Characteristics and prognosis of patients with COVID-19 and hematological diseases in Japan: a cross-sectional study.

The Japanese Society of Hematology performed an observational cross-sectional study to clarify the morbidity, prognosis, and prognostic factors in patients with COVID-19 with hematological diseases (HDs) in Japan. The study included patients with HDs who enrolled in our epidemiological survey and had a COVID-19 diagnosis and a verified outcome of up to 2 months. The primary endpoints were characteristics and short-term prognosis of COVID-19 in patients with HDs. A total of 367 patients from 68 institutes were enrolled over 1 year, and the collected data were analyzed. The median follow-up among survivors was 73 days (range, 1-639 days). The 60-day overall survival (OS) rate was 86.6%. In the multivariate analysis, albumin ≤ 3.3 g/dL and a need for oxygen were independently associated with inferior 60-day OS rates (hazard ratio [HR] 4.026, 95% confidence interval (CI) 1.954-8.294 and HR 14.55, 95% CI 3.378-62.64, respectively), whereas 60-day survival was significantly greater in patients with benign rather than malignant disease (HR 0.095, 95% CI 0.012-0.750). Together, these data suggest that intensive treatment may be necessary for patients with COVID-19 with malignant HDs who have low albumin levels and require oxygen at the time of diagnosis.

Effectiveness of venetoclax and azacytidine against myeloid/natural killer cell precursor acute leukemia.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) is a rare leukemia subtype that possibly originates from precursor NK cells. The disease has a poor prognosis, and information on its treatment is lacking. We herein report the first case of a 46-year-old woman with MNKPL who was refractory to two lines of acute myeloid leukemia (AML)-type intensive chemotherapy but was successfully treated with venetoclax and azacytidine (VEN/AZA). She was diagnosed with MNKPL based on the conformations of immature lymphoblastoid morphology without myeloperoxidase reactivity that showed a CD7/CD33/CD34/CD56/HLA-DR positive phenotype and extramedullary regions. The disease was refractory to induction therapy with daunorubicin and cytarabine (DNR/Ara-C) and to reinduction therapy with mitoxantrone, etoposide, and cytarabine (MEC). After two lines of induction chemotherapy, massive pericardial and pleural effusion was found, and was suspected to be extramedullary lesions. The patient developed cardiac tamponade and required pericardiocentesis. Thus, VEN/AZA was administered as third-line therapy. After two cycles of VEN/AZA, the pericardial and pleural effusion disappeared, and complete remission was achieved. The patient received post-transplant cyclophosphamide-based haploidentical transplantation and has stayed relapse-free as of her last follow-up examination 2 years after diagnosis.

Phagocytosis of Mature Granulocytes by Bone Marrow Macrophages in an Elderly Man with Adult-Onset Primary Autoimmune Neutropenia.

Adult-onset primary autoimmune neutropenia (AIN) is an extremely rare but sometimes life-threatening disease. Its pathophysiology is still to be clarified. We describe a case with adult-onset primary AIN with phagocytosis of mature granulocytes by macrophages in bone marrow. A 77-year-old male was referred to our hospital with severe neutropenia. Based on the normal cellular bone marrow without morphological dysplasia and the positivity of anti-neutrophil antibodies in the serum, adult-onset primary AIN was diagnosed. After five years from the initiation of granulocyte colony-stimulating-factor therapy, neutropenia had progressed. At that time, the second bone marrow examination revealed segmented neutrophils phagocytosed by macrophages. Continuous low dose prednisolone succeeded to increase the neutrophil count. An impressive morphological feature of AIN indicated the destruction of mature granulocytes in bone marrow by antibody-dependent cellular phagocytosis mediated by granulocyte-specific antibodies. More cases should be accumulated to elucidate the precise mechanism and establish the optimal therapy.

Use of Eltrombopag for the First Trimester Pregnancy Complicated with Refractory Idiopathic Thrombocytopenic Purpura: A Case Report and Literature Review.

