High-dose methotrexate-related pneumonitis in a child with acute lymphoblastic leukemia.

INTRODUCTION: Methotrexate is administered through different routes to treat childhood acute lymphoblastic leukemia. Toxicities of low, intermediate, or high doses of methotrexate have been described in the literature. Methotrexate-induced or related pneumonitis is a rare complication that leads, in most cases, to discontinuing this drug. CASE REPORT: We report a case of a 17-year-old female patient with newly diagnosed B-acute lymphoblastic leukemia who received a high-dose methotrexate on an induction course. Eight days after methotrexate infusion, she developed fever, dyspnea, hypoxemia, and dry cough. Chest computed tomography showed mosaic attenuation of lung parenchyma and bilateral interstitial infiltrate in favor of hypersensitivity pneumonitis with no evidence of bacterial or fungal infections. MANAGEMENT AND OUTCOME: Methotrexate-related pneumonitis was diagnosed and corticosteroids were prescribed. Improvement of the symptomatology was noted within four days. Given the importance of methotrexate in the treatment of acute lymphoblastic leukemia, intrathecal methotrexate was administered without incident and high-dose methotrexate was re-introduced successfully two and a half months after the pneumonitis episode while using corticosteroids. According to Naranjo's algorithm, the reaction to the drug was found to be probable with a score of 6. DISCUSSION: Methotrexate is the backbone of acute lymphoblastic leukemia treatment, but numerous adverse reactions have been published of which methotrexate pneumonitis can be fatal in some cases. In this case, we concluded that this drug can be successfully reintroduced after methotrexate-related pneumonitis.

Evaluation of glycopeptide prescription in high-risk febrile neutropenia: A monocentric study of North Africa.

INTRODUCTION: High-risk febrile neutropenia (FN) is one of the main causes of morbidity and mortality in onco-hematology. The initiation of empirical antibiotic therapy is an emergency that can change the prognosis of some patients. Given the emergence of increasingly resistant Gram-positive bacteremia, glycopeptides, as an empirical treatment, have an important place in the management of high-risk FN. The aim of this study is to evaluate the appropriateness of glycopeptide prescription in high-risk FN patients. METHODS: This study was conducted in the Hematology Department of Fattouma Bourguiba University Hospital of Monastir, Tunisia. Patients with high-risk FN were enrolled during the period between January 1 and December 31, 2020. RESULTS: Of the 29 patients included in this study, 88 FN episodes were noted of which 39 episodes treated with glycopeptides were evaluated. Twenty-four febrile episodes were empirically treated with glycopeptides (27.3%) of which 17 prescriptions (70.8%) were appropriate according to the European Conference on Infection in Leukemia and the Infectious Diseases Society of America recommendations. A therapeutic escalation using glycopeptides was noted in 17% of cases and appropriately opted in 6 FN episodes (40%). CONCLUSION: Prescriptions of glycopeptides were appropriate according to the international recommendations in 71% of the empirical prescriptions and in 40% of the therapeutic escalation using glycopeptides. In high-risk FN episodes, glycopeptides prescriptions should be rationalized and limited to the indications detailed in the international guidelines to control the emergence of multidrug-resistant bacteria.

The diagnostic dilemma of idiopathic intracranial hypertension in a child with acute lymphoblastic leukemia: COVID-19 or cytosine arabinoside?

BACKGROUND: Idiopathic intracranial hypertension is a rare neurological condition among children. Its manifestations vary from mild headaches to loss of vision. Although rare, COVID-19 infection and high dose cytosine arabinoside have been reported as risk factors for this neurological disorder. In patients with acute leukemia, idiopathic intracranial hypertension diagnosis is simple, but finding its etiology can be difficult. CASE PRESENTATION: We report a case of a 9-year-old boy with an ongoing treatment for T-acute lymphoblastic leukemia presenting with persistent headaches and diplopia. A diagnosis of idiopathic intracranial hypertension was retained based on clinical, imaging and laboratory findings. Due to its rarity, we describe its clinical and therapeutic features and highlight the challenging etiological dilemma between COVID-19 infection and high dose cytosine arabinoside administration. CONCLUSION: Persistent headache in a pediatric patient with leukemia can be due to many neurological disorders other than leukemic relapse. Given the improvement of the neurological symptoms after the SARS-CoV-2 PCR negativization and the successful re-introduction of high dose cytosine Arabinoside, the diagnosis of idiopathic intracranial hypertension associated with Covid-19 infection was withheld.

