© 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
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.
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).
The median number of transplanted cells was as follows: WBC 4.2 x 10 ^ 8/kg b.w. (0,97-9,56), CD34 + cells 2.36 × 10 ^ 6/b.w. (1,37-6,3), CD3 +cells 30.99 x 10 ^ 7/kg b.w. (5,07-54,54). The detailed data are enclosed in table 2.
Table 2. Characteristics of patients undergoing the alloHSCT.
|Patient/alloHSC*||Phase of the disease before alloHSCT||Donor/recipient||AutoHSCT before alloHSCT Yes/No||Age of recipient during alloHSCT||Conditioning treatment before alloHSCT ||Numer of CD34+|
x 106/kg b.w.
|Number of CD3+|
|Acute GVHD (involved organ)||Chronic GVHD||Survival time after alloHSCT (months)|
|1.66||47.38|| Yes (skin)||Yes||120|
During the alloHSCT procedure one patient died in day +9 due to infectious complications before the engraftment (Transplant Related Mortality up to + 100 days amounted to 22%).
The regeneration time after 8 alloHSCT procedures was as follows: granulocytes count > 0.5 G/l was reached after the median of 22 days (range 13-24 days), and platelets > 50 G/l, after the median of 21 days (range 14-25). Symptoms of acute graft versus host disease (aGVHD) in stage I occurred in 2 patients. The symptoms of aGVHD grade II and III did not occur. Symptoms of chronic graft versus host disease (cGVHD) occurred in two patients.
2 patients underwent re-alloHSCT: because of recurrence of lymphoma in the first one, and in the other one due to the graft failure (chimerism at the day +30 after transplantation was 20%).
The median time of survival is 21 months (range 4-120 months) for 7 reported cases. 4 patients died because of the disease progression despite the alloHSCT.
Two patients of the seven are still alive, which accounts for 28%. These are patients who presented symptoms of the limited chronic graft versus host disease. One patient is still alive for more than 10 years in complete remission without recurrence of lymphoma. In the second patient surviving 21 months after alloHSCT, in the control study, positron emission tomography (FDG PET CT) showed an early recurrence of the disease within the skeletal system. He was treated with local radiotherapy (IF) with a good result. The patient is designated for the procedure of donor lymphocyte infusion (DLI).
Algorithm for treatment of Hodgkin’s lymphoma patients is based on the degree of risk assessed at diagnosis and the effectiveness assessment of the first line chemotherapy (13-16). In cases of refractory and recurrent disease high dose chemotherapy with autologous hematopoietic cells (autoHSCT) (17-22) is used routinely. In some cases, patients are benefiting from a double (tandem) autoHSCT procedures (23-25). Recently in order to assess the effectiveness of treatment including the autoHSCT new diagnostic imaging methods have been in use. They allow not only for determining the presence of morphological changes, but also to assess the metabolic activity, which is detected in FDG-PET CT methods (26-29).
The report of the European Society of Bone Marrow Transplantation (EBMT) stated that in 2009 the European centres of bone marrow transplantation in 1901 cases of Hodgkin’s lymphoma autoHSCT procedures were performed. The report also specified that with this diagnosis there were only 330 allogeneic bone marrow transplantation/hematopoietic cells, including the 92 cases which were performed after autoHSCT (EBMT Activity Survey on Transplant 2009, Basel 11.25.2010). The Department of Hematology and Bone Marrow Transplantation Medical University of Silesia is an accredited centre of the EBMT (Team No. 677) and the European reports also include procedures performed over here.
In our department treatment structure autoHSCT and allogeneic hematopoietic cell transplantations is similar to that published in the EBMT report. Allogeneic hematopoietic cell transplantation in Hodgkin’s lymphoma patients is rarely performed in comparison to the number of autoHSCT.
In the reported group of 7 patients, only 2 cases were autoHSCT treated before alloHSCT procedures. In one of them alloHSCT was performed despite the lack of remission at the time of alloHSCT. The patient is still alive for 21 months and a phase of the disease is assessed as the PR. This good result was confirmed by the Italian group which published the observation that in the absence of remission after conducting autoHSCT patients benefit from alloHSCT compared with the use of salvage chemotherapy (30).
