Zarys objawów klinicznych, leczenia oraz trudności w rozpoznawaniu choroby Gauchera

Gaucher disease, a rare autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, can be difficult to diagnose in the absence of a known affected family member. This is particularly true in non-Jewish patients with mild phenotypes due to the incomplete awareness of signs and symptoms of Gaucher disease among physicians (e.g., internists). Here, we present an outline of clinical manifestations of Gaucher disease with a particular focus on hematologic symptoms. A historical outline of Gaucher disease and currently available treatment options for this disorder are briefly summarized. Last but not least, we present issues related to possible diagnostic pitfalls in non-neuropathic patients with an undiagnosed Gaucher disease

Atypical cytomorphology of Gaucher cells is frequently seen in bone marrow smears from untreated patients with Gaucher disease type 1

Introduction. Gaucher cells (GCs), the lipid-laden storage macrophages, are the pathologic hallmark of Gaucher disease (GD). They are typically 20–100 μm in diameter with eccentrically placed nuclei and cytoplasm with characteristic crinkles and striations. A few previous observations have indicated that sometimes GD patients may display morphology of GCs which is different from this classical description. The aim of our study was to explore the morphological polymorphism of GCs in patients with untreated GD type 1 (GD1). Material and methods. May-Grünwald Giemsa stained bone marrow smears (BM-S) from 6 patients with sporadic GD1 were analysed; each patient sample consisted of two slides where all GCs and non-Gaucher cell macrophages were counted. We have defined for the study purposes and examined the following features of GCs which were considered as atypical: (1) foamy cytoplasm, (2) centrally placed nucleus, (3) cell diameter > 100 μm, (4) multinuclearity, (5) syncytial morphology, (6) unusually large cytoplasmic projections, and (7) apparent haemophagocytosis. Results. All analysed patients showed 22–40% GCs with atypical cytomorphology (median 29%). The median number of atypical features of GCs was 10 per patient (range 6–13). Multinuclearity was the most common atypical feature of GCs, followed by erythrophagocytosis and foamy cytoplasm. There was a strong positive correlation between erythrophagocytosis and foamy cytoplasm in GCs (Spearman’s rank correlation coefficient: 0.9). Although majority of atypical GCs had one atypical feature, there was a considerable amount of GCs presenting ≥ 2 atypical features. Conclusions. Untreated patients with GD1 often show a considerable proportion of GCs with atypical cytomorphology. The knowledge of possible atypical variant forms of GCs can contribute to a quicker and accurate diagnosis of GD, and minimize the risk for misdiagnosis. To the best of our knowledge, this is the first published report on atypical cytomorphology of GCs in untreated patients with GD1.

Długotrwała pancytopenia po chemioterapii jako objaw demaskujący chorobę Gauchera u pacjentki z rakiem płuca

The diagnosis of congenital metabolic disease can be very difficult and often extends in time. This applies particularly to metabolic diseases of milder phenotype, such as an adult form (type 1) of Gaucher disease caused by the inherited (autosomal recessive) deficiency of the lysosomal enzyme glucocerebrosidase.In this work, we present a case of 48-year-old Polish patient (living in Sweden) with lung cancer, who developed a prolonged pancytopenia complicated by sepsis after each cycle of chemotherapy. These symptoms led to initiation of hematological diagnostic work-up and the assumption that the complications are caused by Gaucher disease. Definitive diagnosis of Gaucher disease was confirmed by results of enzymatic analyses, which revealed reduced activity of glucocerebrosidase in peripheral blood lymphocytes to 0.44μkat/kg protein (ref.: 2.1–3.8), increased activity of plasma chitotriosidase to 1241nkat/L (ref.: G (N370S), confirming diagnosis of type 1 Gaucher disease in the patient. The presence of the mutation c.604C>T has never been previously reported in a Polish patient with Gaucher disease. Administration of enzyme replacement therapy with imiglucerase (Cerezyme™) led to a rapid improvement of peripheral blood counts and enabled further continuation of intensive chemotherapy for lung cancer.In conclusion, the authors would like to emphasize that knowledge of the symptoms and the principles of diagnosis of Gaucher disease among hematologists is very important for efficient diagnostics of patients affected by this rare disease

High curability via intensive reinduction chemotherapy and stem cell transplantation in young adults with relapsed acute lymphoblastic leukemia in Sweden 2003-2007

Background A minority of patients with adult acute lymphoblastic leukemia who relapse are rescued. The aim of this population-based study was to assess the results of reinduction treatment and allogeneic stem cell transplantation in patients in second complete remission. Design and Methods Between 2003-2007, 76 adults (<66 years) with relapsed acute lymphoblastic leukemia (Burkitt's leukemia excluded) were prospectively reported to The Swedish Adult Acute Leukemia Registry and later evaluated. Results Reinduction with: (i) mitoxantrone, etoposide, and cytarabine (MEA); (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor (FLAG-Asp); and (iii) cytarabine, betamethasone, cyclophosphamide, daunorubicin, and vincristine (ABCDV) resulted in complete remission in 6/9 (67%), 10/16 (63%) and 9/21 (43%) of the patients, respectively. Allogeneic stem cell transplantation was performed during second complete remission in 29 patients. Multivariate analysis regarding overall survival after relapse revealed that age over 35 years at diagnosis and relapse within 18 months were negative prognostic factors. Overall survival rates at 3 and 5 years were 22% (95% CI: 13-32) and 15% (95% CI: 7-24). Of 19 patients less than 35 years at diagnosis who underwent allogeneic stem cell transplantation in second remission, ten (53%) are still alive at a median of 5.5 years (range, 4.2-8.3) after relapse, whereas all patients over 35 years old at diagnosis have died. Conclusions Allogeneic stem cell transplantation remains the treatment of choice for young adults with relapsed acute lymphoblastic leukemia. Both (i) mitoxantrone, etoposide, and cytarabine and (ii) fludarabine, cytarabine, pegylated-asparaginase plus granulocyte colony-stimulating factor seem effective as reinduction treatments and should be further evaluated. New salvage strategies are needed, especially for patients over 35 years old at diagnosis