Chronic myeloid leukemia patients in Tunisia: epidemiology and outcome in the imatinib era (a multicentric experience).

Data are limited in developing countries regarding the clinicopathologic features and response to therapy of chronic myeloid leukemia (CML) in the era of imatinib (IM). The objective of this study is to report on the clinicoepidemiologic features of CML in Tunisia, to evaluate the long-term outcome of patients in chronic (CP) or accelerated phase (AP) treated with IM 400 mg daily as frontline therapy, and to determine imatinib's efficacy and safety. From October 2002 to December 2014, 410 CML patients were treated with IM in six Tunisian departments of hematology. Response (hematologic, cytogenetic, and molecular responses) and outcome-overall survival (OS), event-free survival (EFS), and progression-free survival (PFS)-were evaluated. The following prognostic factors were analyzed for their impact on the European leukemia net (ELN) response, OS, EFS, and PFS at 5 years: age, sex, leukocyte count, Sokal score, European Treatment and Outcome Study (EUTOS) score, CML phase, time to starting IM, and impact of adverse events. The median age was 45 years (3-85 years). Two hundred ten (51.2%) patients were male. Splenomegaly was present in 322 of the 410 (79%). Additional cytogenetic abnormalities were encountered in 25 (6.3%) patients. At diagnosis, 379 (92.4%) patients were in CP, 31 (7.6%) were in AP. The Sokal risk was low in 87 (22.5%), intermediate in 138 (35.7%), and high in 164 patients (41.9%). The EUTOS risk was low in 217 (74%), and high in 77 (26%) patients. The rates of cumulative complete cytogenetic response (CCyR), major molecular response (MMR), and molecular response 4/5 log (MR4.5) in CP/AP-CML patients were 72, 68.4, and 46.4%, respectively. The median time to reach CCyR, MMR, and MR4.5 was 6 months (3-51), 18 months (3-72), and 24 months (3-100), respectively. According to the ELN criteria, optimal, suboptimal response, and failure were noted in 206 (51.8%), 61 (15.3%), and 125 (31.4%) patients, respectively. Five-year event-free survival (EFS), progression-free survival (PFS), and overall survival (OS) were 81, 90, and 90%, respectively. By multivariate analysis, AP, high EUTOS risk, and baseline WBC ≥ 150G/l remained independent predictive factors of non-optimal response to IM. The adverse events (AE) of IM were moderate and tolerable. With the caveats that the monitoring of the disease was not optimal, response rates were similar to those reported in previous studies. It is clear to us that improvements should be made in treatment of AP-CML and high Sokal risk group of CP-CML. The frontline use of second-generation tyrosine kinase inhibitor (TKI) is expected to improve the results of the first-line treatment of these high-risk Tunisian patients, but cost and accessibility of this therapy remain the problems in developing countries.

Familial hematological malignancies: new IDH2 mutation.

Isocitrate dehydrogenase IDH 1 and IDH 2 mutations were reported in several cancer forms, especially in hematological malignancies, but were never been investigated in familial aggregation. The aim of this study is to determine whether germline isocitrate dehydrogenase genes mutations are involved.We targeted IDH1 and IDH2 genes in 104 familial cases belonging to Tunisian and French populations, including several forms of hematological malignancies and cosegregated solid tumors.We report one IDH1 variant: c.315 G>T, p.Gly105Gly in 15 % of cases, which was assigned to the worst outcome in several studies. Three IDH2 variants were found, among them, one intronic substitution c.543+45 G>A (rs142033117) and two new variants not previously described: c.389 A>T, p.Lys130Met and c.414 T>C, p.Thr138Thr. The p.Lys130Met was found in one case diagnosed with Waldenstrom's disease with familial history of cancer. The enrolled in silico analysis, the functional study, and the absence of this variant in control population strengthen the hypothesis of its deleterious effect.From an extended number of candidate genes analyzed in familial hematological malignancies, IDH2 might be considerably involved since we reported a potential damaging effect.

Extramedullary plasmacytoma of the orbit complicating the evolution of multiple myeloma in complete remission.

