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© Borgis - Postępy Nauk Medycznych 6/2015, s. 391-394
*Anna Koclęga, Małgorzata Krawczyk-Kuliś, Mirosław Markiewicz, Małgorzata Kopera, Sławomira Kyrcz-Krzemień
Znaczenie monitorowania MRD w intensywnym leczeniu przewlekłej białaczki limfocytowej – analiza przypadku klinicznego
The importance of MRD monitoring in intensive treatment for chronic lymphocytic leukemia – a case report
Department of Hematology and Bone Marrow Transplantation, School of Medicine, Medical University of Silesia, Katowice
Head of Department: prof. Sławomira Kyrcz-Krzemień, MD, PhD
Przewlekła białaczka limfocytowa jest najczęstszą białaczką rozpoznawaną u dorosłych. Mediana wieku w momencie diagnozy wynosi 65 lat. Celem leczenia, szczególnie chorych w młodszym wieku, powinno być wprowadzenie ich w głęboką remisję, bez minimalnej choroby resztkowej (MRD). W stosowanym obecnie standardowym monitorowaniu odpowiedzi na leczenie nie uwzględnia się stanu MRD. U prezentowanego pacjenta przewlekłą białaczkę limfocytową zdiagnozowano w 38. roku życia. Czas trwania choroby i obserwacji pacjenta wynosi obecnie 13 lat. W opisywanym przypadku efekty poszczególnych terapii były oceniane nie tylko w oparciu o parametry hematologiczne i badanie fizykalne, ale uwzględniały również stan minimalnej choroby resztkowej. Wyeliminowanie patologicznego klonu komórek CLL nastąpiło dopiero po zastosowaniu intensywnej chemioterapii wspomaganej allotransplantacją macierzystych komórek krwiotwórczych od dawcy rodzinnego.
Chronic lymphocytic leukemia is the most common leukemia diagnosed in adults. The median age of diagnosis is 65. The goal of treatment especially in younger patients should be putting them in deep remission, without a minimal residual disease (MRD). The standard currently used to monitor response to treatment does not take into account the status of MRD. The present case-study is of a patient with chronic lymphocytic leukemia diagnosed in a 38 year old. The duration of illness as well as the observation of the patient has now been 13 years. In our case, the effects of each treatment were evaluated not only on the basis of hematological parameters and physical examination but also taking into account the condition of the minimal residual disease. Eliminating pathological CLL cell clones was only after intensive chemotherapy supportive allogeneic haematopietic stem cell transplantation from a related donor.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia one may encounter in the Western World (25-30%) (1). The standardized incidence rate is 4/100 000 people per annum and increases with age (2). The median age at diagnosis is 65. Men get sick twice as often as women (2).
Monoclonal CLL is a disease characterized by the accumulation of morphologically mature but not functionally B cells (rare T or NK) in peripheral blood, bone marrow, lymph nodes, spleen and, very rarely, in skin (2, 3). Neoplastic cells express the following surface antigens: CD19+, CD5+, CD23+, CD20+/-, slg +/- (4). The moment of the initiation of the treatment depends on the severity of the disease and the choice of treatment depends on the correct assessment of the expectancy of patient survival independent of CLL as well as the biological state of the patient and his comorbidities. The goal of treatment, especially in younger patients, should be putting them into deep remission, without a minimal residual disease (MRD – minimal residual disease). By default, the monitoring response to treatment is carried out in accordance with the criteria of the NCI (National Cancer Institute, 1988) (5), which do not take into account the condition of minimal residual disease.
Case description
A 38 year-old man was hospitalized for the first time in the Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice in August 2002. In an interview in June 2002 he said that he had noticed a significant reduction in body weight (10% within 3 months), night sweats, and recurrent infections. With comorbidities Gilbert’s syndrome diagnosed in adolescence.
