A Case Report of Kidney Transplantation in a Patient With Pre-existing Chronic Myeloid Leukemia: The Role of Achieving Molecular Response and Treatment-Free Remission.

BACKGROUND: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is achieved when a patient who has discontinued tyrosine-kinase inhibitor treatment sustains major molecular response (MMR) and does not require restarting therapy. The feasibility of kidney transplantation (KT), and achieving TFR post-transplantation in patients with a pre-existing CML, are currently not well-studied. METHODS: We describe the clinical course of a 39-year-old Filipino woman with IgA nephropathy who developed CML during treatment. She received nilotinib 600 mg daily and was able to achieve MMR after 5 months. Eight years later, the patient sustained MMR; however, she ultimately underwent KT due to advancing kidney disease. Before the transplant, she was able to achieve deep molecular response. In anticipation of possible drug-to-drug interaction of nilotinib with tacrolimus and everolimus, a shared decision was made to discontinue nilotinib despite not fulfilling the criteria for TFR. Twelve months post-transplant, the patient remains in MMR without nilotinib. Good renal allograft function was maintained, and there were no signs of allograft rejection. CONCLUSIONS: Attempting TFR may be feasible after KT in patients with low-risk chronic phase CML especially if good molecular response is obtained before the transplant. Data regarding the length at which TFR can be maintained after KT is still yet to be determined. In this regard, low-risk chronic phase CML in good disease control may not be considered a contraindication to KT.

A Case Report of Successful Kidney Transplantation in a Patient With Chronic Myelogenous Leukemia (CML) Who Has Been in Remission for 15 Years on Imatinib.

For chronic myeloid leukemia (CML), a Philadelphia chromosome-positive myeloproliferative neoplasm, the introduction of tyrosine kinase inhibitors has transformed CML from a lethal disease into a manageable chronic disease with a close-to-normal life expectancy. Active malignancy is an absolute contraindication to kidney transplantation. However, it is controversial whether kidney transplantation can be safely performed in patients with a history of CML who are in remission. We describe the clinical course of a 64-year-old male patient with chronic kidney disease from diabetic nephropathy (DMN) who underwent living donor kidney transplantation. The patient was diagnosed with CML 15 years ago and promptly achieved cytogenetic and molecular biological remission after starting imatinib. After that, he continued imatinib treatment for 15 years and was in remission, but his chronic kidney disease from DMN gradually worsened. A preemptive living donor kidney transplant was performed in July 2020. Imatinib for CML was discontinued because the patient maintained deep molecular remission (DMR) of major molecular response for more than 15 years before kidney transplantation. After kidney transplantation, the transplanted kidney function remained good at approximate serum creatinine levels of 1.1 mg/dL without histopathologic rejection, and the 3 monthly BCR-ABL1 measurement results were negative and are in progress. Thus, he continues to maintain treatment-free remission status without imatinib for 26 months after renal transplantation. In conclusion, this result suggests that CML with long-lasting DMR on imatinib therapy can be considered an inactive malignancy and therefore a relative indication for kidney transplantation.

Association between bariatric surgery and outcomes in chronic myeloid leukemia.

BACKGROUND: Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown. METHODS: In a retrospective analysis, we screened 652 patients with CML and identified 22 with prior bariatric surgery, and compared their outcomes to a matched cohort of 44 patients with no prior bariatric surgery. RESULTS: The rate of early molecular response (3-month BCR::ABL1 < 10% International Scale) was lower in the bariatric surgery group compared with the control group (68% vs. 91%; p = .05), with longer median times to achieve complete cytogenetic (6 vs. 3 months; p = .001) or major molecular responses (12 vs. 6 months; p = .001). Bariatric surgery was associated with inferior event-free survival (5-year, 60% vs. 77%; p = .004) and failure-free survival (5-year, 32% vs. 63%; p < .0001). In a multivariate analysis, bariatric surgery was the only independent predictor for the risk of treatment failure (hazard ratio, 9.40; 95% CI, 2.71-32.55; p = .0004) or event-free survival (hazard ratio, 4.24; 95% CI, 1.67-12.23; p = .008). CONCLUSIONS: Bariatric surgery is associated with suboptimal responses that require adapted treatment strategies.

Severe spontaneous acute arterial subdural hematoma as an initial symptom of chronic myeloid leukemia.

