PREVENTION AND MANAGEMENT OF RELAPSE OF ACUTE LEUKEMIA AND MYELODYSPLASTIC SYNDROME AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC PATIENTS

The best way to manage acute leukemia relapse after HCT is to prevent it, buying time for GVL with immunomodulation and, if no GVHD between days +60 and + 90, prophylactic DLI can be indicate for very high or high risk patients. Short-term low dose of cyclosporine or methotrexate can add safety to pro-DLI, particularly after mismatched or unrelated transplantation. Maintenance with imatinib or dastinib, recommended for Ph-positive ALL, with sorafenib, for FLT3-ITD AML, or azacitidine, for myelodysplastic syndrome patients, can be effective in reducing relapse rates. However, target agent maintenance can add toxicity, depends on patient adherence and demands physician experience to know when is safe to start, how adjust the dose according individual tolerance after transplant and to detect undesirable drug interactions. The second step to avoid hematological relapse is preemptive approach guided by measurable residual disease or mixed chimerism. In patients off immunosuppression, chemotherapy followed by DLI is a useful strategy, and if no response, interferon alpha can be associated to enhance GVL. Target-specific agents can be start at this point either. After relapse, antigen-directed therapy with blinatumumab for CD19 ALL, inotuzumab for CD22 ALL are excellent options to induce MRD negativity and facilitate HCT. Disadvantages of new immunotherapies are: high incidence of VOD with inotuzumab and gemtuzumab; lower response in patients with high leukemia burden or concurrent extramedullary relapse; necessity of consolidation with HCT after a bridging therapy with BiTE and probably with CAR-T cell therapy also. It is important to realize that if remission after chemotherapy is associated with the development of GVHD, then there may be limited benefit (and possibly harm) in consolidating with any kind of cellular therapy. However, for patients who achieved remission without GVHD, either DLI or second transplant can be recommend. Further studies are necessary to determine at which point each strategy might yield the best results.

Cardiac Relapse of Acute Lymphoblastic Leukemia Following Hematopoietic Stem Cell Transplantation: A Case Report and Review of Literature

Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In some instances, survival times for relapsed ALL at these sites are longer than those for relapsed disease involving only the bone marrow. Isolated relapse of ALL in the myocardium is rare, especially in children, making diagnosis and treatment of it difficult. More recent treatment options such as chimeric antigen receptor T-cell therapy carry a high risk of cytokine release syndrome and associated risk of worsening cardiac function. Herein we present the case of an 11-year-old boy who presented with relapsed symptomatic B-cell ALL in the myocardium following allogeneic hematopoietic stem cell transplantation. This is an unusual presentation of relapsed ALL and this case demonstrates the associated challenges in its diagnosis and treatment. The case report is followed by a literature review of the advances in treatment of pediatric leukemia and their application to extramedullary relapse of this disease in particular.

Other (Non-CNS/Testicular) Extramedullary Localizations of Childhood Relapsed Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma—A Report from the ALL-REZ Study Group

Children with other extramedullary relapse of acute lymphoblastic leukemia are currently poorly characterized. We aim to assess the prevalence and the clinical, therapeutic and prognostic features of extramedullary localizations other than central nervous system or testis in children with relapse of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) treated on a relapsed ALL protocol. Patients and Methods: Patients with relapse of ALL and LBL, treated according to the multicentric ALL-REZ BFM trials between 1983 and 2015, were analyzed for other extramedullary relapse (OEMR) of the disease regarding clinical features, treatment and outcome. Local treatment/irradiation has been recommended on an individual basis and performed only in a minority of patients. Results: A total of 132 out of 2323 (5.6%) patients with ALL relapse presented with an OEMR (combined bone marrow relapse n = 78; isolated extramedullary relapse n = 54). Compared to the non-OEMR group, patients with OEMR had a higher rate of T-immunophenotype (p < 0.001), a higher rate of LBL (p < 0.001) and a significantly different distribution of time to relapse, i.e., more very early and late relapses compared to the non-OEMR group (p = 0.01). Ten-year probabilities of event-free survival (pEFS) and overall survival (pOS) in non-OEMR vs. OEMR were 0.38 ± 0.01 and 0.32 ± 0.04 (p = 0.0204) vs. 0.45 ± 0.01 and 0.37 ± 0.04 (p = 0.0112), respectively. OEMRs have been classified into five subgroups according to the main affected compartment: lymphatic organs (n = 32, 10y-pEFS 0.50 ± 0.09), mediastinum (n = 35, 10y-pEFS 0.11 ± 0.05), bone (n = 12, 0.17 ± 0.11), skin and glands (n = 21, 0.32 ± 0.11) and other localizations (n = 32, 0.41 ± 0.09). Patients with OEMR and T-lineage ALL/LBL showed a significantly worse 10y-pEFS (0.15 ± 0.04) than those with B-Precursor-ALL (0.49 ± 0.06, p < 0.001). Stratified into standard risk (SR) and high risk (HR) groups, pEFS and pOS of OEMR subgroups were in the expected range whereas the mediastinal subgroup had a significantly worse outcome. Subsequent relapses involved more frequently the bone marrow (58.4%) than isolated extramedullary compartments (41.7%). In multivariate Cox regression, OEMR confers an independent prognostic factor for inferior pEFS and pOS. Conclusion: OEMR is adversely related to prognosis. However, the established risk classification can be applied for all subgroups except mediastinal relapses requiring treatment intensification. Generally, isolated OEMR of T-cell-origin needs an intensified treatment including allogeneic stem cell transplantation (HSCT) as a curative approach independent from time to relapse. Local therapy such as surgery and irradiation may be of benefit in selected cases. The indication needs to be clarified in further investigations.

