© Borgis - Postępy Nauk Medycznych 9/2012, s. 694-698
*Małgorzata Krawczyk-Kuliś, Anna Kopińska, Mirosław Markiewicz, Małgorzata Kopera, Sławomira Kyrcz-Krzemień
Alloprzeszczepienie komórek krwiotwórczych w opornych przypadkach chłoniaka Hodgkina szansą na długotrwałą remisję
Allogeneic hematopoietic cell transplantation in refractory Hodgkin’s lymphoma cases, the chance for long-term remission
Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice
Head of Department: prof. Sławomira Kyrcz-Krzemień, MD, PhD
Streszczenie
Skuteczność alloprzeszczepienia komórek hematopoetycznych (alloHSCT) w leczeniu chłoniaka Hodgkina (HLy) jest nadal dyskutowana.
W Klinice Hematologii i Transplantacji Szpiku Śląskiego Uniwersytetu Medycznego spośród 390 przeszczepień w przypadkach HLy w 7 opornych/nawrotowych przypadkach (mediana wieku 22 lata) posiadających zgodnego rodzinnego dawcę szpiku przeprowadzono alloHSCT, u dwóch pacjentów (pts) zabieg wykonano dwukrotnie (analizie poddano 9 zabiegów alloHSCT). Każdy z chorych otrzymał co najmniej trzy linie leczenia, a dwóch pts przebyło wysokodawkowaną chemioterapię z przeszczepieniem autologicznych komórek krwiotwórczych.
Procedury alloHSCT przeprowadzono u 1 pts w całkowitej remisji, u 4 w remisji częściowej, a u 4 w aktywnej fazie choroby. Przed alloHSCT stosowano kondycjonowanie niemieloablacyjne.
Rekonstytucja układu krwiotwórczego przebiegała następująco: granulocyty > 0,5 x 10^9/L – mediana – 22 doba, płytki krwi > 50 x 10^9/L – 21 doba. U dwóch chorych przeprowadzono dwukrotnie alloHSCT: u jednego z powodu progresji HLy, u drugiego z powodu braku wszczepu. W trakcie alloHSCT zmarł 1 pacjent (TRM 22%). Z powodu progresji lub wczesnej wznowy zmarło 4 pacjentów. Dwóch chorych żyje nadal (obaj z przewlekłą chorobą przeszczep przeciw gospodarzowi): jeden w całkowitej remisji trwającej ponad 10 lat, drugi w remisji częściowej trwającej 21 miesięcy. Mediana przeżycia całkowitego wynosi 21 miesięcy (4-120).
Wnioski. AlloHSCT z niemieloablacyjnym kondycjonowaniem może być rozważane jako leczenie dające szansę na długotrwałe przeżycie w opornych/nawrotowych przypadkach chłoniaka Hodgkina posiadających zgodnego rodzinnego dawcę szpiku.
Summary
The role of allogeneic hematopoietic cell transplantation (alloHSCT) in the treatment of Hodgkin’s lymphoma is still debated.
In Department of Hematology and BMT Medical University of Silesia, among the 390 hematopoietic cell transplantations in Hodgkin’s lymphoma patients (pts), 7 pts with refractory or relapsed HD (median age 22), who had the full matched sibling donor, were undergone alloHSCT, two of them twice time. Each patient received at least three lines of chemotherapy. Two pts were undergone autologous hematopoietic cell transplantation before alloHSCT. At the time of alloHSCT 1 pts was in complete remission, 4 were in partial remission and 4 during active phase of the disease. Non-myeloablative conditioning regimens preceding alloHSCT were used.
Due to alloHSCT one patient died (TRM 22%). Hematopoietic recovery after alloHSCT was: ANC > 0.5 x 10^9/L after median of 22 days and platelet > 50 x 10^9/L after 21 days. Two pts had to undergo second alloHSCT, because of relapse for the first, and the second one because of lack of engraftment.
4 pts died due to progression or early relapse. Two pts are still alive (both with chronic graft versus host disease); one survived longer than 10 years in CR and the other one survived 21 months in PR. The median time of survival is 21 months (4-120).
Conclusions. AlloHSCT with non-myeloablative conditioning regimen in patient with relapsed or refractory Hodgkin’s lymphoma could be considered as a treatment option for a patient with full matched sibling donor and can be an opportunity to extend the life of these patients.