Acute subdural hematoma (SDH) is a rare occurrence in chronic myeloid leukemia (CML) patients with only two cases reported in literature. However, sudden severe acute SDH caused by CML has not been reported on. Our patient was admitted for 'sudden unconsciousness for more than 1 hour'. Computed tomography (CT) angiography revealed a large amount of acute SDH on the left side. Physical exam showed the patient's left pupil was dilated and signs of cerebral herniation were present. The preoperative coagulation profile was normal. Emergency craniotomy for hematoma clearance and decompression was performed. During the surgery, a ruptured cerebral artery was located in the perisylvian region and hemostasis was achieved through electrocautery. Pre-operative white blood count was 58,100 cell/µl, with post-operative bone marrow examination、cytogenetic analysis and RT-PCR detection revealing a diagnosis of CML, for which hydroxyurea chemotherapy was initiated. Leukocyte count of the patient gradually returned to normal. After 24 days, the patient regained consciousness and on day 30, repeat CT scan showed no SDH recurrence. The patient recovered with no neurological deficits and achieved a good prognosis.

Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy.

Chronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.

A Case of Multiple Sclerosis-Like Relapsing Remitting Encephalomyelitis Following Allogeneic Hematopoietic Stem Cell Transplantation and a Review of the Published Literature.

Complications involving the central nervous system (CNS) occur in 9-14% of patients following allogeneic hematopoietic stem cell transplantation (HSCT), including stroke-like episodes, demyelination, encephalitis, and nonspecific neurological symptoms. Here we report a case of multiple sclerosis (MS) like relapsing remitting encephalomyelitis following allogeneic HSCT, which did not respond to disease modifying therapies (DMTs) and "domino" autologous HSCT. A 53-year-old male was treated with allogeneic HSCT for lymphoid blast transformation of chronic myeloid leukemia. Ten months later he presented with confusion, slurred speech, left sided facial weakness and ataxia. A magnetic resonance imaging brain scan showed multiple enhancing tumefactive lesions. Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibodies were negative. After extensive investigations for infections, autoimmune disorders and recurrence of malignancy, he underwent brain biopsy, which showed a macrophage rich lesion with severe myelin loss but axonal preservation indicating a demyelinating pathology. Although his symptoms improved with corticosteroids, he relapsed five months later. In the absence of any systemic features suggesting graft versus host disease (GvHD), his presentation was thought to be compatible with MS. The illness followed an aggressive course that did not respond to glatiramer acetate and natalizumab. He was therefore treated with "domino" autologous HSCT, which also failed to induce long-term remission. Despite further treatment with ocrelizumab, he died of progressive disease. An autopsy limited to the examination of brain revealed multifocal destructive leukoencephalopathy with severe myelin and axonal loss. Immunohistochemistry showed macrophage located in the perivascular area, with no T or B lymphocytes. The appearance was unusual and not typical for chronic MS plaques. Reported cases of CNS demyelination following allogeneic HSCT are very limited in the literature, especially in relation to histopathological examination. Although the clinical disease course of our patient following allogeneic HSCT resembled an "MS-like" relapsing remitting encephalomyelitis, the autopsy examination did not show any evidence of active inflammation. The impact of DMTs and HSCT on the histological appearance of "MS-like" CNS pathologies is unknown. Therefore, reporting this and similar cases will improve our awareness and understanding of underlying disease mechanisms.

Outcomes of allogenic hematopoietic cell transplantation for childhood chronic myeloid leukemia: Single-center experience.

BACKGROUND/OBJECTIVES: Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic SCT remains the only curative treatment for CML especially in younger patients, but TRM should be considered. We evaluated the clinical outcomes of pediatric CML patients who had SCT in our center. METHODS: This retrospective study included children with CML, who received an allogeneic SCT at Children Cancer Hospital Egypt, 57357, from 2007 to 2017. All patients received myeloablative conditioning chemotherapy containing busulfan/cyclophosphamide followed by stem cell infusion from MRD. RESULTS: From 121 patients diagnosed with CML, 43 had available MRD and subjected to HSCT while 78 patients continued TKI therapy. The median time to transplant from diagnosis was 13 months. At initial diagnosis, there were 39 patients in CP and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with average stem cell dose of 4.45 × 106 /kg. The probabilities of overall survival and event-free survival at 5 years were 97.4% and 79.8%, respectively. TRM at 100 days and TRM at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P = .004). CONCLUSION: Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML with best using marrow stem cell source to avoid a significant risk of cGVHD and its related complications.

[Postoperative Adjuvant Chemotherapy for Descending Colon Cancer Treated with Imatinib for Chronic Myeloid Leukemia].

A66 -year-old man was diagnosed with chronic myeloid leukemia(CML). Imatinib treatment had been initiated, and a major molecular response(MMR)was achieved. The patient had anemia and was diagnosed with descending colon cancer. The patient was surgically treated, and then received postoperative adjuvant chemotherapy with UFT/LV. However, imatinib was not administered during that period. The patient could undergo postoperative adjuvant chemotherapy for 6 months without acute exacerbation of the CML.

Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT.

