Ruxolitinib in steroid-refractory acute graft-vs-host disease: Japanese subgroup analysis of the randomized REACH2 trial.

Acute graft-versus-host disease (aGvHD) is a major complication after allogeneic hematopoietic stem cell transplantation in Japan and other countries. Nearly one-third of patients do not respond to standard systemic steroid therapy and no standard second-line treatment has been established in Japan. We report efficacy and safety findings of ruxolitinib versus best available therapy (BAT) from a subgroup analysis of the international, phase 3 REACH2 study in Japanese patients with steroid-refractory aGvHD. The primary endpoint was overall response rate (ORR) at day 28. Overall, 9 patients received ruxolitinib and 21 received BAT. The ORR at day 28 (88.9% vs 52.4%) and durable ORR at day 56 (66.7% vs 28.6%) were higher with ruxolitinib versus BAT. The estimated cumulative incidence of loss of response at 6 months was 12.5% with ruxolitinib and 18.2% with BAT. The median failure-free survival was longer with ruxolitinib versus BAT (2.73 vs 1.25 months). The most common adverse events up to day 28 in the ruxolitinib and BAT groups were anemia (55.6% vs 19.0%) and thrombocytopenia (44.4% vs 4.8%, respectively). Ruxolitinib showed better efficacy outcomes and a consistent safety profile compared with BAT in the Japanese subgroup, and the findings were consistent with overall study results.

Improved Long-Term Net Survival after Allogeneic Hematopoietic Cell Transplantation in Patients with Hematologic Malignancies over Two Decades.

Allogeneic (allo-) hematopoietic cell transplantation (HCT) has evolved as a curative therapy for hematologic malignancies and diseases, with practice changes over the past 2 decades. This study aimed to evaluate the change in 5-year net survival (NS) of allo-HCT recipients in a population-based cohort over the past 2 decades, which allows the estimation of a more HCT-specific long-term survival rate by considering background mortality changes. This study included 42,064 patients with hematologic malignancies who underwent their first allo-HCT in Japan between 2000 and 2018 and were reported to the Transplant Registry Unified Management Program. We compared the 5-year NS after allo-HCT in 4 consecutive HCT periods (2000 to 2004, 2005 to 2008, 2009 to 2012, and 2013 to 2018). The 5-year NS of the latest period was estimated using the period analysis method. Adjusted excess hazard ratios (EHRs) for 5-year NS over the HCT period were analyzed using an EHR model. In addition to the analysis of all hematologic malignancies, adjusted 5-year NS for each major hematologic malignancy, including acute myelogenous leukemia, acute lymphoblastic leukemia (ALL), myelodysplastic syndrome, adult T cell leukemia/lymphoma, chronic myeloid leukemia (CML), and malignant lymphoma, was analyzed. The probability of adjusted 5-year NS after HCT improved significantly over time: 35% in 2000 to 2004, 39% in 2005 to 2008, 45% in 2009 to 2012, and 49% in 2013 to 2018. The adjusted EHRs were .90 (95% confidence interval [CI], .86 to .93) in the 2005 to 2008 period, .77 (95% CI, .74 to .80) in the 2009 to 2012 period, and .65 (95% CI, .63 to .68) in the 2013 to 2018 period, with the 2000 to 2004 period as the reference. The 5-year NS improved among all hematologic malignancies, with a significant improvement in CML and ALL. The changes in 5-year NS from the 2000 to 2004 period to the 2013 to 2018 period ranged from 46% to 66% in CML and from 41% to 59% in ALL. In addition to the large improvement of 1-year NS, smaller but continued improvement in NS between 1 and 5 years after transplantation was observed. NS at 5 years conditional on being alive at 1 year increased from 64% in 2000 to 2004 to 73% in 2013 to 2018. Even after subtracting the background mortality in the general population, we found a significant improvement in long-term allo-HCT-specific survival rates for patients with hematologic malignancies over the past 2 decades in Japan.

Dysmegakaryopoiesis and Transient Mild Increase in Bone Marrow Blasts in Patients With Aplastic Anemia Treated With Eltrombopag May Be Signs of Hematologic Improvement and Not Portend Clonal Evolution.

