Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

Myeloablative unrelated cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia: comparison with other graft sources from related and unrelated donors.

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) is a distinct clinical entity among ALL and is associated with adverse outcomes and higher rates of relapse when conventional chemotherapy is used alone. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for patients with Ph+ALL, the impact of graft sources, particularly cord blood transplantation (CBT), on allo-HSCT for patients with Ph+ALL has yet to be clarified. We retrospectively compared clinical outcomes after unrelated CBT (n = 20), unrelated bone marrow transplantation (n = 7), and related bone marrow and peripheral blood stem cell transplantations (n = 13) following myeloablative conditioning in 40 patients with Ph+ALL. Although graft source had no significant impact on survival or relapse, disease status at transplantation did significantly affect outcomes. These data suggest that unrelated CBT is feasible and should be considered early in the course of patients with Ph+ALL when HLA-compatible related and unrelated donors are not available.

Comparable long-term outcome of unrelated cord blood transplantation with related bone marrow or peripheral blood stem cell transplantation in patients aged 45 years or older with hematologic malignancies after myeloablative conditioning.

We investigated whether bone marrow or peripheral blood stem cells from older sibling donors or cord blood from unrelated donors provided a better outcome in allogeneic hematopoietic stem cell transplantation for relatively older patients who were candidates for myeloablative conditioning. Clinical outcomes of 97 patients aged 45 years or older with hematologic malignancies who received unrelated cord blood transplantation (CBT) (n = 66) or bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT) from related donors (n = 31) were compared. The cumulative incidences of grades III to IV acute and extensive chronic graft-versus-host diseases were similar between both groups. Although transplant-related mortality was significantly lower after CBT compared with BMT/PBSCT from related donors (hazard ratio [HR], .29, P = .04), overall mortality (HR, .72, P = .47) and relapse (HR, 2.02, P = .23) were not significantly different after CBT and BMT/PBSCT from related donors. These data suggest that CBT could be as safe and effective as BMT/PBSCT from older related donors for relatively older patients when it is used as a primary unrelated stem cell source.

Effect of ABO blood group incompatibility on the outcome of single-unit cord blood transplantation after myeloablative conditioning.

ABO blood group incompatibility between donor and recipient has been associated with poor transplant outcomes in allogeneic hematopoietic stem cell transplantation. However, its effect on the outcome of cord blood transplantation (CBT) has yet to be clarified. We retrospectively analyzed 191 adult patients who received single-unit CBT after myeloablative conditioning for malignant disease in our institute. Major mismatch showed a significantly lower incidence of platelet engraftment compared with ABO match as a reference (hazard ratio, .57; P = .01). Nevertheless, there was no increase in graft-versus-host disease, transplant-related mortality, and overall mortality after ABO-incompatible CBT. These data suggested that donor-recipient ABO incompatibility does not have a significant impact on outcome after myeloablative CBT for hematological malignancies.

Single-unit cord blood transplantation after granulocyte colony-stimulating factor-combined myeloablative conditioning for myeloid malignancies not in remission.

High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF-combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF-combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.

Development of a Malaysian potentially inappropriate prescribing screening tool in older adults (MALPIP): a Delphi study.

INTRODUCTION: Polypharmacy and potentially inappropriate medications (PIM) are common among older adults. To guide appropriate prescribing, healthcare professionals often rely on explicit criteria to identify and deprescribe inappropriate medications, or to start medications due to prescribing omission. However, most explicit PIM criteria were developed with inadequate guidance from quality metrics or integrating real-world data, which are rich and valuable data source. AIM: To develop a list of medications to facilitate appropriate prescribing among older adults. METHODS: A preliminary list of PIM and potential prescribing omission (PPO) were generated from systematic review, supplemented with local pharmacovigilance data of adverse reaction incidents among older people. Twenty-one experts from nine specialties participated in two Delphi to determine the list of PIM and PPO in February and March 2023. Items that did not reach consensus after the second Delphi round were adjudicated by six geriatricians. RESULTS: The preliminary list included 406 potential candidates, categorised into three sections: PIM independent of diseases, disease dependent PIM and omitted drugs that could be restarted. At the end of Delphi, 92 items were decided as PIM, including medication classes, such as antacids, laxatives, antithrombotics, antihypertensives, hormones, analgesics, antipsychotics, antidepressants, and antihistamines. Forty-two disease-specific PIM criteria were included, covering circulatory system, nervous system, gastrointestinal system, genitourinary system, and respiratory system. Consensus to start potentially omitted treatment was achieved in 35 statements across nine domains. CONCLUSIONS: The newly developed PIM criteria can serve as a useful tool to guide clinicians and pharmacists in identifying PIMs and PPOs during medication review and facilitating informed decision-making for appropriate prescribing.

