the predictive ability of known risk factors. Furthermore, the incidence of VOD/SOS-related mortality was greater in the high ATX group (16.7% vs. 1.3%; p = 0.005). Serum ATX is a potential predictive marker for the development of VOD/SOS.

Lymphoproliferative disorder progressing after partial remission following immunosuppressive drugs withdrawal in a patient with rheumatoid arthritis.

Lymphoproliferative disorders (LPDs) are serious complications that arise in patients with rheumatoid arthritis (RA) receiving immunosuppressive drugs (ISDs). Here, we report a 73-year-old woman was diagnosed with RA at 60 years of age and treated with methotrexate, bucillamine, prednisolone, and infliximab. She was referred to our hospital with general malaise, pancytopenia, a right adrenal mass, and enlarged periaortic lymph nodes. Epstein-Barr virus (EBV) was detected in serum. We suspected LPD development and performed a bone marrow biopsy, on which no malignant cells could be detected. Upon ISDs withdrawal, her symptoms and blood counts improved, and the right adrenal mass and enlarged lymph nodes regressed. The patient was followed up for clinical LPD. However, 7 months after the initial visit to our hospital, she developed fever and pancytopenia. A repeat bone marrow biopsy confirmed the diagnosis of EBV-positive diffuse large B-cell lymphoma complicated by haemophagocytic syndrome (HPS). After pulse steroid therapy, the patient received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy, which resulted in a complete response. In conclusion, when LPDs develop in patients with RA during ISD treatment, LPDs can progress and complicate HPS after partial remission following ISDs withdrawal. Therefore, we should carefully follow up RA patients with LPDs, aim to achieve an early diagnosis of LPD, and promptly initiate chemotherapy.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning.

BACKGROUND: No comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. METHODS: We retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. RESULTS: The median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III-IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III-IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. CONCLUSION: MMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Pretransplant hepatomegaly is linked to relapse in patients with leukemia and myelodysplastic syndrome not in remission.

Hepatomegaly is an extramedullary disease (EMD) manifestation of hematological malignancy. Although EMD before allogeneic hematopoietic stem cell transplantation (allo-HCT) is a risk factor for relapse in patients not in complete remission (NonCR) patients, the significance of hepatomegaly to allo-HCT is unclear. We conducted a single-center retrospective observational study of 140 patients with acute leukemia and myelodysplastic syndrome who underwent allo-HCT at our institution from 2014 to 2019. Hepatomegaly was assessed by ultrasonography using the liver index (LI). In the univariable analysis, the LI/height ratio was significantly associated with relapse (hazard ratio [HR] per standard deviation [sd]: 1.51, 95% confidence interval [CI] 1.18-1.93, p = 0.001, sd = 13.8) in NonCR patients (n = 62), but showed no significant association in CR patients (n = 78) (HR per sd: 0.95, 95% CI 0.64-1.39, p = 0.780, sd = 8.7). In multivariable analysis, the LI/height ratio was significantly associated with relapse (HR per sd: 1.34, 95% CI 1.02-1.78, p = 0.037) after adjusting for the refined disease risk index and conditioning intensity. Interaction analysis showed a noteworthy but not statistically significant association between the LI/height ratio and CR status (p = 0.110). In conclusion, our findings suggest that the LI may be a risk factor for relapse in NonCR patients after allo-HCT.

Invasive fungal infection caused by Blastobotrys mokoenaii in an immunocompromised patient with acute myeloid leukemia: A case report.

Blastobotrys is a genus of rare yeast that is increasingly recognized as a cause of fungal infections in humans. However, there have been no reports of fungal infections in humans caused by Blastobotrys mokoenaii. We describe a case of invasive fungal infection (IFI) caused by B. mokoenaii in an immunocompromised patient with acute myeloid leukemia (AML). A 46-year-old man with relapsed/refractory AML underwent a second allogeneic peripheral blood hematopoietic stem cell transplantation (allo-PBSCT) during remission. The patient had prolonged neutropenia and received systemic steroid therapy for graft-versus-host disease before the second allo-PBSCT. Uncommon yeast was isolated from the blood cultures obtained on day 4. We initially suspected that the uncommon yeast was Trichosporon spp. based on its morphology. However, unlike Trichosporon spp., in vitro antifungal susceptibility tests showed that this yeast isolate was resistant to micafungin, caspofungin, voriconazole, itraconazole, and fluconazole. We performed DNA sequencing and identified it as B. mokoenaii. B. mokoenaii was persistently isolated from blood cultures taken during combination therapy with liposomal amphotericin B and voriconazole. The patient died of multiorgan failure on day 24. B. mokoenaii can cause severe IFI in immunocompromised patients; however, it may not be correctly identified by routine clinical microbiology testing in a hospital laboratory and DNA sequencing is useful for diagnosis.

