Pancytopenia, eosinophilia and coagulation disorders in a patient with T‐acute lymphoblastic leukemia in prolonged remission
Authors: Chrysovalantou Chatzidimitriou, Vasiliki Pappa, Eleftheria Lakiotaki, Eleni Plata, Stylianos Lafioniatis, Maria K. Angelopoulou, Kostas Konstantopoulos, Penelope Korkolopoulou, Theodoros P. Vassilakopoulos
Journal: American Journal of Hematology (2021)

A 68-year-old male patient presented with a new onset, asymptomatic, worsening pancytopenia, and mild eosinophilia. He had been successfully treated with the GMALL 2002 protocol for T-cell acute lymphoblastic leukemia (T-ALL) 15 years earlier, having achieved a sustained complete remission. He was not receiving any medication, neither reported traveling abroad nor contact with pets. Physical examination was unremarkable. The complete blood count on admission was as follows: Ht:28.7%, Hb:10.0 g/dl, RBC:2.86 × 1012/L, MCV:100 fL, MCH:35 pg, MCHC:34.8 g/dl, WBC:3.84 × 109/L (neutrophils:1.8 × 109/L, lymphocytes:0.53 × 109/L, monocytes:0.15 × 109/L, eosinophils:1.2 × 109/L, basophils:0.06 × 109/L, PLT:31 × 109/L). The appearance of pancytopenia in a patient with history of T-ALL firstly raises the clinical suspicion of disease relapse, although such a late relapse is extremely unusual. Szczepański et al. collected data from nine centers and registered 22 late relapses of T-ALL, which occurred >2.5 years after initial diagnosis, and made up approximately 10% of all recurrences.1 The mean time between initial diagnosis and disease recurrence was 5.6 years. The longest time to relapse was 9.5 years and the authors concluded that 36% of late T-ALL recurrences is composed of second malignancies.1 Thus, 15 years is an extremely unusual time for a T-ALL relapse. The next diagnostic possibility to be considered is therapy-related myelodysplastic syndrome (t-MDS), albeit the prolonged time interval of 15 years after the successful treatment of T-ALL is again extremely unusual. In fact, a second malignancy developed in 34/2169 (1.6%) evaluable patients with ALL in the ALL-BFM 95 trial after a median time of 45.7 months (range, 8.7–105.1 months). In 30/34 patients the secondary neoplasm occurred in first CR, with acute myeloid leukemia (AML; n = 9) and MDS (n = 7) being the most frequent, while in 4/34 patients it occurred after treatment for relapse (median follow up time 7.2 years).2 Tavernier et al. analyzed the data from the GET-LALA group, based on 1494 patients with a median follow-up of 6 years from diagnosis. Secondary or concomitant neoplasms were documented in 23 patients, including nine AML or MDS, four non-Hodgkin's lymphomas (NHL) and 10 solid tumors including skin cancers, which developed 0.5–13.8 years after the diagnosis of ALL (median, 4.5 years). The cumulative risk for the occurrence of a second hematologic malignancy was 1.8%, 2.2% and 3.3% at 5, 10 and 18 years respectively.3 Nevertheless, pancytopenia could also arise due to a de novo MDS. However, MDS with eosinophilia is rather uncommon. In a retrospective study of 288 patients with de novo MDS, 12.5% had bone marrow eosinophilia (MDS-Eos) at presentation and 18% of them had peripheral eosinophilia (>0.5 × 109/L) for a total incidence of peripheral eosinophilia of ~2%.4 Patients with MDS-Eos had a poorer survival rate and were at higher risk of evolution to AML compared to MDS patients without eosinophilia. Moreover, a significant correlation of MDS-Eos with chromosome 7 abnormalities, i(17p) and complex karyotype was demonstrated.4 In line with this observation, two case reports of peripheral blood and bone marrow hypereosinophilia in patients with MDS harboring the unbalanced translocation der(1;7)(q10;p10)5 and a ring chromosome 76 have been published. Another study demonstrated that 29/322 patients with MDS (9.0%) had or developed eosinophilia (≥10% of peripheral blood cells), whereas eosinophilia ≥20% was observed in 2.5%.7 The presence of eosinophilia is a clue that could further guide the differential diagnosis in this case. Eosinophilia is defined as an elevation of peripheral blood eosinophil count above 0.5 × 109/L, although various cutoffs have been used, and ranges from mild (<1.5 × 109/L) to moderate (1.5–5.0 × 109/L) and severe (>5.0 × 109/L). The term “hypereosinophilia” (HE) is used to describe cases with persistent eosinophilia (>1.5 × 109/L), which can be divided into the following subtypes: hereditary (familial) HE (HEFA), HE of undetermined significance (HEUS) (previously described as idiopathic), primary (clonal/neoplastic) HE (HEN), and secondary (reactive) HE (HER)(Table 1).8 Invasive aspergillosis and allergic bronchopulmonary aspergillosis, coccidioidomycosis, histoplasmosis No detectable primary or secondary causes for eosinophilia, no end-organ damage attributable to hypereosinophilia Apart from the above possible diagnoses, AML or another hematologic neoplasm with clonal eosinophilia should be ruled out. Note, AML with the recurrent genetic abnormalities t(8;21)(q22;q22.1)(RUNX1-RUNX1T1) and inv16(p13.1q22) or t(16;16)(p13.1;q22) (CBFβ-MYH11) are characterized by bone marrow and occasionally peripheral blood eosinophilia. Chronic eosinophilic leukemia not otherwise specified is another possible diagnosis, but eosinophil count did not exceed 1.5 × 109/L on admission. Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement (PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2, ETV6-JAK2 or BCR-JAK2) should also be included in the differential diagnosis. Among reactive eosinophilias, lymphomas (Hodgkin lymphoma, T-cell NHL and other NHL) or solid tumors with bone marrow infiltration and reactive eosinophilia should be strongly considered in the differential diagnosis as well. Although most other reactive eosinophilias are not associated with pancytopenia, several medical conditions manifesting with pancytopenia and eosinophilia should also be considered. Infections (parasitosis, tuberculosis, and HIV) and autoimmune diseases (connective tissue disorders, vasculitis) should be investigated. Because of the negative history and clinical examination and the presence of pancytopenia, other causes of reactive eosinophilia, such as allergic disorders, dermatological non-allergic causes, gastrointestinal disorders, respiratory diseases, drug-induced eosinophilia, immunodeficiency syndromes, lymphocytic variant of the hypereosinophilic syndrome (HES), or idiopathic HES, miscellaneous and rare causes of eosinophilia would be rather unlikely diagnoses (Table 1). The routine biochemistry profile including renal and liver function, serum lactate dehydrogenase and C-reactive protein (CRP) levels were within normal limits. Serum B12 levels, which, if elevated, might point to a myeloid neoplasm, were normal. End-organ damage assessment by electrocardiograph, echocardiography and lung function tests was negative. The blood smear was not diagnostic showing normal-appearing eosinophils, some of which were degranulated and no blast cells. A peripheral blood analysis for FIP1L1-PDGFRA was pending. A bone marrow aspiration, immunophenotype and karyotype and a trephine biopsy was performed. Shortly after the procedure the patient developed an extended, rapidly growing hematoma at the left gluteal area and the lower extremity, resulting in worsening of anemia and the need of transfusion. The CT imaging was unremarkable, and the patient remained clinically stable, while hospitalized. Coagulation profile revealed PT/INR prolongation, elevated D-Dimers and low fibrinogen levels [PT: 17.0 s, INR: 1.5, APTT: 39.5 s, D-dimers: 27.7 μg/ml (normal: <0.5 μg/ml), fibrinogen: 129 mg/dl (normal range: 180–400 mg/dl)]. Notably, PT/INR was normal 1 week prior to the procedure. The rapid evolution of acute and clinically significant coagulation disorders predominating in the clinical picture, dictated the consideration of an underlying disease that could combine all the major findings, that is, pancytopenia and eosinophilia along with coagulation disorder with severe bleeding diathesis. The most compatible diagnosis for bleeding diathesis according to the diagnostic scoring system of the Scientific and Standardization Committee on disseminated intravascular coagulation (DIC) of the International Society on Thrombosis and Hemostasis (ISTH) would be DIC (Score: six; PLT 31 × 109/L-score: 2, D-dimers strong increase-score: 3, INR: 1.5-score: 1, fibrinogen: 129 mg/dl-score: 0).9 In this setting, a solid tumor with bone marrow metastasis and DIC appeared as the most likely diagnosis. The most common neoplasms presenting in this manner include prostate cancer, small cell lung cancer, neuroblastoma or even a lymphoma. Additionally, monocytic leukemias and acute promyelocytic leukemia frequently present with coagulation disorders and DIC, but are not typically associated with eosinophilia. Tumor markers, including PSA and whole body CT imaging were negative. Endoscopy of the gastrointestinal tract and bronchoscopy were considered but not performed due to the bleeding complications. Immunoglobulins and serum total immunoglobulin E (IgE), fresh stool microscopy for ova, cysts and parasites