The standard conditioning treatment prior to alloHSCT that we used was a non-myeloablative (RIC), considering its lower toxicity for the patient. Such preparation for alloHSCT according to the recent publications (31, 32) is the preferred treatment of choice.
The transplant related mortality during the procedure alloHCT did not differ from the expected and was 1/7.
In one case due to the lack of an engraftment, alloHSCT procedure was performed again with good results.
For the success of alloHSCT good clinical condition of a patient is important as well as a phase of the disease, in which this treatment procedure is performed (33). In the analysed group of the patients only one person was in complete remission and the time from diagnosis to the date of alloHSCT amounted to 119 months. In cases of recurrence after alloHSCT The Report of the Committee on Treatment of Recurrence after Transplantation of Allogeneic Bone Marrow (34) recommends strengthening donor lymphocyte immune activity against lymphoma and the use of donor lymphocyte infusion (DLI). DLI can induce GVHD. In cases of mixed chimerism DLI reduces the risk of the disease recurrence through the induction of antitumor activity (35). Such a procedure is planned to be used in one of our reported patients.
In the reported cases, we observed long-term survival in patients only with the presence of chronic graft versus host disease. It can be assumed that it was due to the immunological effects of transplanted allogeneic cells leading to an active immunological control of the disease in one patient for over 10 years.
Allogeneic hematopoietic cell transplantation should be considered as a therapeutic option with the potential for long-term survival in patients with refractory Hodgkin’s lymphoma who have a fully compatible family donor.
1. Richardson SE, McNamara C: The management of classical Hodgkin’s lymphoma: past, present, and future. Advances in Hematology 2011; doi:10.1155/2011/865870
2. Hodgson DC: Late effects in the era of modern therapy for Hodgkin lymphoma. ASH Education Program Book, San Diego, California, XII 10-13, 2011; 323-329.
3. Josting A, Rudolph C, Reiser M et al.: Time-intensified dexamethasone/cisplatin/cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Annals of Oncology 2002; 13: 1628-35.
4. Von Tresckow B, Plutschow A, Fuchs M et al.: Dose-intensification in early unfavorable Hodgkins lymphoma: Final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol 2012; (Epub ahead of print).
5. Baetz T, Belch A, Couban S et al.: Gemcitabine, dexamethasone and cisplatini as an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin’s disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Annals of Oncology 2003; 14: 1762-7.
6. Friedberg JW: Hodgkin lymphoma: answers take time! Blood 2011; 117: 5274-6.
7. Cole P, Schwartz CL, Drachtman RA et al.: Phase II study of weekly gemcitabine and vinorelbine for children with recurrent or refractory Hodgkin’s disease: A Children’s Oncology Group Report. JCO 2009; 27: 1456-61.
8. Biswas T, Culakova E, Friedberg JW et al.: Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma. Radiother Oncol 2012; doi: 10.1016/j.radonc.2011.12.031
9. Josting A, Rudolph C, Mapara M et al.: Cologne high-dose seguential chemotherapy in relapsed and refractory Hodgkin lymphoma: results of a large multicentre study of the German Hodgkin Lymphoma Study Group (GHSG). Annals of Oncology 2005; 16: 116-23.
10. Czyż J, Dziaduszko R, Knopińska-Posłuszny W et al.: Outcome and prognostic factors in advanced Hodgkin’s disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients. Annals of Oncology 2004; 15: 1222-30.
11. Younes A, Oki Y, McLaughlin P et al.: Phase II study of rituximab plus ABVD in patients with newly diagnosed classical Hodgkin lymphoma. Blood 2012; Feb 27. (Epub ahaed of print).
12. Minich S: Brentuximab Vedotin: A new age in the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma. Ann Pharmacother 2012; 46: 377-83.
13. Peggs KS, Hunter A, Chopra R et al.: Clinical evidence of a graft-versus-Hodgkin’s-lymphoma effect after reduced-intensity allogeneic transplantation. Lancet 2005; 365: 1934-41.
14. Savage KJ, Skinnider B, Al.-Mansour M et al.: Treating limited-stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood 2011; 118: 4585-90.