On admission he was in a generally good condition, ECOG = 0. On physical examination lymphadenopathy was revealed: bilaterally enlarged cervical lymph nodes, axillary and inguinal to about 3 cm. An abdominal ultrasonography showed hepatosplenomegaly (the longitudinal span of the right hepatic lobe was 16 cm, and that of the spleen 13 cm). In the peripheral blood examination we observed hyperleukocytosis: WBC – 15.2 G/L (N: 4-10 G/L) with 12.7 G/L morphology mature lymphocytes displaying the following phenotypes: CD5+, CD19+, CD20+, CD23+, CD79b+, CD22+, CD38+ (70% of the cells), CD43+, ZAP70+ (50% of the cells). In addition, we did not observe anemia, Hgb – 14 g/dl (N: 11.2-15.8 g/dl) and thrombocytopenia, PLT – 235 G/L (N: 130-400 G/L). The relevant laboratory findings included: alanine aminotransferases; Alat – 19 IU/L (N: 10-40 IU/L), asparate aminotransferases; Aspat – 22 IU/L (N: 10-42 IU/L), lactate dehydrogenase; LDH – 201 IU/L (91-180 IU/L), serum bilirubin level – 38 umol/L (N: 3.4-17.1 umol/l), creatinine – 78 umol/L (N: 55-113 umol/l), beta2-micro-globulin – 1975 ug/l (N: 1500-3000 ug/l), immuno-globulin; IgG – 7.2 g/L (N: 7-16 g/L), the negative direct and the indirect Coombs antiglobulin test. In the study of peripheral blood FISH stated did not reveal: deletion of the short arm of chromosome 17p, deletion of the long arm of chromosome 11q, deletion of the long arm of chromosome 13q and trisomy of the chromosome 12. The trephine biopsy showed: diffuse infiltration of the small lymphoid B cells (CD20+, CD23+, CD5+, cyclin D1 occupying 30% of the bone marrow. Ki67 proliferative index in CLL cells were 2-35%. Hematopoiesis preserved. Islands of granulopoiesis MPO(+) and erythropoiesis poorly and rich-cells. Megacaryocytes numerous and scattered.
Chronic lymphocytic leukemia in stage II – by the Rai classification and B – in accordance with the Binet classification was diagnosed. Because of the presence of these general symptoms the patient was qualified for chemotherapy using cladribine alone. From August 2002 to January 2003, the patient received 6 cycles of this treatment. In February 2003 the patient achieved complete remission 1 (CR1) with a positive minimal residual disease examined using flow cytometry MRD = 0.705%. After 28 months of complete remission in June 2005 the patient was re-admitted to the Department of Hematology due to a recurrence of lymphadenopathy, splenomegaly, and lymphocytosis. The first relapse of CLL was diagnosed (Rai-II, Binet-B) and the patient received chemotherapy in accordance with the protocol CC (Cladribine, Endoxan). In October 2005, after 3 cycles of chemotherapy, the patient achieved CR2-positive MRD = 1.2%. In May 2008 there was discovered a second recurrence of the disease: Rai-II, Binet-B and we started treatment in accordance with the protocol Flu-Camp (Fludarabine Campath). During treatment, infectious complications were observed (Herpes viruses, CMV) and the patient required the substitution of immune-globulins. In August 2008, after 2 cycles of treatment both CR3 along with a positive MRD = 0.88% was achieved. After 16 months of complete remission in December 2009, there was a third recurrence of CLL, and the stage was estimated to be: Rai-IV, Binet-C. We started treatment in accordance with protocol R-FC (Mabthera, Fludarabine, Endoxan) which the patient received until October 2010. After 6 cycles of this treatment, there was CR4 but without the eradication of the minimal residual disease MRD = 0.29%. After the findings the CR4 patient was recommended for an allogeneic hematopoietic stem cells transplantation from a HLA-matched related donor. The indications for the transplantation were: young age of the patient, recurrent nature of the disease, short time from remission to progression, following adverse prognostic factors (elevated levels of LDH, increased expression of CD38 and ZAP70, general symptoms and diffuse infiltration CLL in trephine-biopsy) during the estimated diagnosis. In October 2011 the patient received an allogeneic haematopoietic stem cells transplantation from a HLA fully-matched sister. Reduced-intensity conditioning (RIC): Empathic, Fludarabine, Melphalan was applied. In the prevention of acute graft versus host disease (aGVHD) methotrexate and cyclosporin was initially used intravenously, then orally at a dose dependent upon the concentration in the blood. On 19-20.10.2011 there was performed a hematopoietic stem cell transplantation. Transplanted peripheral blood apheresis product contained 7.72 x 10e8 nucleated cells/kg, 5.23 x 10e6 CD34+ cells/kg and 22.7 x 10e7 CD3+ cells/kg.

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otrzymano: 2015-04-07
zaakceptowano do druku: 2015-04-30

Adres do korespondencji:
*Anna Koclęga
Department of Hematology and Bone Marrow Transplantation
ul. Dąbrowskiego 25, 40-032 Katowice
tel. +48 694-768-881

Postępy Nauk Medycznych 6/2015
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