Impact of cytogenetic abnormalities in symptomatic multiple myeloma; a Japanese real-world analysis from Kansai Myeloma Forum.

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis.

Sinusoidal obstruction syndrome associated with disseminated toxoplasmosis involving the liver after allogeneic hematopoietic stem cell transplantation: A case report.

Sinusoidal obstruction syndrome (SOS) is a fatal complication after hematopoietic stem cell transplantation (HSCT). Only a few complications after HSCT have been reported as risk factors for SOS, including sepsis. Here, we report the case of a 35-year-old male diagnosed with Philadelphia chromosome-positive acute lymphoblastic leukemia who underwent peripheral blood HSCT from a human leukocyte antigen-matched unrelated female donor in remission. Graft-versus-host disease prophylaxis contained tacrolimus, methotrexate, and low-dose anti-thymoglobulin. The patient was treated with methylprednisolone for engraftment syndrome from day 22. On day 53, he presented worsening fatigue, breathlessness, and abdominal pain in the right upper quadrant that had persisted for 4 days. Laboratory tests showed severe inflammation, liver dysfunction, and positive for Toxoplasma gondii PCR. He died on day 55. An autopsy showed SOS and disseminated toxoplasmosis. Hepatic infection with T. gondii was identified in zone 3 of the liver, which overlapped with the pathological features of SOS. In addition, the timing of the exacerbation of hepatic dysfunction coincided with the onset of systemic inflammatory symptoms and T. gondii reactivation. This rare case of toxoplasmosis is the first to suggest that hepatic infection with T. gondii is strongly associated with SOS after HSCT.

Recapitulated Late-Onset Inflammatory Toxicities and Progressive Dysautonomia with Persistence of Central Memory CD4+ Chimeric Antigen Receptor T Cells in a Case of Transformed Follicular Lymphoma: Case Report.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has been widely used and is highly effective for B-cell lymphoid malignancies. Immune-mediated adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in the acute phase and are monophasic after CAR T-cell therapy. However, late-onset inflammatory and neurological toxicities have not been well studied. We encountered a patient with recurrent late-onset inflammatory toxicities and progressive dysautonomia after CD19-directed CAR T-cell therapy. A 69-year-old man was treated with CD19-directed CAR T-cell therapy for transformed follicular lymphoma. Triphasic inflammation with stomatitis, cytopenia, and noninfectious pneumonia was first observed 7 months after CAR T-cell infusion. Progressive dysautonomia was also observed and eventually fatal. Residual CAR T cells, predominantly central memory CD4+ cells, were detectable in peripheral blood approximately 1 year after CAR T-cell infusion. The cytokine profile with the lack of tumor necrosis factor-α, interferon-γ, and interleukin-1ß elevation in the peripheral blood and cerebrospinal fluid was inconsistent with that of typical CRS or ICANS. The persistence of central memory CD4+ CAR T cells might be associated with unique manifestations of late-onset immune-mediated adverse effects. More cases should be accumulated to elucidate the mechanism and establish the optimal management strategy of late-onset immune-mediated toxicities previously unrecognized.

Fulminant Metastatic Cellulitis Caused by Stenotrophomonas Maltophilia Infection and Subsequent Candida Parapsilosis Fungemia After Cord Blood Transplantation.

Stenotrophomonas maltophilia is known to be an opportunistic pathogen with intrinsic and acquired resistance mechanisms to multiple antibiotics. Bloodstream infection caused by S. maltophilia is a potentially fatal complication, especially in recipients of umbilical cord blood transplantation (CBT). Infrequent reports of S. maltophilia skin and soft tissue infections (SSTIs), including metastatic cellulitis and ecthyma gangrenosum, have been reported as wound infections. Metastatic cellulitis lesions due to S. maltophilia are typically reported to be tender, erythematous, and to show warm subcutaneous infiltration. There are only a few available reports about the clinical course of metastatic cellulitis due to S. maltophilia. We experienced a case involving the development of metastatic cellulitis with fulminant and extensive exfoliation in a patient who underwent CBT. Despite controlling the bloodstream infection caused by S. maltophilia, the patient succumbed to secondary fungal infection due to the devastation of the skin barrier. Our case highlights that SSTIs due to S. maltophilia can cause the unexpected development of fulminant metastatic cellulitis with systemic epidermal peeling in severely immunocompromised hosts, including CBT recipients undergoing steroid therapy.

Efficacy of elotuzumab for multiple myeloma in reference to lymphocyte counts and kappa/lambda ratio or B2 microglobulin.

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower ß2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/µL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/µL and 1 point for < 1400/µL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system.