Orbital plasmacytoma is rare and has only been reported in the context of the initial diagnosis of multiple myeloma. Moreover, isolated orbital plasmacytoma without any signs of multiple myeloma is extremely rare. We report the case of a 59-year-old female patient diagnosed with IgA Kappa multiple myeloma. It was stage I ISS (International Staging System) and stage I R-ISS (Revised ISS). According to the Tunisian national protocol, the patient was included in the standard-risk group and was eligible for four cycles of CTD (Cyclophosphamide, Thalidomide, Dexamethasone) followed by autologous stem cell transplantation. Taking into account the partial response after the CTD cycles, the patient has benefited from two VTD cycles (Bortezomib, Thalidomide, Dexamethasone). Thus, complete remission was obtained. The patient refused autologous stem cell transplantation. Therefore, maintenance treatment based on Thalidomide only was started and received over a twelve-month period. Five months after the end of maintenance treatment, she reported frontal headaches that were resistant to symptomatic treatment, with ptosis in the right eye in physical examination. Brain MRI revealed the presence of a right cranio-orbital tissue mass with intra-orbital and extra-axial cerebral components. The mass measured 32/36 mm on axial sections and 47 mm in height. The patient underwent a complete resection of the cranio-orbital mass with cranioplasty. The histopathological examination of the mass with Immunohistochemistry staining confirmed the diagnosis of orbital plasmocytoma. An update of the multiple myeloma assessment did not reveal any biological, cytological or radiological signs in favor of multiple myeloma. Therefore the diagnosis of isolated orbital plasmacytoma without signs of multiple myeloma was made. Post-operative brain MRI showed complete disappearance of the right cranio-orbital tissue lesion. There was only a persistent meningeal enhancement of the dura mater at the surgical site, suggestive of post-operative changes. The patient was then referred for cranio-orbital radiotherapy.

Chronic-phase chronic myeloid leukemia: Incidence of BCR/ABL transcript and its correlation with presenting features, response to treatment, and survival.

Introduction: Chronic myeloid leukemia (CML) is characterized by Philadelphia chromosome resulting in the fusion between the BCR gene, located on chromosome 22, and the ABL gene on chromosome 9. The prognostic significance of BCR-ABL transcript variants in CML is controversial. The aim of the current study was to evaluate the clinico-hematological presentation and evolution of the disease, response to treatment and survival according to transcript type in chronic phase CML patients. Results: The median age of our population was 50 years with a slight female predominance (sex-ratio 0.78). Sixty percent had the b3a2 transcript and 34% had the b2a2 type. Patients with the co-expression of these two transcripts (4.5%) and those with e19a2 were excluded from the analysis. Patients with b3a2 subtype were associated significantly with thrombocytosis (p = 0.006) and higher Sokal score (p = 0.038) compared to those with b2a2 transcript. The two isolated transcripts were not significantly associated with gender, age group, blast cell percentage or the identified ranges of spleen size. Complete cytogenetic response at 12 months for b3a2 patients and b2a2 patients was 78.6% and 21.4% respectively. This difference was statistically significant (p = 0.001, HR = 9.5, 95% CI 6.5-13.7). Patients with b3a2 transcript had a higher rate of optimal molecular response at 3 months (p = 0.04, HR = 4.2, 95% CI 1-17.3) and major molecular response at 12 months (p = 0.004, HR = 4.9, 95%CI 1.5-15.1). At the date of last follow-up, most patients achieving deep molecular response (MR4 or deeper) belonged to b3a2 group (79%) (p = 0.003, HR = 5.2, 95% CI 1.6-16.4). We did not find a significant difference in OS and EFS between the two groups. Conclusion: Our study concluded that b2a2 transcript is a prognostic factor in cytogenetic and molecular response but further studies are needed to complete this aspect.

Autoimmune hemolytic anemia complicating a chronic neutrophilic leukemia: A case report of a rare association.

Key Clinical Message: Chronic neutrophilic leukemia is a rare disease with a poor prognosis. Its diagnosis is challenging in the lack of genetic tools. It can infrequently be associated with autoimmune hemolytic anemia. Abstract: Chronic neutrophilic leukemia is a rare disease with poor prognosis, characterized by a sustained mature neutrophilic leukocytosis in the absence of monocytosis or basophilia with few or no circulating immature granulocytes, hepatosplenomegaly, and granulocytic hyperplasia of the bone marrow. In addition, no molecular markers for other myeloproliferative neoplasms are detected. The 2016 WHO classification included the presence of the CSF3R mutation as a key diagnostic criterion for this disease. Although anemia may be present at diagnosis, hemolytic one rarely complicates myeloproliferative neoplasms. Treatment is largely based on cytoreductive agents, but bone marrow allograft remains the only curative option. We report the case of a patient with chronic neutrophilic leukemia associated with autoimmune hemolytic anemia. We describe the epidemiological, clinical, prognostic, and therapeutic features of this disease in addition to the difficulties of its diagnosis and management in Tunisia.

