A Case of Tyrosine Kinase Inhibitor-Induced Bone Marrow Aplasia That Was Successfully Treated with Allogeneic Hematopoietic Stem Cell Transplantation

Here, we present a rare case of tyrosine kinase inhibitor (TKI)-induced bone marrow aplasia. A 58-year-old man presented with leukocytosis and was diagnosed with chronic myeloid leukemia. He was initially treated with imatinib for 6 years and abruptly discontinued treatment by himself. He was administered dasatinib 5 years after treatment interruption, and presented with pancytopenia 6 months after dasatinib initiation. Bone marrow biopsy revealed severe hypocellularity without blasts. Dasatinib was discontinued, and he recovered from pancytopenia 3 months later; however, <i>BCR-ABL1</i> was positive for almost all white blood cells in the peripheral blood. We retreated with ponatinib, but pancytopenia developed again. The clinical course indicated TKI-induced bone marrow aplasia. Therefore, ponatinib was discontinued and the patient received an allogeneic hematopoietic stem cell transplantation from a haploidentical daughter using post-transplant cyclophosphamide. He had a major molecular response and had normal complete blood counts and bone marrow 1 year after transplantation.

Allogeneic transplantation in autoimmune disease and bone marrow aplasia - case report

Ulcerative rectocolitis (UC) is an inflammatory bowel disease of unknown etiology that mainly affects the mucosa of the rectum and colon. Anemia is the most common hematological disorder in patients with UC and may be due to multiple causes such as blood loss, malabsorption, chronic illness and infection. We present a case report, in which UC and severe aplastic anemia (ASA) occur concomitantly, suggesting a common immune compromise between such pathologies.

Hemophagocytosis or emperipolesis by lymphoblast after rapid transformation of chronic myeloid leukemia

A Male, 11-Years-Old, Admitted In March 2019 With Chronic myelogenous leukemia (CML) in treatment with Imatinib. Three months after diagnosis in outpatient visit was observed increase of splenomegaly and appearing of inguinal and cervical adenomegalies. Bone marrow apiration revealed 70% of blasts, some of them with hemophagocytosis (Figure 1). The immunophenotyping showed blasts positive for CD10, CD19, CD20, CD22, CD79a, CD45, HLA-DR, indicating transformation to B precursors ALL. Bone marrow karyotype was 46,XY,t(9;22), FISH (BCR-ABLES probe) confirmed rearrangement with p210. The patient was treated with higher dose of Imatinib (600 mg/m²), but evolved with bone marrow aplasia and infectious process, being then reajusted to 400 mg/m² with clinical and hematologic improvement. After 30 days had disease aggravation and resistance to Imatinib. The patient initiated EsPh-ALL 2009 protocol, but in D33 with no remission of disease continued with protocol. In September, during consolidation phase evolved with Central Nervous System infiltration and disease persistence, dying for disease in progress. This patient had no clinical findings of Hemophagocytic Lymphohistiocytosis (HLH) and bone marrow cytology showed the several hematopoietic cells inside blast cells.

CLINICO HEMATOLOGICAL PROFILE OF PATIENTS WITH PANCYTOPENIA- A THREE-YEAR STUDY

Background: Pancytopenia is a relatively common hematological entity. It may result from relatively benign causes such as viral infections and vitamin B12/folic acid deciency to more fatal bone marrow aplasia and leukaemias. The severity of pancytopenia and the underlying pathology determine the management and prognosis. Objectives: To study the etiology and clinic-hematological prole in patients of peripheral blood pancytopenia. Materials And Methods: This was a retrospective study conducted at G S Medical College, Hapur and Noida international institute of Medical Sciences Greater Noida, during the period of November 2017 to November 2020 Results: A total of 192 patients (103 males and 89 females) were diagnosed to have pancytopenia. Most of the patients presented with generalized weakness and fever. The commonest physical nding was pallor, followed by splenomegaly. The various causes of pancytopenia included infections(n=132), megaloblastic anaemia (MA)(n=46), drugs, aplastic anaemia and subleukaemic leukaemia. We found a signicant association between megaloblastic anaemia and pancytopenia. Conclusion: The present study concluded that infection and megaloblastic anaemia are the most common cause of pancytopenia. The more serious disorders affecting the bone marrow constitute only <5% of all cases of pancytopenia.

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

Background Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications. Case presentation We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis. Conclusions This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.