OBJECTIVES: Eltrombopag, a thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA). Cytomorphologic changes in bone marrow after eltrombopag administration are still unclear. This study examined the effect of eltrombopag on cytomorphologic findings using data from prior phase 2 studies (E1201 and E1202). METHODS: Microscopic examinations were performed in 31 patients with AA (E1201 [n = 21], E1202 [n = 10]). The relationship between hematologic improvement and morphologic findings was also investigated. RESULTS: In 5 patients (E1201 [n = 3], E1202 [n = 2]), the bone marrow blast count increased after initiation of eltrombopag treatment compared with screening values. The blast count was less than 5%, and the increase in bone marrow blasts was transient in all 4 patients who had bone marrow examinations at follow-up. In 8 patients (E1201 [n = 5], E1202 [n = 3]), dysplastic forms of megakaryocytes were found in the bone marrow following treatment initiation. Dysmegakaryopoiesis of 10% or more was found in 3 patients. None of the patients revealed micromegakaryocytes. Ten patients showed an increase in bone marrow blasts and/or dysmegakaryopoiesis following treatment initiation. Nine of 10 patients showed hematologic improvement in 1 or more lineages. CONCLUSIONS: Dysmegakaryopoiesis without micromegakaryocytes and a transient increase of less than 5% in bone marrow blast count may be signs of hematologic improvement with eltrombopag for patients with AA.

Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor grafts are frequently cryopreserved to ensure that a graft is available before starting a conditioning regimen. However, there have been conflicting reports on the effect of cryopreservation on transplantation outcomes. Also, the impact of cryopreservation may differ in bone marrow (BM) transplantation (BMT) and peripheral blood stem cell (PBSC) transplantation (PBSCT). In this retrospective study, we analyzed the clinical data of both cryopreserved unrelated BMTs (n = 235) and PBSCTs (n = 118) and compared these with data from a large control cohort without cryopreservation including 4133 BMTs and 720 PBSCTs. Among the patients with cryopreserved grafts, 10 BMT recipients (4.3%) and 3 PBSCT recipients (2.5%) did not achieve neutrophil engraftment after transplantation, including 4 of the former and all 3 of the latter who died early before engraftment. In a multivariate analysis, cryopreservation was not associated with neutrophil engraftment in BMT but significantly delayed neutrophil engraftment in PBSCT (hazard ratio [HR], .82; 95% confidence interval [CI], .69 to .97; P = .023). There was an interaction with borderline significance between cryopreservation and the stem cell source (P = .067). Platelet engraftment was delayed by cryopreservation after both BMT and PBSCT. Only 2 cryopreserved grafts (<1%) were unused during the study period. The cryopreservation of unrelated donor BM and PBSC grafts is associated with a slight delay in neutrophil and platelet engraftment but an acceptable rate of graft failure. PBSC grafts may be more sensitive to cryopreservation than BM grafts. Cryopreservation is a reasonable option during COVID-19 pandemic, provided that the apheresis and transplantation centers are adept at cryopreservation. © 2022 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Neurolymphomatosis in follicular lymphoma: an autopsy case report.

Neurolymphomatosis is a neurological manifestation of lymphoma that involves the cranial or spinal peripheral nerves, nerve roots, and plexus with direct invasion of neoplastic cells. Neurolymphomatosis is rare among patients with low-grade lymphoma. We report an autopsied case of neurolymphomatosis that arose from follicular lymphoma. A 49-year-old woman who presented with pain of her neck and shoulder and numbness of her chin. Computed tomography revealed enlarged lymph nodes in her whole body, and biopsy from the axillary lymph node revealed grade 2 follicular lymphoma. Although the patient underwent chemotherapy, she gradually developed muscle weakness in the upper limbs and sensory disturbances of the trunk and limbs. 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed increased tracer uptake of the cervical nerve roots. Repeated FDG-PET after additional therapy revealed progression of disease within the nerve roots and brachial plexus, whereas gadolinium-contrast magnetic resonance imaging (MRI) showed weak enhancement of the cervical nerve roots without formation of mass lesions. She died after a total disease duration of 12 months. Postmortem observations revealed invasion of lymphoma cells into the cervical nerve roots, dorsal root ganglia, and subarachnoid spaces of the spinal cord. Neurolymphomatosis was prominent at the segments of C6-Th2. Combined loss of axons and myelin sheaths was observed in the cervical nerve roots and posterior columns. Lymphoma cells also invaded the cranial nerves. The subarachnoid and perivascular spaces of the brain demonstrated focal invasion of the lymphoma. Mass lesions were not observed in the central nervous system. The lymphoma cells did not show histological transformation to higher grades, and the density of the centroblasts remained at grade 2. Our report clarifies that low-grade follicular lymphoma can manifest as neurolymphomatosis and central nervous system invasion in the absence of transformation toward higher histological grades. FDG-PET may be more sensitive to non-mass-forming lesions, including neurolymphomatosis, than gadolinium-contrast MRI.