Rhinovirus/enterovirus identification by electron microscopy in lower respiratory tract infection in a patient with relapsed myelodysplastic syndrome after allogeneic hematopoietic cell transplantation and donor lymphocyte infusion.

Donor lymphocyte infusion (DLI) is a curable treatment option, inducing a graft-versus-tumor effect in patients with relapsed hematological malignancies after allogeneic hematopoietic cell transplantation (allo-HCT). However, not only graft-versus-host disease but also pulmonary complications are problematic adverse events after DLI. Although viral infections can be associated with pulmonary complications after DLI, the mechanism underlying these complications remains unclear. Detecting the causative virus infections after pulmonary complications following DLI is challenging, as invasive examinations, such as bronchoalveolar lavage and lung biopsies, are necessary. Family Picornaviridae, including Human-Rhinovirus (HRV) and Enterovirus (EnV), can induce fatal lower respiratory tract infection (LRTI) in recipients who undergo allo-HCT, which can be underdiagnosed. We encountered a 62-year-old man with relapsed myelodysplastic syndrome 20 days after a second HLA-haplo-identical allo-HCT and 4 DLI procedures who was later found to have HRV and EnV LRTI by postmortem electron microscopy. Despite high-dose immunosuppression, severe hypoxemia did not improve, and he succumbed to respiratory failure. Immunosuppressive therapy for idiopathic pneumonia syndrome after allo-HCT may be effective, but its efficacy for acute respiratory failure after DLI is controversial. Our case indicated that the control of viral replication should be prioritized over that of inflammation in HRV and EnV LRTI after DLI.

Two cases of eosinophilic gastrointestinal disorder due to newly appearing food allergies after cord blood transplantation.

Eosinophilic gastrointestinal disorders (EGIDs) are infrequent complications after allogeneic hematopoietic cell transplantation (allo-HCT). Furthermore, it is well-known that allergic diseases are transferable after allo-HCT from allergic donors to non-allergic recipients. However, the type of graft-versus host disease (GVHD) prophylaxis that leads to allergic disease transfer is unclear. Furthermore, no study has reported a case of acquired food allergy resulting in EGID that was detected based on the clinical course and the detection of antigen-specific immunoglobulin E after allo-HCT. We encountered two patients with acute leukemia accompanied by eosinophilic esophagitis (EoE) and eosinophilic gastroenteritis (EGE) due to newly appearing food allergy after cord blood transplantation (CBT) with T-cell non-depletion GVHD prophylaxis. Despite having no history of allergic disease, the patients experienced allergic symptoms due to dairy products (Case 1) and eggs (Case 2) after CBT. They subsequently experienced severe nausea, heartburn, and anorexia (Case 1) and diarrhea (Case 2). Cases 1 and 2 were diagnosed with EoE and EGE, respectively, based on endoscopic and histological examinations. Dietary treatment without steroids improved the symptoms in both cases. These cases highlight that the unexpected transfer of food allergy after CBT can lead to EGIDs, especially in patients receiving T-cell non-depletion GVHD prophylaxis.

Successful treatment of proven coronavirus disease 2019-associated pulmonary aspergillosis with liposomal amphotericin B in a patient with bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation.

Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) is being increasingly recognized as a severe complication that contributes to poor prognoses among patients with COVID-19. However, little is known regarding the clinical course of CAPA with hematological malignancies, especially after allogeneic hematopoietic stem cell transplantation (HSCT). A 29-year-old woman was diagnosed with proven CAPA with an Aspergillus fumigatus identified by cultures of bronchoalveolar lavage and lung biopsy four years after haploidentical HSCT for acute myelogenous leukemia. She had been taking oral prednisolone for bronchiolitis obliterans syndrome that developed after HSCT. Although prolonged RT-PCR positivity for SARS-CoV-2 (133 days after the onset of COVID-19) without shedding of viable virus was observed, the COVID-19 was treated with favipiravir, remdesivir, dexamethasone, and enoxaparin. However, the CAPA did not respond to combination therapy, which included triazole (voriconazole, itraconazole, posaconazole) and echinocandin (caspofungin, micafungin), even though the Aspergillus fumigatus isolate was found to be susceptible to these agents in vitro. Nevertheless, a total of 16 weeks of liposomal amphotericin B (L-AMB) therapy led to a favorable response, and the patient was discharged from the hospital on day 213. This case provided essential experience of CAPA treated with L-AMB in a recipient with chronic respiratory disease after HSCT.

Monocyte or white blood cell counts and ß2 microglobulin predict the durable efficacy of daratumumab with lenalidomide.

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower ß2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/µl; 1 point for <200/µl) or WBC counts (0 points for ⩾3500/µl; 1 point for <3500/µl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.