Identification of Predictive Markers of Severe and Prolonged Neutropenia after CD19-Specific CAR T-Cell Treatment in Patients with Relapsed/Refractory B-Cell Malignancies

Introduction: Genetically engineered CD19-specific CAR T-lymphocytes have emerged as a powerful new class of immunotherapeutic agents in relapsed/refractory B-cell malignancies. However, their utility is hampered by unique toxicities including prolonged cytopenias that can predispose for severe infectious complications. Here, we evaluate predictive markers of hematotoxicity in patients treated in the real-world setting. Methods: To define the incidence and nature of CAR T-cell associated hematotoxicity, we performed a retrospective chart review across three German academic hospitals (LMU Munich, Tübingen, Hamburg-Eppendorf). Between January 2019 and June 2020, a total of 69 patients (58 r/r B-NHL, 11 BCP-ALL) were studied following treatment with the commercial CD19-specific CAR T-cell products Axi-cel (n=43) or Tisa-cel (n=26). The relative impact of baseline (=prior to lymphodepletion) demographic, laboratory and clinical characteristics on hematotoxicity was analyzed by uni- & multivariate analysis using the following primary endpoint: duration of clinically significant neutropenia - defined as an ANC &lt;500/µl - between days 0-60. Results: In this heavily pre-treated cohort, the incidence of severe neutropenia (ANC &lt;500/µl) was 97% with a median duration of 12 days (95% CI: 10-15). Neutropenia followed a bimodal temporal curve with intermittent hematopoietic recovery upon G-CSF support. Profound, protracted (ANC &lt;100/µl for ≥7 days) and prolonged (ANC &lt;1000/µl after day 21) neutropenia was common, occurring in 36% and 78% of patients respectively. The incidence of severe anemia (Hb &lt;7 g/dl or requiring pRBC transfusion) and severe thrombocytopenia (PLT count &lt;50 G/l) was 68% and 71% respectively. Of note, a total of 12 patients (17 %) observed severe, G-CSF-refractory bone marrow aplasia with an ANC &lt; 500/µl greater than 30 days. The following baseline clinical markers were significantly correlated with the duration of neutropenia by univariate or logistic regression analysis (Figure 1): Platelet Count (r = -0.45, P=0.0001), Hemoglobin (r = - 0.33, P=0.006), ANC (r = - 0.28, P=0.02), C-reactive Protein (r = +0.35, P=0.004), Ferritin (r = +0.52, P= &lt;0.0001), and BM Infiltration for lymphoma (LR=6.7, P=0.0096). Interestingly, the following baseline factors were not significantly correlated: LDH, age, prior lines of cytotoxic therapy, and eGFR. On stepwise multivariate analysis using a binary logistic regression for the outcome severe neutropenia ≥ 14 days, baseline ferritin, hemoglobin and platelet count retained significance. In terms of dynamic clinical variables, both peak IL-6 and peak CRP were not associated with increased hematotoxicity, though peak IL-6 exhibited a trend towards significance (r = +0.22, P= 0.077). While peak ferritin was associated with a longer duration of neutropenia (r = +0.37, P=0.025), the peak value was less predictive than the baseline value. Moreover, we observed no nested dependency between hematotoxicity and CRS/ICANS. CRS grade in particular was not associated with prolonged neutropenia in our study cohort. Furthermore, the application of G-CSF was not associated with an increased rate or severity of neurotoxicity. When comparing the duration of neutropenia by CAR product (Axi-cel vs. Tisa-cel) and disease entity (DLBCL vs. BCP-ALL), no statistically significant difference was observed. Conclusions: Profound and prolonged neutropenia was common in our study cohort. This included cases of severe, G-CSF-refractory bone marrow aplasia. The identified predictive markers point toward a multifactorial model of pathogenesis for CAR T-cell associated hematotoxicity. They include markers of impaired hematopoietic reserve (e.g. low baseline PLT count, Hemoglobin, ANC), inflammatory state (e.g. hyperferritinemia, elevated CRP), and tumor microenvironment (e.g. BM infiltration). These findings carry important implications for both risk-stratification and the development of predictive clinical tools. The identified factors are currently being validated in an independent patient cohort and prospective validation is ongoing. Figure 1 Disclosures Blumenberg: Novartis: Research Funding; Gilead: Consultancy, Research Funding; Celgene: Research Funding. Buecklein:Celgene: Research Funding; Pfizer: Consultancy; Amgen: Consultancy; Novartis: Research Funding; Gilead: Consultancy, Research Funding. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Subklewe:Morphosys: Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria, Research Funding; Roche AG: Consultancy, Research Funding.

Postvaccination graft dysfunction/aplastic anemia relapse with massive clonal expansion of autologous CD8+ lymphocytes

Key Points Acquired aplastic anemia is a T-cell–mediated autoimmune bone marrow aplasia, without a known etiologic trigger. Clonal expansion of CD8+ effector T lymphocytes can occur following vaccination and accompany graft dysfunction or aplastic anemia relapse.