High relapse rate of T cell acute lymphoblastic leukemia in adults treated with Hyper-CVAD chemotherapy in Sweden

Background Hyper-CVAD is widely used to treat acute lymphoblastic leukemia (ALL) and aggressive lymphomas. This multicenter, population-based study assessed the efficacy of Hyper-CVAD as first-line therapy in patients with T-cell ALL (T-ALL). Patients and methods Between October 2002 and September 2006, 24 patients were diagnosed with T-ALL in Sweden; 19 were eligible for treatment with the protocol. Results The median age was 32yr (range 18-72yr). Complete remission (CR) was obtained in 17 of 19 (89%) patients, and the treatment was relatively well tolerated. Allogeneic stem cell transplantation (SCT) was recommended in high-risk disease and was performed in four patients upfront. Two- and 5-yr leukemia-free survivals (LFS) in 17 patients with CR achievement were identical, at 29% (95% confidence interval [CI]: 8-51). Two- and 5-yr overall survival (OS) in whole cohort was 63% (95% CI: 42-85) and 47% (95% CI: 26-69), respectively. The 5-yr LFS for 15 patients who did not receive allogeneic SCT upfront were 20% (95% CI: 0-40), although 14 of 15 completed the protocol (eight cycles). Relapse occurred in 2 of 4 upfront-transplanted patients and in 12 of 15 patients treated with chemotherapy alone, six of whom received allogeneic SCT in CR2. Age >= 35yr influenced OS negatively in univariate analysis (HR 5.1, 95% CI: 1.55-16.7). Conclusions Hyper-CVAD treatment resulted in a high CR rate and appeared safe, but it showed poor efficacy at preventing relapse. Therefore, this treatment is no longer recommended for adults with T-ALL in Sweden

Satisfactory outcome after intensive chemotherapy with pragmatic use of minimal residual disease (MRD) monitoring in older patients with Philadelphia-negative B cell precursor acute lymphoblastic leukaemia: a Swedish registry-based study

The introduction of minimal residual disease (MRD) monitoring, in the Swedish national guidelines for acute lymphoblastic leukaemia, was evaluated in 35 patients aged 46-79 years (median 61), who were diagnosed from 2007 to 2011 and treated with high-intensity, block-based chemotherapy (ABCDV/VABA induction). Both a high complete remission rate (91 %) and acceptable overall survival (OS) rate (47 %) at 5 years were achieved. MRD by flow cytometry was measured in 73 % of the patients reaching complete remission after the first course, but was omitted by the clinicians for eight patients who were either over 70 years of age or already met conventional high-risk criteria. Factors negatively influencing OS were age over 65 years and WHO status >= 2. MRD < 0.1 % after induction had positive impact on continuous complete remission but not on OS. Only five patients were allocated to allogeneic haematopoietic stem cell transplantation in first remission, mainly due to conventional high risk factors. Thus, use of intensive remission induction therapy is effective in a selection of older patients. In a population for whom the possibilities of treatment escalation are limited, the optimal role of MRD monitoring remains to be determined

Recurrent pulmonary aspergillosis and mycobacterial infection in an unsplenectomized patient with type 1 Gaucher disease

BACKGROUND: The clinical presentation of Gaucher disease (GD), an inherited lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, is highly variable, and three clinical types are distinguished based upon the presence of neurologic symptoms. Thrombocytopenia, anemia, hepatosplenomegaly, and bone manifestations are the most typical signs of GD type 1 (GD1). CASE PRESENTATION: We present the case of an unsplenectomized man suffering from heterozygous GD1 with mutations of c.1226A>G (N370S) and RecNci I (L444P, A456P, and V460V) in the GBA1 gene, who developed recurrent pulmonary aspergillosis caused by Aspergillus fumigatus and a mycobacterial infection caused by Mycobacterium avium. Despite long-lasting therapy of both aspergillosis (including antifungal drugs and surgery), and the mycobacterial infection (triple therapy with rifampicin, ethambutol, and clarithromycin), recurrent positivity for M. avium and A. fumigatus was detected. CONCLUSIONS: Symptomatic lung involvement and an increased susceptibility to pulmonary infections are uncommon in GD and, if present, are often associated with more severe disease manifestations. To our knowledge, this is the first published report on the association of GD and pulmonary aspergillosis and mycobacterial infection. It illustrates the increased susceptibility of untreated GD patients to opportunistic pulmonary infections and ineffective eradication of these infections despite adequate therapy