as well as serological tests for suspected parasitic infections (strongyloidiasis, schistosomiasis, filariasis, toxocariasis), serology for coeliac or connective tissue disease or vasculitis-related autoantibodies and serology for hepatitis B, hepatitis C, human immunodeficiency virus, cytomegalovirus and parvovirus B19 were negative. The bone marrow smear was poor in cellular elements with marked eosinophilia but no increased blasts, no unequivocal dysplastic features or evidence of non-hematologic neoplastic cell infiltration. Bone marrow immunophenotype confirmed the presence of eosinophilia without findings consistent with T-ALL relapse or elevated CD34+ blast cells. Based on the negative whole body CTs and tumor markers, the presence of a solid tumor with associated DIC, which was the most likely diagnosis, became rather unlikely. Moreover, after extended investigation, no secondary causes of eosinophilia were revealed. Taken together, a hematologic neoplasm with clonal eosinophilia, specifically a myeloid/lymphoid neoplasm with eosinophilia and gene rearrangement (PDGFRA, PDGFRB, FGFR1, PCM1-JAK2), systemic mastocytosis, AML, ALL, aCML or CMML with eosinophilia must be excluded. Interestingly, myeloid/lymphoid neoplasms with FGFR1 rearrangements are frequently T-cell lymphoblastic lymphomas/ALL, while rare cases of T-cell ALL/lymphoblastic lymphoma have been described in the setting of PDGFRA-associated or PDGFRB-associated disorders. Myeloid/lymphoid neoplasms with PDGFRA rearrangements may present with anemia and/or thrombocytopenia in addition to eosinophilia, but leukopenia is not typically observed.10 Bone marrow aspirate cytology was inconclusive, and only confirmed marked eosinophilia, but the obtained material was of rather poor quality and could exclude neither solid tumor metastasis nor acute leukemia or MDS. Bone marrow immunophenotype was also non-diagnostic but carried the same limitations. A bone marrow (BM) biopsy and cytogenetic analysis, which was pending, would be of paramount diagnostic importance in this setting. Serum tryptase and molecular testing for the aforementioned gene rearrangements should also be performed. Serum tryptase levels were > 200 ng/ml (normal: <20), thus significantly elevated. The RT-PCR for PDGFRA rearrangements was negative. The BM biopsy revealed myelodysplastic features with fibrosis and mastocytic infiltration consistent with systemic mastocytosis (SM), as concluded by the presence of clusters of spindle-like cells, which were ckit+, tryptase+, CD25+ (Figure 1). Monosomy 7 was demonstrated by bone marrow conventional cytogenetic analysis (45, XY, −7[5]/45, X, -Y[8]/46, XY[7]). The absence of the corresponding lesions in conventional cytogenetic analysis obviated the need for molecular assays to exclude PDGFRB, FGFR1, and PCM1-JAK2 rearrangements. Further molecular testing revealed the cKIT D816V mutation. Based on the BM findings (MDS and SM) and the mutation of KIT D816V, the diagnosis of SM with associated hematologic neoplasm (SM-AHN) was made, fulfilling the major and three of four minor criteria required. Interestingly, PDGFRA-related and PDGFRB-related myeloproliferative neoplasms may show an increase in mast cells in trephine biopsy, which may be organized or not in clusters and may be spindle-shaped, resembling those of SM,10 but the KIT D816Vmutation undoubtedly favored the diagnosis of SM in this case. Elevated serum tryptase levels, although a minor diagnostic criterion for SM, is not considered diagnostic in case of SM-AHN, because tryptase is often elevated in the context of haematologic disorders. Monosomy 7 is a characteristic cytogenetic finding in t-MDS. Coagulation disorders can be fully interpreted in the context of SM. The main pathogenetic mechanisms of the hemorrhagic diathesis are related to the enhanced release of mast cell mediators during degranulation and are described in detail below. The patient was treated with interferon-alpha (IFN-α) and had rapid clinical and laboratory improvement, while the use of corticosteroids and fresh frozen plasma had previously failed to improve the coagulation disorder (Figure 2). However, he could not tolerate IFN-α and refused the option of midostaurin. Despite this decision, he maintained a normal coagulation panel for 9 months. Independently, he was treated with azacytidine and achieved a complete morphologic and cytogenetic remission of MDS. A consultation for a potential allogeneic stem cell transplant was obtained. However, after 6 months he decided to discontinue treatment and presented