15. Carella AM, Bellei M, Brice P et al.: High-dose therapy and autologous stem cell transplantation versus conventional therapy for patients with advanced Hodgkins lymphoma responding to front-line therapy: long-term results. Haematologic 2009; 94: 146-8.
16. Josting A, Engert A, Diehl V, Canellos GP: Prognostic factors and treatment outcome in patients with primary progressive and relapsed Hodgkin’s disease. Annals of Oncology 2002; 13 (suppl I): 112-6.
17. Greaves P, Wilson A, Matthews J et al.: Early relapse and refractory disease remain risk factors in the anthracycline and autologous transplant era for patients with relapsed/refractory classical Hodgkin lymphoma: a single centre intention-to-treat analysis. Br J Haematol doi:10.1111/j.1365-2144.2011.08993.x
18. Advani R: Optimal therapy of advanced Hodgkin lymphoma. Haematology. ASH Education Program Book, San Diego, California, XII 10-13, 2011; 310-316
19. Kuruvilla J, Keating A, Crump M: How I treat relapsed and refractory Hodgkin lymphoma. Blood 2011; 117: 4208-17.
20. Sirohi B, Cunningham D, Powles P et al.: Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin’s lymphoma. Annals of Oncology 2008; 19: 1312-9.
21. Visani G, Malerba L, Stefani PM et al.: BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood 2011; 118: 3419-25.
22. Moore S, Kayani I, Peggs K et al.: Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL. Br J Haematol 2012; doi: 10.1111/j.1365-2141.2012.09096.x. (Epub ahead of print)
23. Smith SM, vanBesien K, Carreras J et al.: Second autologous stem cell transplantation for relapsed lymphoma after a prior autologous transplant. Biol Blood Marrow Transplant 2008; 14: 904-12.
24. Josting A, Raemakers JM, Diehl V, Engert A: New concepts for relapsed Hodgkin’s disease. Annals of Oncology 2002; 13 (suppl I): 117-21.
25. Morschhauser F, Brice P, Ferme C et al.: Risk-adapted salvage treatment with single or tandem autologous stem-cell transplantation for first relapse/refractory Hodgkins lymphoma: results of the prospective multicenter H96 trial by the GELA/SFGM study group. JClinOncol 2008; 36: 5980-7.
26. Okosun J, Warbey V, Shaw K et al.: Interim fdg-pet predicts response and progression free survival in patients with Hodgkin lymphoma and HIV infection. AIDS 2012; Feb 13: (Epub ahead of print)
27. Devillier R, Coso D, Castagna L et al.: Positron emission tomography response at time of autologous stem cel transplantation predict outcome of patients with relapsed and/or refractory Hodgkin Lymphoma responding to prior salvage therapy. Haematologica 2012 (Epub ahaed of print).
28. Moskowitz CH, Matasar MJ, Zelenetz AD et al.: Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood 2012; 119: 1665-70.
29. Connors JM: Positron emission tomography in the management of Hodgkin lymphoma. ASH Education Program Book, San Diego, California, XII 10-13, 2011; 317-322.
30. Sarina B, Castagna L, Farina L et al.: Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retrospective study based on the time of HLA typing and donor availability. Blood 2010; 115: 3671-7.
31. Robinson SP, Sureda A, Canals C et al.: Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin’s lymphoma: identification of prognostic factors predicting outcome. Haematologica 2008; 94: 230-8.
32. Thomson KJ, Peggs KS, Smith P et al.: Superiority of reduced-intensity allogeneic transplantation over conventional treatment for relapse of Hodgkin’s lymphoma following autologous stem cell transplantation. Bone Marrow Transplantation 2008; 41: 765-70.
33. Claviez A, Canals C, Dietrick D et al.: Allogeneic hematopoietic stem cell transplantation in children with recurrent and refractory Hodgkin lymphoma: an analysis of the European Group for Blood and Marrow Transplantation. Blood 2009; 114: 2060-7.
34. Porter DL, Alyea EP, Antin JH et al.: NCI First International Workshop on the Biology, Prevention and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 1467-1503.
35. Peggs KS, Kayani I, Edwards N et al.: Donor lymphocyte infusions modulate relapse risk in Mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for Hodgkin’s lymphoma. JCO 2011; 29: 971-8.