Severe idiopathic thrombocytopenic purpura (ITP) is thought to occur in approximately one in 10,000 pregnancies and refractoriness for conventional treatment is life-threatening. We herein describe a pregnant case of refractory ITP successfully treated with eltrombopag, orally medicated thrombopoietin receptor agonist (TPO-RA). The patient was diagnosed with ITP at the age of 22 and corticosteroid, immune globulin treatments, or splenectomy was invalid. Eltrombopag was administered at 25 mg/day and the platelet count was maintained at 50-80 × 109/L. At the age of 32, she discontinued the medication out of fear of the possible adverse events of TPO-RA. She became pregnant and visited our hospital at the gestational age of 9th week with the result of a platelet count at 18 × 109/L. Two weeks later, her platelet counts further decreased to 9 × 109/L, and eltrombopag administration was resumed with 12.5 mg/day after informed written consent. The platelet counts subsequently increased and were maintained between 30 and 90 × 109/L. At 34th gestational week, the dose of eltrombopag was increased to 25 mg/day in preparation for delivery and the count increased to 123 × 109/L by the 38th gestational week. A healthy female infant weighing 2370 g was vaginally delivered by induced labor. Maternal blood loss was 0.4 L at delivery, and the newborn's platelet count was 173 × 109/L on the second day after birth and 174 × 109/L on the fifth day. The infant is neurologically and developmentally intact at 6 months of age. Regarding TPO-RA treatment for refractory ITP during pregnancy, only six pregnant cases including the present one treated with eltrombopag have been reported so far. This case is rare with reference to the use of eltrombopag for the first trimester and we increased the dose of eltrombopag at the gestational age of 34 in preparation for delivery and vaginal delivery was successful without platelet transfusion. Despite the very limited information on eltrombopag, its use might be a possible optional treatment for refractory ITP during pregnancy.

A phase II study of post-transplant cyclophosphamide combined with tacrolimus for GVHD prophylaxis after HLA-matched related/unrelated allogeneic hematopoietic stem cell transplantation.

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

[Diffuse large B-cell lymphoma with markedly improved chylothorax by lymphangiography].

Chylothorax is a rare clinical sign in patients with diffuse large B-cell lymphoma (DLBCL), which is often challenging to manage and has a poor prognosis. We report the case of a 59-year-old woman who presented with right pleural effusion at the time of DLBCL diagnosis. Lymphadenopathy rapidly improved in response to chemotherapy. However, the pleural effusion progressed and was identified as chylothorax by thoracentesis. Because attempts to manage the condition with fasting and central venous nutrition were unsuccessful, we performed ultrasound-guided intranodal lipiodol lymphangiography from the inguinal lymph node. Although leak sites were not detected, the pleural effusion markedly improved on the day after the examination and resolved after 2 months. Lymphangiography is a minimally invasive examination with few complications. It contributes not only to the identification of leak sites but also to the improvement and resolution of chylothorax. Therefore, lymphangiography should be considered for refractory chylothorax that is unresponsive to chemotherapy or nutritional management.

Risk Factor and Long-Term Outcome Analyses for Acute Limbic Encephalitis and Calcineurin Inhibitor-Induced Encephalopathy in Adults following Allogeneic Hematopoietic Cell Transplantation.

Post-transplantation acute limbic encephalitis (PALE) is a rare, severe inflammatory disorder in the bilateral limbic system, including the hippocampus. To date, only a few studies have reported details, including risk factors for PALE; however, further clinical evidence of PALE, especially in cerebrospinal fluid human herpesvirus 6-negative cases, is warranted. In addition, data are sparse regarding the risk factors for calcineurin inhibitor (CNI)-induced encephalopathy (CNIE) following allogeneic hematopoietic cell transplantation (allo-HCT) in adults. Therefore, we examined the risk factors for and clinical details of PALE and CNIE. We retrospectively analyzed consecutive patients who underwent allo-HCT between January 2005 and November 2017. A total of 485 patients age 46 years (median) were eligible. In total, 14 PALE cases and 11 CNIE cases were identified. Multivariable analyses identified older age, use of an HLA-mismatched unrelated donor (URD), graft-versus-host disease (GVHD) prophylaxis with CNI and mycophenolate mofetil, and grade II-IV acute GVHD as significantly associated with an increased risk of PALE. In 13 patients who received high-dose methylprednisolone (mPSL) therapy, 6 (46%) responded to mPSL therapy, and 3 (23%) achieved complete remission at day 90 after mPSL administration. Furthermore, myelodysplastic syndrome (MDS), HLA-mismatched URD, and grade II-IV acute GVHD were significantly associated with an increased risk of CNIE. The 5-year nonrelapse mortality rate was 50% in PALE and 63% in CNIE, suggesting a very poor prognosis. In conclusion, this study provides evidence that HLA-mismatched URD and acute GVHD may independently contribute to the development of PALE, possibly in part through HLA-mismatch-derived alloimmune responses. Other than acute GVHD, we have identified MDS and HLA-mismatched URD as novel predictors of CNIE after allo-HCT.