Predictive value of surveillance cultures for bacteremia caused by extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales among patients with hematological diseases.

PURPOSE: Due to the increasing prevalence of extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales, empirical therapies with cefepime or piperacillin/tazobactam for hematology patients with febrile neutropenia have become ineffective. Carbapenems should be administered as soon as possible in such patients with ESBL bacteremia. If the surveillance culture results are consistent with the blood culture findings, the time to adequate treatment initiation can be shortened. METHODS: All consecutive patients with Enterobacterales bacteraemia who were admitted from January 2013 to December 2018 at the hematology wards were enrolled in this study. Surveillance rectal swab and blood culture results were compared. RESULTS: In total, 67 patients with Enterobacterales bacteremia underwent surveillance culture prior to the onset of infection. Regarding the presence or absence of ESBL-producing Enterobacterales, 64 (95.5%) patients had surveillance results concordant with blood culture results. The positive predictive value of surveillance culture for bacteremia caused by ESBL-producing Enterobacterales was 95.0%. Moreover, the negative predictive value of surveillance culture for bacteremia caused by non-ESBL-producing Enterobacterales was 95.7%. CONCLUSION: The concordance rate between the surveillance rectal swab and blood cultures was highly acceptable. Surveillance rectal swab cultures are useful for identifying patients at high risk for ESBL bacteremia.

Decision Analysis for Unrelated Bone Marrow Transplantation or Immediate Cord Blood Transplantation for Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia in First Complete Remission.

An HLA-matched relative is the first-choice donor for patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) in first complete remission (CR1). The most promising alternative donor is thought to be an HLA-matched unrelated donor (MUD) in patients who do not have an HLA-matched related donor. Cord blood transplantation (CBT) is an alternative option. Higher rates of engraftment failure and nonrelapse mortality (NRM) are significant problems, but the ready availability of cord blood can be an advantage, because patients can immediately undergo transplantation before progression. This study was conducted to identify an appropriate alternative donor in patients with Ph-negative ALL in CR1 who do not have an HLA-matched related donor (MRD). Decision analyses using a Markov model were performed to compare immediate CBT, in which CBT was performed at 1 month after the achievement of CR1, with elective unrelated bone marrow transplantation (uBMT) from an 8/8 MUD (8/8 uBMT) or uBMT from a 7/8 MUD (7/8 uBMT), in which uBMT was performed at 4 months, in patients age 16 to 55 years with Ph-negative ALL in CR1 who did not have an MRD. We constructed a decision tree. The cycle length was set at 3 months, and analyses were performed for 19 cycles for uBMT and 20 cycles for CBT, resulting in evaluation of the 5-year life expectancy after both decisions. Transition probabilities (TPs) and utilities were estimated from prospective and retrospective Japanese studies and the registry database of Japan. Subgroup analyses were performed according to risk stratification based on WBC count and cytogenetics at diagnosis and according to age stratification, with a cutoff of 25 years. One-way sensitivity analyses for TPs and utilities were performed as well. The baseline analyses showed that 8/8 uBMT or 7/8 uBMT had superior results to CBT, with quality-adjusted life years (QALYs) of 2.86 in 8/8 uBMT, 2.84 in 7/8 uBMT, and 2.75 in CBT. One-way sensitivity analyses showed that the results of the baseline analyses were reversed if the probability of NRM in CBT improved. Subgroup analyses showed similar results in younger, older, and high-risk patients. However, QALY was worse in 8/8 uBMT compared with CBT in standard-risk patients. In one-way sensitivity analyses, the probabilities of NRM in uBMT and CBT affected the baseline results in all analyses except for comparisons between 8/8 uBMT and CBT in younger and high-risk patients. In these 2 populations, the superiority of 8/8 uBMT was consistently demonstrated throughout the one-way sensitivity analyses. For patients with Ph-negative ALL in CR1 who decide to undergo transplantation from an alternative donor, elective uBMT from either an 8/8 MUD or a 7/8 MUD is expected to yield a better outcome than immediate CBT. Nonetheless, CBT is a viable option, and improvements to reduce the risk of NRM in CBT may change these results.

Assessment of cellular response to mitogens in long-term allogeneic hematopoietic stem cell transplantation survivors.

