Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

Does recipient body mass index inform donor selection for allogeneic haematopoietic cell transplantation?

It is not known whether obesity has a differential effect on allogeneic haematopoietic cell transplantation outcomes with alternative donor types. We report the results of a retrospective registry study examining the effect of obesity [body mass index (BMI) > 30] on outcomes with alternative donors (haploidentical related donor with two or more mismatches and receiving post-transplant cyclophosphamide [haplo] and cord blood (CBU)] versus matched unrelated donor (MUD). Adult patients receiving haematopoietic cell transplantation for haematologic malignancy (2013-2017) (N = 16 182) using MUD (n = 11 801), haplo (n = 2894) and CBU (n = 1487) were included. The primary outcome was non-relapse mortality (NRM). The analysis demonstrated a significant, non-linear interaction between pretransplant BMI and the three donor groups for NRM: NRM risk was significantly higher with CBU compared to haplo at BMI 25-30 [hazard ratio (HR) 1.66-1.71, p < 0.05] and MUD transplants at a BMI of 25-45 (HR, 1.61-3.47, p < 0.05). The results demonstrated that NRM and survival outcomes are worse in overweight and obese transplant recipients (BMI ≥ 25) with one alternative donor type over MUD, although obesity does not appear to confer a uniform differential mortality risk with one donor type over the other. BMI may serve as a criterion for selecting a donor among the three (MUD, haplo and CBU) options, if matched sibling donor is not available.

Human multipotent adult progenitor cells effectively reduce graft-vs-host disease while preserving graft-vs-leukemia activity.

Graft-vs-host disease (GvHD) limits successful outcomes following allogeneic blood and marrow transplantation (allo-BMT). We examined whether the administration of human, bone marrow-derived, multipotent adult progenitor cells (MAPCs™) could regulate experimental GvHD. The immunoregulatory capacity of MAPC cells was evaluated in vivo using established murine GvHD models. Injection of MAPC cells on day +1 (D1) and +4 (D4) significantly reduced T-cell expansion and the numbers of donor-derived, Tumor Necrosis Factor Alpha (TNFα) and Interferon Gamma (IFNγ)-producing, CD4+ and CD8+ cells by D10 compared with untreated controls. These findings were associated with reductions in serum levels of TNFα and IFNγ, intestinal and hepatic inflammation and systemic GvHD as measured by survival and clinical score. Biodistribution studies showed that MAPC cells tracked from the lung and to the liver, spleen, and mesenteric nodes within 24 hours after injection. MAPC cells inhibited mouse T-cell proliferation in vitro and this effect was associated with reduced T-cell activation and inflammatory cytokine secretion and robust increases in the concentrations of Prostaglandin E2 (PGE2) and Transforming Growth Factor Beta (TGFß). Indomethacin and E-prostanoid 2 (EP2) receptor antagonism both reversed while EP2 agonism restored MAPC cell-mediated in vitro T-cell suppression, confirming the role for PGE2. Furthermore, cyclo-oxygenase inhibition following allo-BMT abrogated the protective effects of MAPC cells. Importantly, MAPC cells had no effect on the generation cytotoxic T lymphocyte activity in vitro, and the administration of MAPC cells in the setting of leukemic challenge resulted in superior leukemia-free survival. Collectively, these data provide valuable information regarding the biodistribution and regulatory capacity of MAPC cells, which may inform future clinical trial design.

Chronic Myeloid Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph) which results from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase CML.

Aggressive lymphoma subtype is a risk factor for venous thrombosis. Development of lymphoma - specific venous thrombosis prediction models.

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score. A group of 790 patients were diagnosed from 2002 to 2014 (DLBCL = 542, FL = 248). Median follow- up was 49 months. We observed 106 VTE, with higher incidence in DLBCL (5-year cumulative incidence = 16.3% vs 3.8% in FL patients). Five-year OS for patients with VTE was 51.4% vs 73.1% in patients without VTE (P < .001). Baseline VTE risk factors identified in the training cohort included lymphoma subtype, previous VTE, ECOG performance status ≥2, decreased albumin, increased calcium, elevated WBC, absolute lymphocyte count or monocyte count, and presence of bulky disease. Addition of new variables to the Khorana score improved its performance measured by Akaike information criterion and Concordance index. A new risk model including lymphoma subtype, albumin, WBC count, and bulky disease was validated in time-based ROC analyses. These findings were confirmed in the validation cohort. Lymphoma subtypes have different VTE risk. The effect of lymphoma subtype was independent from disease burden and the use of systemic therapy. The Khorana risk-score was validated in time to event analyses, and a more robust lymphoma-specific VTE risk score is proposed. These findings suggest lymphoma patients with highest VTE risk can be identified with baseline parameters.

Posttransplant maintenance therapy for acute leukemias.

PURPOSE OF REVIEW: Allogeneic hematopoietic stem cell transplantation cures a significant proportion of patients with hematological malignancies. Unfortunately, leukemia recurrence is the main cause of transplant failure. Risk factors for relapse include presence of minimal residual disease and a variety of well-recognized leukemia prognostic factors. Posttransplant therapy could decrease the risk of leukemia relapse and is under investigation. In this review, we summarize the current research in maintenance therapy for the prevention of acute leukemia recurrence after allogeneic transplant. RECENT FINDINGS: Epigenetic modifiers, tyrosine kinase inhibitors, and antibody-drug conjugates are among potential maintenance therapies given their side-effect profile and many are currently under investigation. In the posttransplant setting, the phase I/II data are maturing and have been encouraging enough to lead to the initiation of multicenter phase III randomized clinical trials. SUMMARY: Currently, there is no standard of care for posttransplant maintenance for acute leukemias. Further investigation into the efficacy and safety of posttransplant maintenance is warranted given phase I/II clinical trials results. Beyond chemo-immunotherapy, the use of targeted cellular therapy, such as chimeric antigen receptor T cells, is a potential therapy as well.

Gastrointestinal Microbiome and Mycobiome Changes during Autologous Transplantation for Multiple Myeloma: Results of a Prospective Pilot Study.

Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome.

Chronic Myeloid Leukemia, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.

Human mesenchymal stromal cells attenuate graft-versus-host disease and maintain graft-versus-leukemia activity following experimental allogeneic bone marrow transplantation.

We sought to define the effects and underlying mechanisms of human, marrow-derived mesenchymal stromal cells (hMSCs) on graft-versus-host disease (GvHD) and graft-versus-leukemia (GvL) activity. Irradiated B6D2F1 mice given C57BL/6 BM and splenic T cells and treated with hMSCs had reduced systemic GvHD, donor T-cell expansion, and serum TNFα and IFNγ levels. Bioluminescence imaging demonstrated that hMSCs redistributed from lungs to abdominal organs within 72 hours, and target tissues harvested from hMSC-treated allogeneic BMT (alloBMT) mice had less GvHD than untreated controls. Cryoimaging more precisely revealed that hMSCs preferentially distributed to splenic marginal zones and regulated T-cell expansion in the white pulp. Importantly, hMSCs had no effect on in vitro cytotoxic T-cell activity and preserved potent GvL effects in vivo. Mixed leukocyte cultures containing hMSCs exhibited decreased T-cell proliferation, reduced TNFα, IFNγ, and IL-10 but increased PGE2 levels. Indomethacin and E-prostanoid 2 (EP2) receptor antagonisms both reversed while EP2 agonism restored hMSC-mediated in vitro T-cell suppression, confirming the role for PGE2 . Furthermore, cyclo-oxygenase inhibition following alloBMT abrogated the protective effects of hMSCs. Together, our data show that hMSCs preserve GvL activity and attenuate GvHD and reveal that hMSC biodistribute to secondary lymphoid organs wherein they attenuate alloreactive T-cell proliferation likely through PGE2 induction.

NCCN Guidelines Insights: Chronic Myeloid Leukemia, Version 1.2017.

The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.

Impact of Visceral Obesity on Clinical Outcome and Quality of Life for Patients with Multiple Myeloma: A Secondary Data Analysis of STaMINA (BMT CTN 0702) Trial.

Obesity is a common health problem in patients with multiple myeloma (MM) that has been linked to poor clinical outcomes and quality of life (QoL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of 3 treatment interventions after a single hematopoietic cell transplantation (HCT) (n = 758), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QoL in MM patients. A total of 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high-risk disease according to cytogenetic assessment. The median duration of follow-up was 6 years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QoL measures. This study suggests that visceral obesity, as measured by WHR, might not have a significant impact on clinical outcomes in MM patients undergoing HCT. These findings add to the existing literature on the topic and provide valuable information for healthcare professionals and MM patients. Further studies are needed to confirm these results and to investigate other potential factors that may affect clinical outcomes and QoL in this patient population using modern imaging technologies to assess visceral obesity.

Haplo-cord transplant. Realizing the potential of umbilical cord blood grafts. - A review of techniques and analysis of outcomes.

The combination of cord blood transplant with progenitor cells from partially HLA-matched adult donors (haplo-cord transplant) has been used over the past two decades. In Europe and the US the adult donor graft is CD34 selected and provides early hematopoiesis, but durable engraftment derives from the cord blood graft (CD34 selected haplo-cord). Neutrophil recovery is prompt and rates of acute and chronic GVHD are low. Recent Chinese studies combine cord blood grafts with T-replete haplo-identical grafts (unmodified haplo-cord). The haplo graft usually establishes dominance and UCB chimerism is rarely detected. Comparison studies suggest considerably decreased rates of relapse and improved outcomes, compared with either haplo-identical transplant or CBU transplant, particularly in patients with advanced leukemia. A recent prospective randomized study confirms this. Haplo-cord mitigates the engraftment delay of UCB transplant. The unique biology of UCB grafts results in low GVHD and improved GVL especially beneficial in high-risk disease.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

ABSTRACT: The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post-allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a "3+3" model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post-allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491.

Umbilical cord blood derived cellular therapy: advances in clinical development.

While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.

Vactosertib, a novel TGF-ß1 type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma.

Functional blockade of the transforming growth factor-beta (TGF-ß) signaling pathway improves the efficacy of cytotoxic and immunotherapies. We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF-ß type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma patients who had received ≥2 lines of chemoimmunotherapy. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, while pomalidomide alone historically achieved 20% PFS-6. Following treatment, the immunosuppressive marker PD-1 expression was reduced on patient CD8+ T-cells. Following ex vivo treatment, vactosertib decreased PD-1 expression on patient CD138+ cells, reduced PD-L1/PD-L2 on patient CD138+ cells and enhanced the anti-myeloma activity of autologous T-cells. Taken together, vactosertib is a safe immunotherapy that modulates the T-cell immunophenotype to reinvigorate T-cell fitness. Multiple myeloma (MM) is a genetically heterogeneous hematologic malignancy characterized by the excessive proliferation of clonal plasma cells (1, 2). MM remains mostly incurable but a small group of patients can achieve long-term remission (3). Treatment of MM presents unique challenges due to the complex molecular pathophysiology and genetic heterogeneity (4, 5). Given that MM is the second most common blood cancer characterized by cycles of remission and relapse, the development of new therapeutic modalities is crucial (6, 7). The prognosis for MM patients has improved substantially over the past two decades with the development of more effective therapeutics, e.g., proteasome inhibitors, and regimens that demonstrate greater anti-tumor activity (8-10). The management of RRMM represents a vital aspect of the overall care for patients with disease and a critical area of ongoing scientific and clinical research (10-12).

Placental expanded mesenchymal-like cells (PLX-R18) for poor graft function after hematopoietic cell transplantation: A phase I study.

Persistent cytopenia in the post-hematopoietic cell transplantation (HCT) setting can occur despite adequate engraftment of donor cells. PLX-R18, a placental-derived mesenchymal-like cell product, is expanded ex vivo in a 3-dimensional environment. PLX-R18 cells secrete a large array of hematopoietic factors, which promote regeneration, maturation, and differentiation of hematopoietic cells and stimulate their migration to peripheral blood. This phase 1, first-in-human study (NCT03002519), included 21 patients with incomplete hematopoietic recovery post-HCT. Patients were treated with escalating doses of PLX-R18: 3 patients received 1 million cells/kg, 6 received 2 million cells/kg, and 12 received 4 million cells/kg via multiple intramuscular injections. While patients received only two administrations of cells during the first week, peripheral blood counts continued to increase for months, peaking at 6 months for hemoglobin (Hb, p = 0.002), lymphocytes (p = 0.008), and neutrophils (ANC, p = 0.063), and at 9 months for platelets (p < 0.001) and was maintained until 12 months for all but ANC. The need for platelet transfusions was reduced from 5.09 units/month at baseline to 0.55 at month 12 (p = 0.05). Likewise, red blood cell transfusions decreased from 2.91 units/month at baseline to 0 at month 12 (p = 0.0005). PLX-R18 was safe and well tolerated and shows promise in improving incomplete hematopoietic recovery post-HCT.

Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.

Impact of Visceral Obesity on Clinical Outcome and Quality of Life for Patients with Multiple Myeloma: A Secondary Data Analysis of STaMINA (BMT CTN 0702) Trial.

Obesity is a common health problem among multiple myeloma (MM) patients, and it has been linked to poor clinical outcomes and quality of life (QOL). We conducted a secondary analysis of the BMT CTN 0702, a randomized, controlled trial comparing outcomes of three treatment interventions after a single hematopoietic cell transplant (HCT), to investigate the impact of visceral obesity, as measured by waist-to-hip ratio (WHR), on clinical outcomes and QOL in MM patients. 549 MM patients, median age 55.5 years, were enrolled in the study. The majority of patients received triple-drug antimyeloma initial therapy before enrollment, and 29% had high-risk disease according to cytogenetic assessment. The median follow-up time was six years. There was no significant association between WHR and progression-free survival (PFS) or overall survival (OS) in MM patients undergoing HCT. Similarly, body mass index (BMI) did not significantly predict PFS or OS. Furthermore, there was no significant correlation between WHR and QOL measures. In conclusion, this study suggests that visceral obesity, as measured by WHR, may not significantly impact clinical outcomes in MM patients undergoing HCT. Further studies utilizing imaging technologies to assess the impact of visceral obesity distribution are warranted.

Machine Learning to Predict Risk of Relapse Using Cytologic Image Markers in Patients With Acute Myeloid Leukemia Posthematopoietic Cell Transplantation.

PURPOSE: Allogenic hematopoietic stem-cell transplant (HCT) is a curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Relapse post-HCT is the most common cause of treatment failure and is associated with a poor prognosis. Pathologist-based visual assessment of aspirate images and the manual myeloblast counting have shown to be predictive of relapse post-HCT. However, this approach is time-intensive and subjective. The premise of this study was to explore whether computer-extracted morphology and texture features from myeloblasts' chromatin patterns could help predict relapse and prognosticate relapse-free survival (RFS) after HCT. MATERIALS AND METHODS: In this study, Wright-Giemsa-stained post-HCT aspirate images were collected from 92 patients with AML/MDS who were randomly assigned into a training set (St = 52) and a validation set (Sv = 40). First, a deep learning-based model was developed to segment myeloblasts. A total of 214 texture and shape descriptors were then extracted from the segmented myeloblasts on aspirate slide images. A risk score on the basis of texture features of myeloblast chromatin patterns was generated by using the least absolute shrinkage and selection operator with a Cox regression model. RESULTS: The risk score was associated with RFS in St (hazard ratio = 2.38; 95% CI, 1.4 to 3.95; P = .0008) and Sv (hazard ratio = 1.57; 95% CI, 1.01 to 2.45; P = .044). We also demonstrate that this resulting signature was predictive of AML relapse with an area under the receiver operating characteristic curve of 0.71 within Sv. All the relevant code is available at GitHub. CONCLUSION: The texture features extracted from chromatin patterns of myeloblasts can predict post-HCT relapse and prognosticate RFS of patients with AML/MDS.

A Phase I Study to Determine the Maximum Tolerated Dose of ex Vivo Expanded Natural Killer Cells Derived from Unrelated, HLA-Disparate Adult Donors.

The administration of allogeneic natural killer (NK) cells following a lymphodepleting chemotherapy regimen is emerging as a well-tolerated therapeutic approach in the management of various malignancies. Contrary to the expected complications of allogeneic T cell therapy, there remains no evidence of graft-versus-host disease (GVHD) mediated by NK cells in numerous clinical trials. On the contrary, preclinical and clinical studies suggest that NK cells do not induce GVHD and in fact may prevent its development following allogeneic hematopoietic cell transplantation (HCT). In this study, we sought to determine the maximum tolerated dose of non-HLA-matched donor NK cells derived from peripheral blood and ex vivo expanded using a novel feeder cell platform. In a single-center Phase I clinical trial using a 3 × 3 design, 9 subjects each received 2 infusions of NK cells 2 weeks apart following a preparative regimen of cyclophosphamide (60 mg/kg i.v.) and fludarabine (25 mg/m2/day i.v for 5 days). No exogenous cytokines were administered. NK cells were administered at 3 dose levels: 1 × 107/kg, 2.5 × 107/kg, and 5 × 107/kg. Three subjects had myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), and the other 6 subjects had colorectal carcinoma. Recipients were monitored over a 4-week period for GVHD as well as other adverse events and for persistence of donor NK cells in systemic circulation. Disease assessment was started at 28 days following the first NK cell infusion and continued until postinfusion day 100 or disease progression. In all 9 study subjects, there was no occurrence of GVHD and no dose-limiting toxicities that would warrant cohort expansion at any of the 3 planned cell dose levels. Low-level donor NK cell persistence was observed up to 4 weeks after the first NK cell infusion at all dose levels. The best observed response was a complete response with incomplete platelet recovery in a MDS subject who experienced disease relapse after prior allogeneic HCT. Other responses were stable disease in 1 subject with MDS and 2 subjects with colorectal cancer up to postinfusion day 100. This off-the-shelf, third-party NK cell product can be administered safely without inducing GVHD and exhibits in vivo persistence promoted by preparative lymphodepletion alone. The observed clinical responses could be enhanced by administration of exogenous cytokine support, as well as complementary approaches that promote NK cell function in the tumor microenvironment.