High-grade B-cell lymphoma developed during the treatment of chronic myeloid leukemia with bosutinib.

Tyrosine kinase inhibitor (TKI) can help to increase the survival time in chronic myeloid leukemia (CML) patients; however, the risk of secondary malignancies due to TKIs is a growing concern. Only few reports showed clinical course of patients who developed lymphoma during TKI therapies. Herein, we report a case of high-grade B-cell lymphoma diagnosed in the course of CML treatment with bosutinib. The 75-year-old male patient had been diagnosed with CML 25 years ago. After receiving TKIs (imatinib, nilotinib, and bosutinib), he achieved a major molecular response. Over 3 years after starting bosutinib, he was diagnosed with a high-grade B-cell lymphoma. A total of six courses of DA-EPOCH-R therapy brought complete remission of the lymphoma. Moreover, BCR-ABL1 transcript copies remained undetectable by RT-PCR, 8 months after stopping bosutinib. The risk of secondary malignancy due to TKI has been controversial. It is reported that TKI induces irreversible chromosomal abnormalities or chromosome aberrations and inhibits the proliferation or function of T cells, B cells, and NK cells. These mechanisms of TKI may contribute to the development of secondary malignancy. There remains no consensus on the management of secondary lymphoma during TKI therapies. At present, the only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma.

Interactive Web Application for Plotting Personalized Prognosis Prediction Curves in Allogeneic Hematopoietic Cell Transplantation Using Machine Learning.

BACKGROUND: Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for malignant hematological disorders. Transplant clinicians estimate patient-specific prognosis empirically in clinical practice based on previous studies on similar patients. However, this approach does not provide objective data. The present study primarily aimed to develop a tool capable of providing accurate personalized prognosis prediction after allo-HCT in an objective manner. METHODS: We developed an interactive web application tool with a graphical user interface capable of plotting the personalized survival and cumulative incidence prediction curves after allo-HCT adjusted by 8 patient-specific factors, which are known as prognostic predictors, and assessed their predictive performances. A random survival forest model using the data of patients who underwent allo-HCT at our institution was applied to develop this application. RESULTS: We succeeded in showing the personalized prognosis prediction curves of 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality (NRM) interactively using our web application (https://predicted-os-after-transplantation.shinyapps.io/RSF_model/). To assess its predictive performance, the entire cohort (363 cases) was split into a training cohort (70%) and a test cohort (30%) time-sequentially based on the patients' transplant dates. The areas under the receiver-operating characteristic curves for 1-year overall survival, progression-free survival, relapse/progression, and nonrelapse mortality in test cohort were 0.70, 0.72, 0.73, and 0.77, respectively. CONCLUSIONS: The new web application could allow transplant clinicians to inform a new allo-HCT candidate of the objective personalized prognosis prediction and facilitate decision-making.

Recurrence of Acute Lymphoblastic Leukemia with Bone Marrow Necrosis: A Case Report and Review of the Literature on the MRI Features of Bone Marrow Necrosis.

Bone marrow necrosis (BMN) is a rare but important complication of hematological malignancies. We report the case of a 52-year-old male patient with a recurrence of acute lymphoblastic leukemia (ALL) accompanied by BMN. After re-induction therapy, bone marrow aspiration (BMA) and biopsy from the iliac bone showed necrotic cells and eosinophilic debris, respectively. Magnetic resonance imaging (MRI) showed heterogeneous signals in the bilateral iliac bone, possibly reflecting various stages of BMN. BMA from the sternum eventually revealed the recurrence of ALL after a few weeks. Comprehensive assessments, including MRI and repeated bone marrow tests, are required when evaluating the underlying hematological malignancies of patients with BMN.

[Erythrocytosis following allogeneic hematopoietic stem cell transplantation].