An integrated life cycle multi-objective optimization model for health-environment-economic nexus in food waste management sector.

Food waste is a universal problem in many countries. In line with Sustainable Development Goals 7 and 12, it is crucial to identify a cost-effective food waste valorization management framework with the least human health and environmental impacts. However, studies on the synergistic effect of life cycle assessment and mathematical optimization interconnected with human health, environment, and economic are relatively few and far between; hence they cannot provide holistic recommendations to policymakers in developing environmental and economic feasibility of food waste management frameworks. Taking Malaysia as a case study, this study proposes a simple and deterministic model that integrates life cycle assessment and multi-objective mathematical optimization to unpack the health-environment-economic wellbeing nexus in food waste management sector. The model evaluates the life cycle human health, environmental, and economic impacts of five food waste disposal and valorization technologies: open landfill, sanitary landfill, aerated windrow composting, high-temperature drying sterilization, and anaerobic digestion, and identifies the optimal food waste valorization configuration solution in Malaysia. Based on the results modeled by SimaPro 9.0 and General Algebraic Modeling System with augmented ε-constraint, valorization of food waste into electricity via anaerobic digestion is the most favorable option, with 146% and 161% reduction of human health and ecosystems, respectively, as compared with open landfill. If cost is combined as an objective function with human health and ecosystems, high-temperature drying sterilization is the most attractive scenario due to the high livestock feed revenue. Among the 10 Pareto-optimal solutions, 9% sanitary landfill, 3% aerated windrow composting, 30% high-temperature drying sterilization, 30% anaerobic digestion to electricity, and 28% anaerobic digestion to cooking gas, is recommended as future food waste management configuration. The sensitivity results demonstrate that prices of electricity, cooking gas, and livestock feed affect the optimal configuration food waste management system.

The FLT3 internal tandem duplication mutation at disease diagnosis is a negative prognostic factor in myelodysplastic syndrome patients.

The role of the FMS-like tyrosine kinase 3 (FLT3) gene in acute myeloid leukemia (AML) has been well documented and the FLT3-internal tandem duplication (FLT3-ITD) mutation has been identified as a prognostic factor in AML. Due to its low incidence, the role of the FLT3 mutation remains unclear in myelodysplastic syndrome (MDS) patients. To investigate the impact of the FLT3-ITD status on the prognosis of MDS at diagnosis, we retrospectively analyzed 72 MDS patients admitted to Teikyo University Hospital. FLT3-ITD was examined by a reverse transcription-polymerase chain reaction using complementary DNA synthesized from mRNA extracted from bone marrow mononuclear cells at the diagnosis of MDS. Fifteen patients (20.8 %) were positive for FLT3-ITD and had significantly worse overall survival (OS) and progression-free survival (PFS) than patients who were negative (P < 0.001 and P < 0.001, respectively) in a multivariate analysis. We also investigated whether the Wilms' tumor gene-1 (WT-1) copy number was associated with the FLT3-ITD mutational status using data available on WT-1 from 57 patients. A WT-1 transcript copy number ≥50/µg total mRNA in peripheral blood was detected in 35 patients (61.4 %). All FLT3-ITD-positive patients showed WT-1 ≥50. The FLT3-ITD-positive group showed significantly higher WT-1 transcription levels than the negative group. These results indicate that the FLT3-ITD mutation has a prognostic impact at the diagnosis of MDS and is associated with a high level of WT-1.

Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults.

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III-IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.

Serum high-density lipoprotein cholesterol level has a significant prognostic impact on outcomes of follicular lymphoma patients.

We investigated the potential of nutritional and inflammatory parameters as prognostic factors for follicular lymphoma (FL), and also examined the predictive value of the early progression of disease within 24 months of first-line chemo-immunotherapy (POD24). We retrospectively analyzed 46 patients with FL admitted to Teikyo University Hospital and treated with chemo-immunotherapy between May 2009 and July 2019. Physical characteristics, blood parameters, and markers or scores for consumptive/inflammatory and nutritional conditions were used as variables. Nine parameters correlated with poor overall survival (OS) in univariate analysis: An Eastern Cooperative Oncology Group (ECOG) scale performance status (PS) ≥2, five or more involved nodal sites, positive bone marrow (BM) involvement, a serum albumin level <3.5 g/dL, CRP >0.5 mg/dL, lactate dehydrogenase (LD) higher than the upper normal limit (UNL), high-density lipoprotein cholesterol (HDL-C) <40 mg/dL, modified Glasgow prognostic score of 1-2, and the geriatric nutritional risk index <82. In multivariate analysis, ECOG PS ≥2, positive BM involvement, and a serum HDL-C level <40 mg/dL remained significant for poor progression-free survival. One-year OS rate after receiving salvage chemotherapy was lower in the POD24 group (50%) and POD24 correlated with ECOG PS ≥2, positive BM involvement, a serum lactate dehydrogenase >UNL, and HDL-C <40 mg/dL by Fisher's exact test. These results indicate that low serum HDL-C levels appear to be important for predicting the risk of POD24 and the worse prognosis of FL.

Second allogeneic transplantation using umbilical cord blood for a patient with relapsed ALK+ anaplastic large cell lymphoma after allogeneic bone marrow transplantation in the era of ALK inhibitors: A case report.

RATIONALE: Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet. PATIENT CONCERNS: An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT). DIAGNOSIS: However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy. INTERVENTION: Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR. OUTCOMES: The patient has been in CR under maintenance therapy of alectinib for more than 16 months. LESSONS: Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.

Gemtuzumab ozogamicin monotherapy prior to stem cell infusion induces sustained remission in a relapsed acute myeloid leukemia patient after allogeneic stem cell transplantation: A case report.

RATIONALE: Patients with relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have poor prognosis. Many patients are not eligible for 2nd HSCT due to organ dysfunction or other complications that prevent them from tolerating conditioning chemotherapy. In those ineligible patients for 2nd HSCT with myeloablative conditioning regimen, reduced intensity conditioning (RIC) are often used. RIC regimens are less toxic but has a less direct anti-tumor efficacy so that RIC regimens are not suitable for the patients with high tumor burden. To overcome this dilemma, Gemtuzumab Ozogamicin (GO) has been used as a part of RIC regimens to add anti-tumor efficacy. We report here a relapsed AML patient who was treated with GO monotherapy followed by stem cell infusion. PATIENT CONCERNS: A 25-year-old male with AML experienced relapse 9 months after allo-HSCT. DIAGNOSIS: Since he had mild renal and cardiac dysfunction and his AML did not progress rapidly, we decided not to give him an intensive chemotherapy. However, after azacitidine (AZA) and donor lymphocyte infusion therapy, his leukemic blasts did not decrease. INTERVENTIONS: Originally, we had planned to proceed with a 2nd allo-HSCT with RIC regimen that consisted of fludarabine, melphalan and fractionated GO (3 mg/m/dose) on day -21, -18, and -15. However, the patient developed appendicitis after the last dose of GO when his neutrophil was 0 cells/µl. Based on his medical acuity, we terminated the rest of the patients conditioning regimen and the patient did not receive any further chemotherapeutics. The patient was still infused with peripheral blood stem cells from the donor on day 0. OUTCOMES: His appendicitis was resolved by antibiotics without surgery. His AML has been in CR more than 18 months under AZA maintenance therapy. LESSONS: GO monotherapy could be a conditioning regimen of 2nd allo HSCT from the same donor as the first HSCT for relapsed AML patients.