BACKGROUND: Anti-thymocyte globulin (ATG) is widely used to prevent graft-versus-host disease (GVHD) after allogeneic peripheral blood stem cell transplantation (alloPBSCT). The goal of this study was to retrospectively assess the effect of ATG on outcomes in the setting of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). METHODS: In the analysis, 1170 adult patients undergoing alloPBSCT from human leucocyte antigen-matched sibling or unrelated donors in the first complete remission between 2007 and 2016 were included. ATG was used in 429/575 (75%) and 121/595 (20%) patients transplanted from unrelated or sibling donors, respectively. RESULTS: The incidence of chronic GVHD was 35% for patients treated with ATG compared with 52% in those not receiving ATG (p < 0.001), while the rate of extensive chronic GVHD was 16% and 36%, respectively (p < 0.001). The probability of survival free from GVHD and relapse (GRFS) was 42% and 32%, respectively (p = 0.002). In a multivariate model, the use of ATG was associated with reduced risk of overall chronic GVHD (hazard ratio [HR] = 0.52, p < 0.001) and extensive chronic GVHD (HR = 0.46, p < 0.001). It was also associated with better GRFS (HR = 0.77, p = 0.007), despite increased risk of relapse (HR = 1.41, p = 0.02). No significant effect was found with regard to the risk of non-relapse mortality and overall mortality. CONCLUSIONS: The use of ATG for patients with Ph+ ALL undergoing alloPBSCT is associated with reduced risk of chronic GVHD without impact on survival and therefore, could be considered. However, increased risk of relapse suggests the need for strict monitoring of minimal residual diseases and appropriate interventions after transplantation.

[A Case of Chronic Myelogenous Leukemia That Developed Fibrous Pericarditis Owing to Nilotinib Use].

A 64-year-old man was diagnosed with chronic-phase chronic myelogenous leukemia(CML)in May 2009. He was treated with imatinib and achieved complete cytogenetic response(CCyR)in 2 months. After 4 months of treatment, he developed interstitial pneumonia and became intolerant to imatinib. He was then switched to nilotinib from October of the same year. In June 2013, he was diagnosed with drug-induced pericarditis resulting from nilotinib use, and thus, nilotinib was discontinued. Subsequently, he was followed up without specific treatment for CML. In January 2014, he was admitted to the Dept. of Cardiovascular, Renal and Metabolic Medicine at our hospital because of heart failure. After examinations of cardiac function, he was diagnosed with constrictive pericarditis. Therefore, pericardiolysis was performed by the Dept. of Cardiovascular Surgery at our hospital. Pathologic findings showed hyaline-like fibrous tissue proliferation in the pericardium, which was diagnosed as fibrous pericarditis induced by nilotinib. We report a case of chronic myelogenous leukemia that developed fibrous pericarditis owing to nilotinib use.

BCR-ABL1 transcripts (MR4.5) at post-transplant 3 months as an early predictor for long-term outcomes in chronic myeloid leukemia.

BACKGROUND/AIMS: The aim of this study was to identify the role of BCR-ABL1 transcript level as a predictor for post-transplant relapse and outcome in patients who underwent allogeneic stem cell transplantation (SCT) for chronic phase (CP) chronic myeloid leukemia (CML). METHODS: Of 101 patients receiving allograft in CML CP, 85 had available quantitative reverse transcriptase polymerase chain reaction data at post-transplant 3 months. These patients were divided into two groups according to molecular response (MR4.5), defined as a BCR-ABL1 transcript level ≤ 0.0032% on the international scale, at 3 months based on receiver operating characteristic curve analysis of relapse. RESULTS: The 4-year overall survival and event-free survival (EFS) were 80.6% and 57.3%, respectively, and the cumulative incidence of relapse at 4 years was 29.6% after a median follow-up of 126.4 months. We performed multivariate analyses including potential variables to evaluate the early predictive role of MR4.5 at 3 months and found that MR4.5 at 3 months was associated with a higher EFS (p = 0.028) and showed a trend for a lower relapse rate (p = 0.089). CONCLUSIONS: our results imply that frequent molecular monitoring and immune suppressive therapy modulation are required for patients without reduction of BCR-ABL1 transcripts to this level after SCT.

Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myelogenous Leukemia.