Photodistributed pustular acute febrile neutrophilic dermatosis revealing an acute myeloid leukemia.

Sweet syndrome is a rare inflammatory dermatosis that can be associated with various diseases, including leukemias. Physicians should be aware that a photodistributed clinical presentation of a pustular SS may reveal underlying malignancies, particularly hemopathies. If the hemopathy is known, recurrence lesions should be suspected of a relapse.

Mutational analysis of TP53 gene in Tunisian familial hematological malignancies and sporadic acute leukemia cases.

Mutations are responsible for familial cancer syndromes which account for approximately 5-10 % of all types of cancers. Familial cancers are often caused by genetic alterations occurring either in tumor suppressor or genomic stability genes such as TP53. In this study, we have analyzed the TP53 gene by direct sequencing approach, in a panel of 18 Tunisian familial hematological malignancies cases including several forms of leukemia, lymphoma and myeloid syndrome and 22 cases of sporadic acute leukemia. In one familial case diagnosed with acute lymphoblastic leukemia, we reported an intronic substitution 559+1 G>A which may disrupt the splice site and impact the normal protein function. Most of the deleterious mutations (Arg158His; Pro282Trp; Thr312Ser) as classified by IARC data base, were commonly reported in ALL cases studied here. The cosegregation of the two variants rs1042522 and rs1642785 was observed in most patients which may be in favor of the presence of linkage disequilibrium. The most defined TP53 mutations found here were identified in acute lymphoblastic leukemia context whereas only 3 % of mutations have been in previous studies. The cosegregation of the two recurrent variant rs1042522 and rs1642785 should be further confirmed.

[Adult primary myelodysplastic syndromes. Report of 36 cases]. / Syndromes myelodysplasiques primitifs de l'adulte. A propos de 36 cas.

Between 1989 and 1999, 36 cases with primary myelodysplastic syndromes were diagnosed. They were 15 male and 21 females, the median age was 62 years (range: 22 to 90 years). Eighty one per cent of patients were presented symptoms of anemia. Lymphadenopathy, splenomegaly and skin manifestations were noted in 25% of cases. Hemogram showed anemia, leucopenia and thrombocytopenia respectively in 97%, 44% and 55% of cases. Refractory anemia with excess blasts (AREB) is the most frequent FAB subtypes of MDS (17 cases). Cytogenetic study concerned 24 patients. In 13 cases the karyotype was pathological with deletion 5 q in 64% of cases. Seventeen patients have received a chemotherapy. Survival rate to 36 months is 11%. At the time, the only curative treatment is the bone marrow transplantation, which is proposed to young patients with HLA identical donor.

[Epidemiologic, clinical and therapeutic aspects of chronic lymphoid leukemia: apropos of 120 cases]. / Aspects épidémiologiques, cliniques et thérapeutiques de la leucémie lymphoïde chronique: à propos de 120 cas.

We retrospectively studied 120 cases of chronic lymphocytic leukemia diagnosed between January 1988 and December 1998. The median age of our patients was of 66 years, 75% among them were male. The discovery of the illness was fortuitous in 20% of the cases, the peripheral adenopathy and the splenomegaly were noted respectively in 72 and 48% of the cases. The blood lymphocytosis was on average 51.109/1 with extremes of 5 and 818.109/1. Anemia was noted in 71% of the cases and a thrombopenia in 42%. Fifty patients were classified C stage of BINET and sixty elevated risk according to RAI. The therapeutic attitude was according to patient's age and the CLL stage. Thus, 94 patients received a chemotherapy and a complete or partial response was observed in 58 of the cases. The overall survival at 5 years were 47%. The retained prognostic factors were the stage according to the classifications of BINET and RAI, the thrombopenia and the lymphocytosis blood overhead 100.109/1.

Molecular cytogenetic study of derivative chromosome 9 deletion in chronic myeloid leukemia patients.