Post-transplant erythrocytosis (PTE) following allogeneic hematopoietic stem cell transplantation (alloHSCT) is rare, and the clinical characteristics of this condition remain unknown. In this study, we examined the clinical characteristics of three PTE cases among 321 patients who received allo HSCT from January 1992 to December 2011 at our institution. All three patients exhibited normal levels of white blood cell and platelet counts when their hemoglobin levels reached their peak. Two patients exhibited normal levels of erythropoietin. No thrombosis or hemorrhage was observed in any of the three patients without cytoreductive therapy or an antiplatelet agent. All three patients tested negative for JAK2V617F mutations. Two patients had high levels of IL-13, an upstream signal for the JAK/STAT pathway. JAK2 is known to significantly contribute to the pathology of polycythemia vera; however, this pathology may differ from that of PTE. We believe that it is necessary to construct a more appropriate management structure for PTE by analyzing more case data in the future.

Effect of Prophylactic Post-transplant Ponatinib Administration on Outcomes in Patients With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia.

BACKGROUND: The objective of the present retrospective study was to evaluate the effect of ponatinib administration as maintenance therapy on the outcomes after allogeneic hematopoietic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. PATIENTS AND METHODS: We retrospectively analyzed the data from 34 consecutive patients treated at our institution from January 2008 to June 2019. We had administered post-transplant tyrosine kinase inhibitors preemptively before December 2017. Thereafter, we had initiated the prophylactic use of post-transplant ponatinib. The initial ponatinib dose was 15 mg/d. Ponatinib plasma trough levels were measured using the liquid chromatography-tandem mass spectrometry method 8 days after the first administration and subsequently. RESULTS: Nine patients received ponatinib maintenance. The 2-year overall survival and leukemia-free survival in the ponatinib maintenance group tended to be better than that in the non-ponatinib group (100% vs. 70.5%, P = .10; and 100% vs. 50.8%, P = .02, respectively). In the first 7 of the 9 consecutive patients, the median plasma concentration after ponatinib administration (15 mg/d) was 15.6 ng/mL (range, 4.8-23.3 ng/mL). Although the treatment schedule for 1 patient was altered because of adverse effects (elevation of serum amylase and neutropenia), ponatinib administration was continued for all the patients, except for 1 patient with molecular relapse. One patient developed a transient elevation of serum lipase. No patient presented with any arterial occlusive events. CONCLUSION: Our results have indicated that the strategy of ponatinib maintenance after allogeneic hematopoietic stem cell transplantation is safe, efficacious, and promising.

Acquired Gray Platelet Syndrome Associated with Primary Myelofibrosis.

A 53-year-old man presented with uncontrolled bleeding caused by acquired platelet dysfunction accompanied by calreticulin-mutated primary myelofibrosis. Based on the detection of abnormal platelets, including large gray platelets, under light microscopy and the loss of the second wave of aggregation observed by light transmission aggregometry, the patient was diagnosed with platelet dysfunction accompanied by myeloproliferative neoplasms (MPNs). In addition, the absence of platelet α-granules was confirmed by electron microscopy. Therefore, this condition may be termed "acquired gray platelet syndrome." Acquired platelet dysfunction must be ruled out when abnormal platelets are observed in patients with MPNs.

Clinical usefulness of very high serum soluble interleukin-2 receptor levels for the detection of tuberculous peritonitis in a patient with chronic myelogenous leukemia.

Tuberculous peritonitis is difficult to diagnose due to the disadvantages of ascitic culture and peritoneal biopsy. Although previous reports suggested that very high serum soluble interleukin-2 receptor (sIL-2R) levels may reflect the clinical activity of tuberculosis, little is known about the diagnostic utility of serum sIL-2R for tuberculous peritonitis. We describe a case of tuberculous peritonitis with chronic myelogenous leukemia. The abnormally high serum sIL-2R value and negative findings for other possible causes including lymphoma suggested tuberculous peritonitis and we administered anti-tuberculosis treatment before definitive diagnosis. Abnormally high serum sIL-2R levels may contribute to earlier diagnosis of tuberculous peritonitis, along with ruling out other potential differential diagnoses.

[High-dose polyclonal intravenous immunoglobulin therapy for refractory viral infections including viremia after allogeneic hematopoietic cell transplantation].