Infection is one of the major causes of death in hematopoietic stem cell transplantation (HSCT) survivors. Precise assessments of immune function after HSCT will be critical in establishing appropriate treatment and prophylaxis, such as re-vaccination. Although several surrogate markers for prediction of clinical outcomes after HSCT have been proposed, definitive markers of immune reconstitution and data on those markers in long-term survivors are lacking. In this study, cellular response to mitogens was assessed and clinical features associated with a poor response to mitogens were investigated in long-term allogeneic HSCT survivors. Age at transplantation and age at the time of mitogen stimulation test were each identified as significant risk factors for poor response to phytohemagglutinin and concanavalin A, respectively (P < 0.001 each). However, time elapsed since transplantation was not found to be correlated with responsiveness to mitogens in this study. Prospective, in-depth studies on immune reconstitution are needed to establish appropriate prophylaxis against infections after HSCT and a schedule for re-vaccination.

A multicenter, phase II study of R-THP-COP therapy for elderly patients with newly diagnosed, advanced-stage, indolent B-cell lymphoma.

The optimal combined chemotherapy regimen with rituximab has yet to be established for elderly patients with advanced-stage indolent B-cell lymphoma (B-NHL). A multicenter study was performed to evaluate the efficacy and toxicity of R-THP-COP therapy in elderly patients (aged 70-79 years) with newly diagnosed advanced-stage indolent B-NHL using the complete response rate (%CR) as the primary endpoint. Patients with newly diagnosed, clinical stage III/IV, indolent B-NHL, aged 70-79 years, with a performance status of 0-2 were eligible for this study. R-THP-COP consists of 375 mg/m2 of rituximab, 50 mg/m2 of pirarubicin, 750 mg/m2 of cyclophosphamide, 1.4 mg/m2 of vincristine, and 100 mg/day of oral prednisolone for 5 days. This study was discontinued due to poor accrual after the enrollment of 18 patients, although the planned sample size was 40 patients. The numbers of patients with follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, and mantle cell lymphoma were 16, 1, and 1, respectively. The median age was 73 (range, 70 to 79) years. The %CR including unconfirmed CR was 45% (95% confidence interval: 25-66%) and the overall response rate was 72%. The estimated 5-year overall survival and progression-free survival rates were 55% and 28%, respectively. The major toxicity observed was grade 4 neutropenia (94%). Grade 4 non-hematological toxicities were not observed and no patients developed grade 3/4 cardiac toxicities. This phase II study provides useful information regarding the efficacy and toxicity of R-THP-COP therapy for patients aged 70 years or older with newly diagnosed, advanced-stage, indolent B-NHL, although the sample size was small.

Cryopreservation of Unrelated Hematopoietic Stem Cells from a Blood and Marrow Donor Bank During the COVID-19 Pandemic: A Nationwide Survey by the Japan Marrow Donor Program.

During the COVID-19 pandemic, donor hematopoietic stem cell grafts are frequently cryopreserved to ensure the availability of graft before starting a conditioning regimen. However, the safety of cryopreservation has been controversial in unrelated hematopoietic stem cell transplantation (HSCT), especially for bone marrow (BM) grafts. In addition, in unrelated HSCT, the effect of the time from harvest to cryopreservation of donor grafts required for the transportation of donor graft has not been fully clarified. In this study, we retrospectively analyzed the first 112 patients with available data who underwent cryopreserved unrelated blood and marrow transplantation through the Japan Marrow Donor Program during the COVID-19 pandemic. There were 112 patients, including 83 who received BM grafts and 29 who received peripheral blood stem cell (PBSC) grafts. The median time from stem cell harvest to cryopreservation was 9.9 hours (range, 2.6 to 44.0 hours), and the median time from cryopreservation to infusion was 231.2 hours. The incidence of neutrophil engraftment at day 28 after HSCT was 91.1%, and among 109 patients (excluding 3 patients with early death), all but 1 patient achieved neutrophil engraftment within 60 days after HSCT. The time to neutrophil engraftment and time to platelet engraftment were shorter in PBSC transplantation compared with BM transplantation (BMT), but the differences were not statistically significant (P = .064 and .18). Multivariate analysis among BM recipients revealed that a higher number of frozen nucleated cells and the absence of HLA mismatch were associated with faster neutrophil engraftment. The time to neutrophil engraftment after unrelated cryopreserved BMT was not different from that after unrelated BMT without cryopreservation. Our findings suggest that unrelated donor BM and PBSC grafts can be safely cryopreserved even after transit from the harvest center to the transplantation center. In the current COVID-19 pandemic, cryopreservation can be considered as an option while balancing the risks and benefits of the procedure.