Extramedullary relapse in a patient with multiple myeloma: a rare cause of gastrointestinal perforation and massive bleeding

Multiple myeloma (MM) patients live longer due to more effective treatment, and we now see previously uncommon manifestations of MM, like extramedullary disease. We present a case of a 74-year-old man known with MM that relapsed with extramedullary manifestations at different locations. One of them as a gastric plasmacytoma (GP). He was successfully treated with chemoradiotherapy (Daratumumab, Bortezomib and Dexamethasone), which resulted in clinical response for 8 months, confirmed by biopsy and histopathology. Perforation of the GP occurred, and he underwent partial gastrectomy (Billroth II gastrojejunostomy). The patient’s disease progressed again 5 months after surgery, and he did not want any additional treatment. He accepted palliative care and died 10 months after the operation. A lack of knowledge about the characteristics and treatment of extramedullary MM exists, and prospective studies to investigate incidence, prognosis and treatment for extramedullary MM are needed for improving the poor prognosis of this manifestation.

CD19 CAR-T Cells With Membrane-Bound IL-15 for B-Cell Acute Lymphoblastic Leukemia After Failure of CD19 and CD22 CAR-T Cells: Case Report

ObjectivesAt present, reinfusions of chimeric antigen receptor (CAR)-T cell have exhibited limited efficacy, while their efficacy on extramedullary relapse remains to be further elucidated in B-cell acute lymphoblastic leukemia (B-ALL). Although combination with IL-15 demonstrated the potential to enhance antitumor activity of CAR-T, the efficacy of this approach remains to be validated clinically.MethodsWe reported a patient with B-ALL with extramedullary relapse after allogeneic stem cell transplantation and who was resistant to chemotherapy and radiotherapy. In total, he received four treatments with CAR-T cells repeatedly under the status of disease progression.ResultsFirst, the patient received autologous murine CAR19-CD28-CD3ζ-T cells and achieved full resolution of extramedullary leukemia lasting 8 months. After systemic disease relapse, he received autologous humanized CAR22-41BB-CD3ζ-tEGFR-T cells and achieved complete remission (CR) with incomplete blood count recovery (CRi) with minimal residual disease (MRD) negativity in the bone marrow and shrinkage of extramedullary leukemia. Over 2 months later, he experienced a relapse of the systemic disease and he received autologous murine CAR19-41BB-CD3ζ-mIL15-T cells and achieved CRiMRD- lasting 5 months with the strongest expansion and persistence of CAR. Finally, on relapse of CD19− medullary disease, he received allogeneic humanized CAR22-41BB-CD3ζ-tEGFR-T cells but only achieved a transient decrease in the number of blasts. No CAR-T-cell-related encephalopathy syndrome was observed, and all side effects were manageable.ConclusionOur report hints the feasibility and safety of CD19 CAR-T cell expressing membrane-bound IL-15 for patient with B-ALL even if relapsed after multiple CAR-T-cell therapies.

Treatment of Central Nervous System Relapse in Acute Promyelocytic Leukemia by Venetoclax: A Case Report

Extramedullary relapse of acute promyelocytic leukemia is a rare phenomenon and is associated with a poor prognosis, with the central nervous system being the most common site of relapse. The current treatments are still limited. Venetoclax, a selective inhibitor of BCL2, is a small molecule that can cross the blood-brain barrier and shows a potential efficacy in the treatment of chronic lymphocytic leukemia with central nervous system involvement. Although venetoclax has also been used in the treatment of acute myeloid leukemia in recent years, there are no reports of its use in the treatment of central nervous system relapse in acute promyelocytic leukemia. Here, we report a case of central nervous system relapse in acute promyelocytic leukemia that achieved complete remission after oral treatment with venetoclax. The presence of venetoclax in the patient’s CSF was confirmed by testing CSF and plasma by mass spectrometry. The concentration of venetoclax in CSF was approximately 1/300 of that in plasma trough concentration. The treatment experience in this case demonstrates the potential ability of venetoclax to treat of central nervous system relapse/involvement in acute promyelocytic leukemia, thus providing a new treatment option for this kind of patient.