Author: Blue Whale Xiaohu
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Case sharing
The patient, a 35-year-old female, was transferred to our department due to "abnormal blood routine found after pancreas-kidney combined transplantation for 1 week".
The patient underwent pancreatic and kidney transplantation 2 weeks ago due to end-stage renal disease. Induction therapy with 100 mg of thymoglobulin and 500 mg of methylprednisolone was received prior to transplantation. The maintenance immunosuppressive regimen is tacrolimus + prednisone + mycophenolate mofetil.
Blood count 1 week after transplantation: white blood cell count 80×109/L (reference range 4-10), neutrophils 29×109/L (1.5-8), eosinophils 0.8×109/L (0-0.5), basophils 0.8×109/L (0-0.5), hemoglobin 95 g/L (120-160), platelet count 440×109/L (150-400), granulocyte system: promyelocytes 2% (0%) ), myelocytes 1% (0%), late myelocytes 11% (0%-1%). Peripheral blood smear shows normal cell hypochromic anemia, mild polychromatic erythrocytosis with acanthocytes, markedly pleutrophils (lobulated nuclear granulocytes) with left shift and no blasts, and normal platelet morphology. Transferred to our department for further treatment.
Anamnesis: Diagnosed with type 1 diabetes 27 years ago, diabetic retinopathy 10 years ago, diabetic nephropathy.
A greater proportion of myelocytes in bone marrow cells than late myelocytes is one of the classic manifestations of chronic myeloid leukemia, with an increased absolute basophil count in more than 90 percent of patients [1]. The results of routine blood examination 1 month before transplantation were reviewed: leukocytes 20×109/L, hemoglobin 106 g/L, platelets 281×109/L, granulocyte system: promyelocytes 2%, mesomyelocytes 2%, and late myelocytes 2%.
Combined with the course and clinical manifestations of the patient before and after transplantation, the lack of infection, solid tumors, massive bleeding, acute hemolysis and other related triggers was used to rule out leukemia-like reactions. High suspicion of hematologic malignancy with specialist tests such as flow cytometry, molecular testing, and bone marrow biopsy.
BCR-ABL1 fusion gene P210 (e13a2) was detected by fluorescence in situ hybridization of peripheral blood. Bone marrow cytology showed that myeloproliferasia was extremely active (90%) with trilineage hematopoietic function (Fig. 1).
Figure 1. Bone marrow aspirate showed active myeloid hyperplasia, and the ratio of granulo-red (M/E) = 19.3 (Wright-Giemsa staining: A. Raw magnification× 200;B. Raw magnification×1000)[2]
The BCR-ABL1 transcript was examined by PCR of bone marrow specimens, and the results showed that BCR-ABL1(IS): 92%, which was highly suggestive of CML. Cytogenetic examination showed abnormal female karyotype, and a total of 20 cells were analyzed, and all (20/20) had translocations between the long arm of chromosome 22 and the long arm of chromosome 9, forming the BCR-ABL1 fusion gene, and the diagnosis was CML chronic phase.
The patient was started on dasatinib 70 mg/day (Note: Although data showed that dasatinib 50 mg/day was effective and had a better safety profile, the approved dose for the chronic phase of CML was 100 mg/day. Considering the patient's medical comorbidities and possible interaction with tacrolimus, the dose was reduced to 70 mg/day).
At follow-up after 3 months, the patient achieved molecular remission, with BCR-ABL1 transcript reduced to 0.42% and BCR-ABL1IS reduced to 0.06% at 6 months.
Subsequently, the patient's immune status is assessed periodically by mixed lymphocyte response assay (CFSE-MLR) and immunosuppressive therapy is adjusted accordingly. After 12 months of treatment with dasatinib, limited CD4+ and CD8 T+ cell proliferation was observed in the anti-host response (Figure 2), and allogeneic kidney biopsy showed no signs of rejection. Twelve months after her diagnosis of chronic myeloid leukemia, she maintained a complete hematologic response (CHR) and achieved MMR.
Figure 2. Kinetics of CD4+ and CD8+ T cell stimulation index (SI).
Chronic myeloid leukemia
Chronic myeloid leukemia (CML) is a malignant disease of hematopoietic stem cells dominated by myeloid hyperplasia, accounting for about 15% of adult leukemia. The Philadelphia chromosome (Ph) is a characteristic alteration of CML, seen in 95% of CML patients, and can form the BCR-ABL1 fusion gene at the molecular level, which encodes a BCR-ABL1 protein with extremely strong tyrosine kinase activity, which can lead to the loss of regulation of cell proliferation, leading to malignancy [3].