The aims of this study are to investigate the frequency of derivative chromosome 9 (der (9)) deletion in Tunisian patients with chronic myeloid leukemia (CML) and to assess the correlation between this deletion and the cytogenetic response for patients treated with hydroxyurea (HU) or imatinib (IM). Karyotype analysis of 336 patients with CML was performed with R-banding technique. Fluorescence in situ hybridization (FISH) was carried using home-brew probes 17L7 and 248J22 for detecting, respectively, adjacent 5'ABL and 3'BCR deletions on der(9). Cytogenetic study demonstrated typical t(9;22)(q34;q11) translocation in 89.6% and variant translocation in 10.4% of patients. Interphase FISH studies showed deletion of der(9) in 59 (17.6%) of the 336 patients, 23 (39%) of them had variant rearrangements. There are 19 patients with solely 5'ABL deletion and 40 with concomitant 5'ABL and 3'BCR deletions. Cytogenetic response was evaluated during 18 months with HU or IM therapy. Our results demonstrate that (a) 3'BCR deletion is associated with 5'ABL deletion in all patients with der(9) deletions, (b) the 5'ABL and 3'BCR deletions arise simultaneously with t(9;22), (c) deletions on der(9) chromosome were frequently encountered in older patients and in patients presenting variant rearrangements, (d) both 5'ABL and 3'BCR deletions were associated with cytogenetic response failure in patients treated with HU, however, patients treated with IM and carrying der(9) deletions presented better cytogenetic response.

Molecular study of the perforin gene in familial hematological malignancies.

Perforin gene (PRF1) mutations have been identified in some patients diagnosed with the familial form of hemophagocytic lymphohistiocytosis (HLH) and in patients with lymphoma. The aim of the present study was to determine whether patients with a familial aggregation of hematological malignancies harbor germline perforin gene mutations. For this purpose, 81 unrelated families from Tunisia and France with aggregated hematological malignancies were investigated. The variants detected in the PRF1 coding region amounted to 3.7% (3/81). Two of the three variants identified were previously described: the p.Ala91Val pathogenic mutation and the p.Asn252Ser polymorphism. A new p.Ala 211Val missense substitution was identified in two related Tunisian patients. In order to assess the pathogenicity of this new variation, bioinformatic tools were used to predict its effects on the perforin protein structure and at the mRNA level. The segregation of the mutant allele was studied in the family of interest and a control population was screened. The fact that this variant was not found to occur in 200 control chromosomes suggests that it may be pathogenic. However, overexpression of mutated PRF1 in rat basophilic leukemia cells did not affect the lytic function of perforin differently from the wild type protein.

[Acute renal failure caused by renal lymphoma. A case report]. / Insuffisance rénale aiguë révélatrice d'un lymphome rénal. A propos d'un cas.

Acute renal failure, as the initial manifestation of lymphoma, has been reported only in a few cases. In this work, we report the case of a 28-year-old women admitted for acute renal failure. Her physical examination detected bilateral kidney enlargement. Laboratory evaluation revealed a serum creatinine value 218 micromol/l. A 24-hour urine collection analysis allowed the detection of 1g of protein. No red cells were found after urinanalysis. Renal ultrasound showed massively enlarged kidneys. Renal biopsy of the kidney and pathologic examination showed diffuse infiltration of the interstitium with lymphocytes and atypical cells positive for CD20 markers. A diagnosis of diffuse large B-cell type non-Hodgkin lymphoma was made. However, investigations revealed the presence of two others sites of lymphoma: gastric and ophthalmic. The patient's renal function and kidney size as well as the other lymphoma locations were normalized after the initiation of chemotherapy.

Molecular cytogenetic characterization of variant Philadelphia translocations in chronic myeloid leukemia: genesis and deletion of derivative chromosome 9.

The mechanisms for the formation of variant Philadelphia (Ph) translocations that occur in 5-10% of patients with chronic myeloid leukemia (CML) are not fully characterized. Studies on the prognosis of these variant translocations have yielded conflicting results, especially regarding imatinib outcome and the status of deletions on the derivative chromosome 9. To shed light on these controversial subjects, we sought to analyze all variant translocation cases presented at diagnosis and identified in our institution between the years 2001 and 2008. Of 336 CML patients who presented at diagnosis and were studied by conventional cytogenetics and fluorescence in situ hybridization (FISH), 25 patients (7.44%) exhibited variant Ph-rearrangements. All chromosomes could be implicated in variant Ph rearrangements, with 32 breakpoints defined. Their distribution was located preferentially in the CG-richest regions of the genome. Deletions on der(9) were observed in 15 of the 25 cases (60%), a greater proportion in typical Ph translocations (12-15%). Both one- and two-step mechanisms were encountered in our series, as well as multiple-step mechanisms, which originate more complex rearrangements. Higher prevalence was observed for the two-step mechanism (56%). Proper assessment of the prognostic significance of variant translocations requires better categorization of these translocations based on their mechanisms of genesis and 9q34 deletion status.