PURPOSE: To compare the relative merits of imatinib and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML). MATERIALS AND METHODS: This cohort study was designed to compare the outcomes of imatinib (n=292) versus allo-HSCT (n=141) for CML, the clinical data of these patients being retrospectively analyzed so as to compare the event free survival (EFS) and overall survival (OS) between these two groups with patients in the chronic phase (CP) and advanced phases, including accelerate (AP) and blast phases (BP). RESULTS: (1) Patients treated with imatinib (278 in the CP) demonstrated superior EFS, OS, 5-year EFS and 5-year OS rates of 88.5% versus 70.0% (P<0.05), 93.2% versus 80.0% (P<0.05), 84% versus 75.0% (P<0.05) and 92% versus 79.0% (P<0.05), respectively, to those treated with allo-HSCT (120 patients in the CP). (2) Both treatments resulted in similar survival, with EFS and OS rates of 42.9% versus 47.6% (P>0.05), 42.9% versus 57.1% (P>0.05), respectively, for imatinib (14 patients in the AP and BP) and allo-HSCT (21 patients in the AP and BP). CONCLUSIONS: Imatinib confers signi cant survival advantage (EFS and OS) for CML patients with CP compared with allo-HSCT treatment. However, the outcomes are equally good with both treatments in AP and BP patients.

Pyomyositis at the surgical site in a patient with chronic myeloid leukemia: a case report and literature review.

BACKGROUND: Pyomyositis is a rare, subacute, deep pyogenic infection of the muscle tissue. This disease has been previously described in patients that were immunocompromised due to a hematological malignancy. CASE PRESENTATION: A 68-year-old man with a history of chronic myeloid leukemia was treated with imatinib. He was diagnosed with ascending colon cancer and underwent curative surgery. His postoperative course was uneventful, and he was healthy at 6 months after surgery, allowing for reinitiation of imatinib therapy. After the reinitiation of therapy, a computed tomography (CT) scan revealed a mass shadow in the right iliopsoas muscle. This lesion was clinically diagnosed as recurrent colon cancer with an abscess, which was resected surgically. A pathological examination uncovered both edema and inflammation. Two months after the second surgery, imatinib therapy was reinitiated; however, he again developed painful swelling and erythema in his right thigh. A CT scan revealed a similar shadow as described previously. He was then diagnosed with pyomyositis; he underwent incisional drainage and was administered linezolid. Following the treatment for pyomyositis, there was no cancer recurrence or evidence of any recurrent pyomyositis. CONCLUSIONS: Findings from this case suggest that both undergoing surgery and receiving imatinib therapy may modulate an individual's immune response, whereby the surgical site becomes more prone to infection and may predispose an individual to pyomyositis. The case report is followed by a discussion of the literature regarding this disease, including potential risk factors and the underlying pathogenesis.

Bacterial Pneumonia-induced Persistent Remission of Severe Immune Thrombocytopenia after Allogeneic Hematopoietic Stem Cell Transplantation.

A 53-year-old woman with chronic myeloid leukemia received allogeneic hematopoietic stem cell transplantation. After neutrophil engraftment, her platelet count exceeded 100,000/µL at day 64. While she was receiving corticosteroid treatment for chronic graft versus host disease (GVHD), her platelets suddenly dropped to 6,000/µL at day 210 and she was diagnosed with immune thrombocytopenia (ITP). Corticosteroids, intravenous high-dose gamma globulin (IVIg) and a splenectomy failed to increase her platelet count. She developed bacterial pneumonia at day 599 and antibiotic therapy was initiated. Soon after, her platelet count continuously increased. Her GVHD and ITP are now in remission without any ongoing treatment.

A Successful Renal Transplantation Case After Stem Cell Transplantation.

Renal transplantation is the most effective treatment method for end-stage renal disease (ESRD). However, new treatment modalities are being investigated, such as immunotoleration, to avoid the acute and chronic side effects of immunosuppressant drugs. We report a case in which a man had undergone allogenic stem cell transplantation from his brother 16 years ago due to chronic myeloid leukemia, and who then developed ESRD due to arterial hypertension and underwent renal transplantation (Rtx) from the same brother. The patient was followed up without immunosuppression due to full chimerism.

Total hip arthroplasty in very young bone marrow transplant patients.

Concerns remain about total hip arthroplasty (THA) performed in very young patients, especially those with complex medical history such as allogeneic bone marrow transplantation (ABMT). This study retrospectively reviews the perioperative courses and functional outcomes of ABMT patients <21 years old undergoing primary uncemented THA. Nine THAs were performed in five ABMT patients at an average age of 19.7 years. The interval between ABMT and THA was 73.0 months with clinical follow-up of 25.8 months. Harris Hip Scores (HHS) increased dramatically from preoperatively 44.5 (range, 31.1-53.4) to postoperatively 85.2 (range, 72.0-96.0) and all patients subjectively reported a good (four hips) to excellent (five hips) overall outcome. There was one reoperation for periprosthetic fracture fixation but there were no infections or revisions performed. Despite the history of severe hematopoietic conditions requiring ABMT, these very young patients do appear to have improved pain and function following primary THA with short-term follow-up.

Lymphoproliferative Disorders in Patients with Chronic Myeloid Leukemia: A Single-Center Case Series.

Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon.