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A new study from Vanderbilt University Medical Center found that a 10-second video of leukocyte movement in the skin's microvascular vessels greatly improved the prediction of their recurrence in blood cancer patients after hematopoietic stem cell transplantation.
1. Background
Leukemia, commonly known as blood cancer, is a malignant neoplastic disease of the hematopoietic system. It may invade various systems, organs, and tissues, and clinically manifest as anemia, bleeding, infectious fever, and infiltration of various organs.
Hematopoietic cell transplantation (HCT) is an important treatment for leukemia, especially in high-risk, refractory patients. According to CIBMTR (International Bone Marrow TransplantAtion Research Center), the recurrence mortality rate after autologous hematopoietic stem cell transplantation (Auto-HSCT) accounts for 78% of all causes of death, and the recurrence mortality rate after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) accounts for 23 to 34% of all causes of death. Post-transplant recurrence generally has a poor prognosis, and effective treatment with minimal side effects is limited.
Therefore, studies of dynamic biomarkers that predict a high risk of recurrence after transplantation are important, which may help clinicians identify and monitor patients at risk of recurrence and death and weigh the risks and benefits of more intensive treatment after hematopoietic stem cell transplantation. For example, patients at higher risk of recurrence may be prioritized for clinical trials.
2. Clinical trials
Between June 2017 and January 2020, Vanderbilt University Medical Center conducted a study using reflex confocal microscopy to non-invasively and dynamically record the flow of white blood cells in the skin's microvessels. Reflex confocal microscopy is a device technology dedicated to living skin examination, based on the principle of laser confocal, through computed tomography, to achieve non-invasive, real-time, dynamic imaging of skin tissue.
In a typical immune response, white blood cells interact with the lining of blood vessels, rolling along the lining of a blood vessel like a bowling ball, then attaching to the lining of a vessel and eventually passing through the vessel into the site of inflammation. Transplant patients with higher levels of leukocyte adhesion and greater rolling along the walls of blood vessels are more than three times more likely to relapse or die than patients with normal levels of adhesion and rolling.
The trial included a total of 56 post-transplant patients, with a median age of 59 years, of which 68% were men. Two researchers counted (A&R) white blood cells that adhere to the blood vessel wall and roll along the blood vessel wall every hour. Based on the clinically meaningful threshold of adhesion or rolling of leukocytes in microvascular vessels (A&R), patients participating in the study were divided into 2 groups, one group of patients with low A&R for a total of 35 (62%), and the other group of patients with high A&R, with a total of 21 (38%).
Results showed that patients with high A&R had a higher recurrence rate (HR, 4.24; 95% CI, 1.32-13.58; P=.02), decreased recurrence-free survival (HR, 3.29; 95% CI, 1.26-8.55; P=.02), decreased overall survival (HR, 3.06, 95% CI, 1.02-9.19; P=.05）。
In addition, the researchers followed up the participants through electronic health records, and within a median 15-month follow-up period, 13 relapsed and 14 died. Of these 13 relapse cases, 9 had higher A&R, of which 8 relapsed within 4 months of imaging.
Comparison of A&R and existing forecasting models
The revised Disease Risk Index (rDRI) is associated with deaths from recurrence, a traditional risk assessment based on retrospective data that may be difficult to reflect improvements associated with new therapies.
With only A&R and rDRI considered, without considering other clinical variables, A&R accounted for 95% (6.44/6.81) of the prognostic information provided by the combined A&R and rDRI prediction OF RFS. In terms of the adequacy of all assessments (OS, CIR, and RFS), new imaging biomarkers (A&R) account for 82% to 95% of prognostic information. In contrast, the best clinical predictors of rDRI accounted for 10 to 28 percent of the prognostic information in the same model. Based on this indicator, A&R is more effective at predicting relapse or death than rDRI.
Fourth, the test summary
The study identified a promising systemic disease biomarker from the interaction of white blood cells with endothelial cells by performing non-invasive confocal video microscopy imaging of skin microvascular. The method can be used to directly quantify a patient's immune process in many clinical applications and can reveal new skin biomarkers that inform systematic treatment decisions.
V. How to prevent recurrence after transplantation in blood cancer patients
The key to preventing recurrence after transplantation lies in good disease control before transplantation, the use of pretreatment protocols, the selection of healthy donors, the monitoring of minimal residual disease, and maintenance therapy.
(1) Whether the disease has been well controlled before transplantation is closely related to the prognosis after transplantation. Prior to transplantation, the disease should be achieved as completely as possible, especially with a high-quality complete remission of a negative micro residual disease. Methods that can be used at this stage include: chemotherapy, CAR-T cell therapy, antibodies and other immunotherapy.
(2) If the patient still cannot achieve complete remission after aggressive treatment, then the appropriate pretreatment plan is very important. In general, the better the pretreatment, the better the clearance effect on the tumor, the recurrence rate may be reduced, and the toxicity may also increase, so it is necessary to balance the efficacy and safety, and develop an individualized pretreatment plan according to the situation of different patients.
(3) The choice of donor at the time of transplantation is also very important, in addition to the matching requirements, it is also required that the donor's hematopoietic and immune functions are normal. In addition, through the screening of genetic susceptibility genes, donors with more immunodeficiency or leukemia-susceptible genes should be avoided as much as possible, which is conducive to reducing the chance of recurrence after transplantation.
(4) For patients with a high risk of recurrence, it is recommended to continue the corresponding maintenance treatment after transplantation.
6. How to deal with recurrence after transplantation
Post-transplant recurrence usually has a poor prognosis, and treatments that are effective and have few side effects are often limited. On the other hand, due to the different patients' physical state, previous treatment methods, recurrence period and other factors, it is recommended to consider the development of individualized treatment plans.
(1) If graft-versus-host disease (GVHD) is absent or mild, the application of immunosuppressants should be appropriately reduced.
(2) For patients with recurrence of graft-versus-host disease, try to switch to immunosuppressants with anti-tumor activity, and new treatment methods such as CAR-T cell therapy can be adopted.
(3) Secondary transplantation. Secondary transplantation is an effective treatment for recurrence after the first transplant, and studies have shown that the treatment-related mortality rate of patients after secondary transplantation is 18.8%-63%, the recurrence rate is 16%-65%, the overall survival rate is 21%-43%, the disease-free survival rate is 10%-30%, the incidence of acute graft-versus-host disease (aGVHD) is 21%-45%, and the incidence of chronic graft-versus-host disease (cGVHD) is 37%-52%.
(4) Chemotherapy. Chemotherapy alone after relapse is ineffective and is usually used as an adjunct to secondary transplantation.
Graft-versus-host disease (GVHD)
Graft-versus-host disease is a systemic disease of multi-system damage (skin, esophagus, gastrointestinal, liver, etc.) that occurs after hematopoietic stem cell transplantation, and is one of the important causes of death. There are acute (aGVHD) and chronic (cGVHD), the former occurring within 3 months after transplantation and the latter occurring after 3 months of transplantation. Immunocompromised people who transfuse HLA differently into blood can also develop GVHD and can be fatal.