In patients with advanced clinical stages of Hodgkin’s lymphoma who demonstrated the presence of risk factors at the time of diagnosis, after the standard treatment using chemo-therapy and/or radiotherapy complete remission (CR) in more than 80% of patients is obtained (1, 2). In some patients the disease is, however, refractory and recurrent despite the regular treatment. In these cases, the following methods can be applied: chemotherapies with increased strength (so-called second- or third-line therapies such as ESHAP, DHAP (3, 4)), introducing a new medication (e.g. gemcitabine (5, 6, 7)), supplemental radiation therapy (8) and an intensive multidrug chemotherapy with autologous hematopoietic cells transplantation (autoHSCT) are used as well (9, 10). For the treatment of Hodgkin’s lymphoma monoclonal antibodies: anti-CD20 (rituximab) (11) and a new generation of monoclonal anti-CD30 antibody (brentuximab vedotin) have been introduced also. The last one is applied mainly in order to eradicate residual tumor remaining despite aggressive treatment and for the treatment of refractory and recurrent form of lymphoma showing the expression of CD 30 (12). The role of allogeneic bone marrow hematopoietic cell transplantation (alloHSCT) for the treatment of Hodgkin’s lymphoma cases, where the immunological effect of allogeneic transplanted cells play the main role (GVL – graft versus lymphoma), is still under consideration. Some patients benefited from treatment using alloHSCT, as evidenced, however, only few papers are published (6). In the Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice, 390 hematopoietic cells transplantations in Hodgkin’s lymphoma cases were performed (the total number of transplantations performed in this Department amounts over 2600 procedures), including only 9 procedures of allogeneic transplantation.
This paper presents a retrospective long term analysis of the procedures of allogeneic hematopoietic cells transplantations from sibling donors in heavily pretreated patients with refractory Hodgkin’s lymphoma., who, before alloHSCT, were treated using chemotherapy programs including autoHSCT.
MATERIAL and METHODS
During the period from December 2004 until July 2011 seven patients with refractory or relapsed Hodgkin’s lymphoma underwent alloHSCT procedure, including two double alloHSCT which means 9 alloHSCT procedures in the Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia in Katowice.
The median age of patients at diagnosis was 22 years (from 15 to 29 years), most of them male (n = 5, 71%). The clinical stages of the disease at diagnosis, according to the Anbor Ann classification, were as follows: II-16%, III-12%, IV-72%. 70% of patients presented B symptoms. All the patients received at least three types of chemotherapy (tab. 1) as well as involved field radiotherapy (IF).
Table 1. The type and numer of cycles of chemotherapy before the alloHSC procedures.
| Patient* | First line of treatment** | Second line therapy | Third line of treatment |
| 1 | ESHAP (6) | BEACOPP (3) | CN3OP (6) |
| 2 | ABVD (6) | ESHAP (6) | BEACOPP (2) |
| 3 | MVPP (4) | B-DOPA (4) | ABVD (1) |
| 4 | ABVD (8) | BEACOPP (3) | ESHAP (2) |
| 5 | CMOPP (6) | ABVD (6) | ICE (6) |
| 6 | ABVD (3) | ESHAP (6) | BEACOPP (1) |
| 7 | MOPP (6) | ABVD (5) | BEACOPP (4) |
*ordinal numer of patient
**total numer of cycles
The time from diagnosis of Hodgkin’s lymphoma to alloHSCT procedures ranged from 23 to 119 months.
Before alloHSCT 2 patients were treated using high dose chemotherapy with autoHSCT. For autoHSCT, stem cells were collected from peripheral blood after IVE chemotherapy (IVE – ifosfamide 3 g/m2 iv in days 1-3, etoposide 200 mg/m2 in 1-3 d., epirubicine 50 mg/m2 iv in 1 d.) and subsequent administration of granulocyte-colony stimulating factor (G-CSF) at a dose of 10 ug/kg/day, starting from +5 day after chemotherapy until the last day of collection. The patients collected the sufficient number of CD34+ cells for AHSCT procedure. Conditioning regimens before autoHSCT consisted of BEAM (carmustine 300 mg/m2, etoposide 200 mg/m2, cytosine arabinoside 300 mg/m2, melphalan 140 mg/m2). Despite the use of high dose chemotherapy with autologous haematopoietic cells transplantation a sustained remission was not achieved.
Before the start of alloHSCT the disease’s phases were as follows: complete remission (CR) in 1 patient, a partial remission (PR) in 4, the active phase of the disease without remission (NR) was also seen in 4 patients.
All patients had a fully compatible family donor for HLA tissue antigens evaluated using low-resolution methods (LR).
The conditioning regimens, which applied used before alloHSCT, were nonmieloablative one; 5 patients received treatment which included: melphalan, fludarabine, alemtuzumab, and the remaining: fludarabine, busulfan (1 patient), carmustine, melphalan, gemcitabine (1 patient), carmustine, meplhalan, etoposide (2 patients).
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