The CML phenotype may vary depending on the type of BCR-ABL1 fusion. The transcripts of the three BCR-ABL1 fusion genes were P190/P210/P230, with the former being the most common. With the clinical application of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 fusion genes, such as imatinib, nilotinib, dasatinib and flumatinib, the prognosis of CML patients has been greatly improved, and second-generation TKIs can achieve faster and deeper molecular remission. The 10-year overall survival rate of patients with newly diagnosed chronic myeloid leukemia (CML-CP) is 85%-90%, and the life expectancy is close to normal.
Autoimmune diseases and myeloproliferative neoplasms
Autoimmune diseases (AID) increase the risk of myeloproliferative neoplasms. A population registry-based study in Sweden reported that patients with CML were at higher risk of developing autoimmune disease prior to diagnosis compared with healthy controls (table 1) [4].
Table 1. The odds ratio (OR) of 984 patients diagnosed with CML who had autoimmune disease prior to diagnosis between 2002 and 2012 [4]
The clinical diagnosis of AID often precedes CML, and may be due to the aberrant activation of the innate immune system and pro-inflammatory signals in the bone marrow microenvironment due to inflammation caused by AID. Dysregulation of the monocyte NF-κB pathway in a variety of AID can produce an inflammatory microenvironment, inhibit normal hematopoiesis in the bone marrow, and promote clonal hematopoiesis through somatic mutations to drive the occurrence of leukemia [5]. However, it is not clear whether AID directly contributes to the myeloid microenvironment, and this hypothesis relies mainly on epidemiological studies with certain limitations. Given the history of type 1 diabetes mellitus in this patient, autoimmune mechanisms may be one of the predisposing factors for CML.
How does an organ transplant increase myeloid tumor risk?
Malignancy is the second leading cause of death in solid organ transplant recipients, with a reported incidence of 2.6 to 11.5 percent of tumors after transplantation, and 25 percent of tumors found within two years of transplantation [6]. With the improvement of the survival rate of transplant recipients and the long-term use of immunosuppressants, the emerging problem of tumors after solid organ transplantation has become increasingly prominent. It is generally believed that the use of immunosuppressants reduces the body's immune surveillance function of tumors, affects DNA repair, leads to irreversible damage, and then causes tumorigenesis.
The incidence of hematologic malignancies after solid organ transplantation varies from study to study and across organ transplants. A 2018 review published in Am J Transplant [7] showed that among all organ transplant recipients, the incidence of Hodgkin lymphoma (HL) was 11 per 100,000 person-years, plasma cell neoplasia was 15.2 per 100,000 person-years, acute myeloid leukemia (AML) was 13.2 per 100,000 person-years, and acute lymphoblastic leukemia (ALL) was 2.2 per 100,000 person-years.
Pathogenesis may be related to the following factors [6,8]:
- The use of exogenous and non-specific immunosuppressants to prevent and treat allogeneic transplant rejection and impairing the immune surveillance of tumor cells;
- Drugs such as azathioprine may have a direct DNA-damaging effect on cells;
- Epstein-Barr virus plays a key role in the pathogenesis of post-transplant lymphoproliferative disorders (PTLDs).
Morton et al. [9] analyzed the standardized incidence ratios (SIRs) of 207859 cases of myeloid tumors after solid organ transplantation in the United States between 1987 and 2009 as follows:
Table 2. Risk ratio of specific myeloid tumors in solid organ transplant recipients
*Risk ratio compared to normal healthy people
According to a case series published by mainland scholars [10], the median interval from organ transplantation to tumor diagnosis in 23 patients with myeloid tumors (inclusive) was 56 months. The incidence of myeloid tumors increases with age, but in organ transplant recipients, all myeloid tumors are more susceptible in younger recipients, with the exception of polycythemia vera, and the SIR decreases with age (Figure 3) [9].
Figure 3. Specific myeloid neoplasm incidence (per 100,000 person-years) and standardized incidence ratio in solid organ transplant recipients stratified by age at transplant [9]
Oncology screening in solid organ transplant recipients
At present, there are many clinical practice guidelines (CPG) related to the screening of solid organ transplant malignancies, but most of the CPG malignancy screening is based on the screening of the general population. Multiple CPGs [11] recommend screening for hematologic malignancies by history, physical examination, and complete blood count (table 3).
Although CML was diagnosed 3 weeks after kidney transplantation, the pre-transplant complete blood count with differential showed clear signs suggestive of hematologic malignancy. Unexplained leukocytosis should be examined in more detail and detail, including a peripheral blood smear.
Table 3. Recommendations for tumor assessment in solid organ transplant recipients from multiple foreign clinical practice guidelines[11]