Refractory viremia/viral disease is a major life-threatening complication that may arise among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). This study aimed to clarify the therapeutic effect of high-dose polyclonal intravenous immunoglobulin (IVIG) against viremia/viral diseases after allo-HCT. We conducted a pilot study to investigate the therapeutic effect of 400 mg/kg of IVIG given for 5 consecutive days against refractory viremia/viral disease after allo-HCT. Overall, 7 patients were drug-resistant and the other 7 had not previously received any drug for their viremia/viral disease. All patients completed the 5-day therapy regimen of IVIG. A complete response at Day 56 was observed for 8 of 14 patients (57.1%). Additionally, 10 of 14 patients (71.4%) were alive at Day 56, although only one death occurred due to the viremia/viral disease. Remarkably, all 3 cases who developed exogenous viremia/viral diseases including respiratory syncytial virus pneumonia/bronchitis and human parvovirus B19 viremia achieved a complete response, suggesting that high-dose polyclonal IVIG may be more effective against exogenous viruses rather than endogenous ones. Congestive heart failure was observed in 1 patient. High-dose polyclonal IVIG could be an effective and feasible therapy for refractory viremia/viral disease after allo-HCT.

[Pulmonary infiltration of acute monoblastic leukemia diagnosed by transbronchial lung biopsy].

A 65-year-old woman was urgently admitted to our hospital for antibiotic-resistant fever, hypoxemia, and hyperleukocytosis and was diagnosed with acute monoblastic leukemia. Chest computed tomography revealed interlobular septal thickening, central ground-glass opacity, and a nodular shadow in the left lower lobe. Although several treatments for infectious disease and acute heart failure were administered, they were less effective. Transbronchial lung biopsy was performed on day 7 of hospitalization, and subsequently, pulmonary leukemic infiltration was confirmed. Based on the diagnosis, we decided to start intensive chemotherapy. Consequently, the abnormal lung shadow on computed tomography vanished, and complete hematological remission was achieved. Although acute myeloid leukemia is frequently associated with lung infiltration during onset, it is often difficult to distinguish it from other pulmonary complications. In clinical practice, intensive chemotherapy is often initiated based on the clinical evaluation without pathological confirmation of the lung disease. Our patient was accurately diagnosed based on the pulmonary leukemic infiltration observed pathologically and recovered well. Here we report our case along with a discussion of the relevant literature.

Donor KIR2DS1-Mediated Decreased Relapse and Improved Survival Depending on Remission Status at HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using post-transplantation cyclophosphamide (PT/Cy-haplo) is becoming the standard of care for patients without an HLA-matched related or unrelated donor. PT/Cy-haplo can give more patients the opportunity to undergo allo-HCT, because most patients have multiple available HLA-haploidentical related donor candidates. The optimal donor selection algorithm in the PT/Cy-haplo setting has not yet been established, however. To contribute to the establishment of a donor selection formula based on disease status and killer-cell immunoglobulin-like receptor (KIR) genotype, we retrospectively analyzed 91 patients who underwent PT/Cy-haplo at our institution. In both patients and donors, HLA allele genotyping was performed for HLA-A, -B, -C, and -DRB1, and 16 KIR genes were genotyped. Patients in complete remission (CR) who underwent PT/Cy-haplo from a KIR2DS1-positive donor had a significantly lower cumulative incidence of relapse (CIR) than those who underwent PT/Cy-haplo from a KIR2DS1-negative donor (1-year CIR: 0% versus 32.6%, P = .037; 2-year CIR: 9.2% versus 42%, P = .037). Moreover, PT/Cy-haplo from a KIR2DS1-positive donor was significantly associated with improved overall survival (OS) (1-year OS: 91.7% versus 58.7%, P = .010; 2-year OS: 83% versus 34%, P = .010). In contrast, in non-CR individuals, PT/Cy-haplo from KIR2DS1-positive donors did not significantly improve CIR or OS (1-year CIR: 56.5% versus 64.7%, P = .973; 2-year CIR: not reached versus 64.7%, Pnot evaluable; 1-year OS: 25.4% versus 20.6%, P = .418; 2-year OS: 5.1% versus 20.6%, P = .418). In addition, lower infused CD34+ cell dose, female-to-male transplantation, and acute myelogenous leukemia were significantly associated with increased risk of relapse and mortality. This study demonstrates that graft-versus-leukemia/tumor effects were exerted through donor KIR2DS1 at PT/Cy-haplo when patients have low tumor burdens. It would be worth examining the inclusion of donor KIR genotyping and disease status assessment in establishing optimal donor selection criteria for PT/Cy-haplo.