again with asymptomatic hypofibrinogenemia and pancytopenia. He responded well to a short course of IFN-α and then to midostaurin and azacytidine but again had poor compliance. He died 20 months since initial diagnosis. Regarding treatment of SM-AHN, it is generally accepted to manage the two components of the disease simultaneously and independently. In the present case, treatment with IFN-α and azacitidine and, subsequently, midostaurin and azacitidine, resulted in the reversal of the severe coagulation disorder, normalization of hematologic parameters and serum tryptase levels and morphologic and cytogenetic remission of MDS. Despite initial treatment success, long-term effectiveness could not be evaluated in this case due to poor compliance. Systemic mastocytosis is a rare clonal disease, characterized by bone marrow and other target organ/tissue infiltration by neoplastic mast cells and release of their mediators in the circulation, resulting in highly heterogenous clinical presentations, relevant to most medical specialties. According to the WHO classification, the following SM subtypes are defined on the basis of mast cell burden and clinical signs of end organ dysfunction: Indolent SM (ISM), including the bone marrow mastocytosis (BMM) subtype, smoldering SM (SSM), SM with an associated hematological neoplasm (SM-AHN), aggressive SM (ASM) and mast cell leukemia (MCL). Whereas ISM and SSM have an indolent clinical course and no effect on life expectancy, advanced mastocytosis is characterized by an aggressive clinical course with reduced life expectancy.11 Note, SM-AHN is the second most common SM subgroup.12 In SM-AHN the non-mast cell lineage disease is usually of myeloid origin, most commonly including a myeloproliferative neoplasm (MPN), MDS, myelodysplastic/myeloproliferative (MDS/MPN) neoplasm or AML.13 Lin et al. and Pardanani et al. reported a 45% incidence of SM-MPN, 29% SM-chronic myelomonocytic leukemia (SM-CMML) and 23% SM-MDS. Only 11% had non-myeloid disease, namely lymphoma, myeloma, chronic lymphocytic leukemia or primary amyloidosis.12, 14 Although SM-MDS is common among SM-AHN, the involvement of t-MDS in this entity has not been adequately studied. In the present case, clinical history and karyotypic abnormalities (monosomy 7) strongly support the diagnosis of t-MDS developing 15 years after the initial treatment of T-ALL, providing information on a unique case in the literature, to the best of our knowledge. A second notable aspect in this case is the rare presentation of SM with a severe bleeding disorder as a leading symptom. There are some published cases and small series reporting SM-associated coagulation disorders.15-18 The main pathogenetic mechanisms underlying bleeding diathesis are related to the release of mast cell mediators during degranulation. Firstly, tryptase may exert fibrinogenolytic and kininogenolytic actions causing hypofibriginonemia and bleeding tendencies.19-21 Secondly, bleeding diathesis may be mediated by the anticoagulant action of heparin, which is exerted either through upregulation of thrombomodulin and consequent activation of protein C and S pathways,22 or through binding to and blockade of von Willebrand factor (vWF) and impairment of platelet adhesion via glycoprotein Ib (GPIb) and aggregation via GPIb and GPIIbIIIa,23 thus leading to an acquired vW disease.15 In addition, release of antithrombin III may represent an additional bleeding mechanism in SM.24, 25 In this case, the extremely low levels of fibrinogen strongly supported the first mechanism. Of note, the coagulation disorders were reversible only after treatment of SM, while use of vitamin K, FFP and corticosteroids proved ineffective, which has also been noted by Carvalhosa et al as well. This is rather expected on the grounds of involvement of the first mechanism, since the infused fibrinogen will be cleaved in vivo by tryptase. In conclusion, SM-AHN involving t-MDS as a second malignancy, and particularly with very late onset after treatment of T-ALL is unique information in the literature. The associated bleeding diathesis, a rare complication of SM, further contributed to this exceptional disease presentation. So, SM should be considered in the differential diagnosis of coagulation disorders. A screening for coagulation abnormalities might eventually be incorporated at the initial diagnostic work-up of SM in order to avoid unnecessary procedures and minimize bleeding risk. The authors declare no conflict of interest. This section is not applicable, since this is a case report.