Myeloablative unrelated cord blood transplantation for acute leukemia patients between 50 and 55 years of age: single institutional retrospective comparison with patients younger than 50 years of age.

Increasing recipient age is a well-known risk factor for graft-versus-host disease (GVHD) and treatment-related mortality (TRM) and has a negative impact on allogeneic hematopoietic stem cell transplantation. Since the incidence of severe GVHD after cord blood transplantation (CBT) is lower than that after transplants using bone marrow or mobilized peripheral blood grafts from adult cells, we should expect better outcomes from CBT in older patients. To evaluate the feasibility and efficacy of myeloablative unrelated CBT in patients aged between 50 and 55 years, we performed a retrospective comparison of 100 patients with acute leukemia who received cord blood grafts at our institution. Nineteen older patients (median age, 52; range, 50-55) and 81 younger patients (median, 36; range, 16-49) received a myeloablative conditioning regimen including 12 Gy of total body irradiation and chemotherapy. GVHD prophylaxis included cyclosporine with (n = 96) or without (n = 4) methotrexate. There were no significant differences in the incidences of grades II to IV acute GVHD, extensive-type chronic GVHD, TRM, and the probability of overall and disease-free survival between these groups. These results suggest that, in patients with acute leukemia, myeloablative CBT might be as safe and effective in patients aged between 50 and 55 years as in younger patients.

Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia.

We analyzed the disease-specific outcomes of adult acute myelogenous leukemia (AML) patients treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and February 2008, 77 adult patients with AML were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning. The median age was 45 years, the median weight was 55 kg, the median number of nucleated cells was 2.44 x 10(7)/kg, and the median number of CD34-positive cells was 1.00 x 10(5)/kg. All patients received a single and HLA mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 50 and platelet recovery at day 200 was 94.8% and 91.7%, respectively. A higher CD34-positive cell dose was associated with faster hematopoietic recovery. The cumulative incidence of grade III to IV acute graft-versus-host disease (aGVHD) and extensive-type chronic GVHD (cGVHD) was 25.1% and 28.6%, respectively. With a median follow-up of 78 months, the probability of event-free survival (EFS) at 5 years was 62.8%. The 5-year cumulative incidence of treatment related-mortality (TRM) and relapse was 9.7%, 25.8%, respectively. In multivariate analyses, the risk factor identified for event free survival (EFS) was disease status and cytogenetics. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with AML.

Recipient-derived cells after cord blood transplantation: dynamics elucidated by multicolor FACS, reflecting graft failure and relapse.

Although umbilical cord blood has been increasingly used as an alternative donor source to treat hematologic malignancies, cord blood transplantation (CBT) is frequently complicated by graft failure and relapse of primary diseases. Because persistence or increase of recipient-derived hematopoietic or malignant cells has pathogenic import under these conditions, analysis of recipient-derived cells should be useful to understand the pathogenesis of graft failure and relapse of primary disease. Because most CBT involves human leukocyte antigen (HLA)-mismatched transplantation, we developed a 9-color fluorescence activated cell sorter (FACS)-based method of mixed chimerism (MC) analysis using anti-HLA antibodies to detect mismatched antigens (HLA-Flow method). Among CD4(+) T cells, CD8(+) T cells, B cells, NK cells, monocytes, and granulocytes, donor- and recipient-derived cells alike could be individually analyzed simultaneously in a rapid, quantitative and highly sensitive manner, making the HLA-Flow method very valuable in monitoring the engraftment process. In addition, this method was also useful in monitoring recipient-derived cells with leukemia-specific phenotypes, both as minimal residual disease (MRD) and as early harbingers of relapse. Leukemia relapse can be definitively diagnosed by cytogenetic or PCR studies using recipient-derived cells sorted for leukemia markers. Multicolor HLA-fFlow analysis and cell sorting in early diagnosis of graft failure and relapse was confirmed as valuable in 14 patients who had received HLA-mismatched CBT.