Biology of Blood and Marrow Transplantation
Volume 12, Issue 6 , Pages 599-602, June 2006

Reduced Intensity Conditioning for Allogeneic Stem Cell Transplantation in Relapsed and Refractory Hodgkin Lymphoma: Where Do We Stand?

Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, Texas

Received 3 October 2005; accepted 28 March 2006.

Article Outline

Abstract 

Allogeneic stem cell transplantation following myeloablative conditioning in relapsed and refractory Hodgkin lymphoma (HL) has been associated with substantial transplant-related morbidity and mortality, as well as high relapse rates. Despite these problems, a minority of patients have experienced long-term remissions and presumably cure. As in other hematologic malignancies, reduced intensity conditioning (RIC) has now been introduced as an alternative approach. The published experience with RIC in HL patients is reviewed. While early transplant-related morbidity and mortality seem markedly reduced and preliminary data on patient outcome look promising, this remains a challenging area and additional work will be needed to clearly define the role of RIC in relapsed and refractory HL.

Key Words:  Reduced-intensity conditioning , Allogeneic stem cell transplantation

 

Back to Article Outline

Introduction 

Allogeneic stem cell transplantation (allo-SCT) with reduced intensity conditioning (RIC), as opposed to conventional myeloablative conditioning, has been gaining increasing acceptance in the management of a variety of hematologic malignancies [1, 2]. Because the role of allo-SCT in relapsed/refractory Hodgkin lymphoma (HL) has been controversial, it is not surprising that this area has not received the same level of attention as other hematologic disorders. As a consequence, published reports remain somewhat sketchy, but interest seems to be growing, partly because the preliminary data appear very encouraging. This review briefly summarizes the current status of the field from a clinical, evidence-based perspective.

Back to Article Outline

Allo-SCT with myeloablative conditioning: Published results 

The role of allo-SCT in the management of relapsed/refractory HL has historically been controversial. Published data remain largely limited to registry series and retrospective historical data from large transplantation centers [3, 4, 5, 6, 7] and are summarized in Table 1. The vast majority of these patients received transplants from related donors. The consistent pattern that emerges from these reports paints a disappointing picture. It is a pattern of high transplant-related mortality (TRM) and relapse rates, with only a minority of patients (15% to 20%) achieving long-term remissions and possibly cure. This poor outcome is likely to reflect the nature and poor prognosis of the patients undergoing transplantation, with the vast majority being extensively pretreated with chemotherapy and radiation and having advanced, chemoresistant, or truly refractory disease.

Table 1. Published Results for Allogeneic Stem Cell Transplantation with Conventional Myeloablative Conditioning Regimens in Relapsed/Refractory Hodgkin Disease⁎
ReferencePatients, nPeriod CoveredTRMDisease Progression/RelapsePFSOSGraft-vs-Hodgkin Effect?
IBMTR [3]1001982-199413%(day30)65%(3y)15%(3y)21%(3y)No
61%(3y)
EBMT [5]451983-199331%(day100)61%(4y)15%(4y)25%(4y)Possibly
48%(4y)
FHCRC [4]†531970-199158%(4y)48%(4y)22%(5y)21%(5y)Possibly
JHOC [6]531985-199832%(100d)53%(10y)26%(10y)30%(10y)Possibly
43%(total)
EBMT [7]‡1671982-199852%(4y)65%(5y)16%(4y)25%(4y)Possibly

⁎ IBMTR indicates International Bone Marrow Transplant Registry; EBMT, European Group for Blood and Marrow Transplantation; FHCRC, Fred Hutchinson Cancer Research Center; JHOC, Johns Hopkins Oncology Center; TRM, transplant-related mortality; PFS, progression-free survival; OS, overall survival.

† Includes 6 patients who underwent allograting from a mismatched related donor and 3 from a matched unrelated donor.

‡ Includes 5 patients who underwent allograting from unrelated donors.

Whether a graft-versus-HL effect exists in this context is uncertain and the results of at least some of these studies have raised this possibility. Milpied et al [5] (and subsequently Peniket et al [7]) showed such an effect with grade ≥2 acute graft-versus-host disease (GVHD) [5, 7]. Anderson et al [4] reported a lower relapse rate in patients with HL who received an allo-SCT compared with recipients of an autologous SCT, and Akpek et al [6] reported a trend toward lower relapse rates in patients with HL who underwent transplantation while in chemosensitive relapse and patients who developed GVHD. Even if present, it could have been obscured by the substantial early and late TRMs. Nevertheless, because of these data, clinicians have frequently been reluctant to consider this as a viable option except in selected patients with suitable donors (eg, extensive marrow involvement, inability to collect stem cells).

It would be easy to argue that these largely historical data (most patients underwent transplantation from the 1970s to the early 1990s; Table 1) no longer reflect current clinical practice, which is characterized by improved supportive care and GVHD management. The most recent reference seems to paint a somewhat rosier picture, with improved TRM, progression-free survival, and overall survival [6]. Conversely, patient selection may have contributed to better patient outcome, and a cumulative TRM of 43% remains very problematic.

Back to Article Outline

Allo-SCT with RIC: Published results 

In view of the high TRM after myeloablative allo-SCT in HL, these patients seem to be particularly well suited to an RIC approach. The underlying assumption is that patients will tolerate the procedure much better, which may allow them ultimately to benefit from a graft-versus-HL effect. Currently available data on RIC allo-SCT in relapsed/refractory HL are summarized in Table 2. If one excludes case reports and studies with a very small sample size, they come primarily from the 5 sources listed. It should be emphasized that these reports are quite difficult to interpret and compare due to a variety of factors (such as patient and preparative regimen heterogeneity, short follow-up, different GVHD prophylaxis regimens, etc). Despite these problems, several tentative conclusions can be drawn.

Table 2. Published Results for Allogeneic Stem Cell Transplantation with Reduced Intensity Conditioning Regimens in Relapsed/Refractory Hodgkin Lymphoma⁎
ReferencePatients, nDonor TypeConditioning RegimenTRMDisease Progression/RelapsePFSOS
EBMT [9]311
MRD (n = 211)

MUD (n = 61)

Other (n = 39)

Miscellaneous (primarily fludarabine-alkylating agents)
17% (100-d)

24% (1-y)

27% (2-y)
48% (1-y)

64% (2-y)

26% (2-y)46% (2-y; projected)
UKCG [8]49
MRD (n = 31)

MUD (n = 18)

Fludarabine-melphalan-alemtuzumab
4% (100-d)

16% (2-y)

43%32% (4-y; projected)55% (4-y; projected)
SPCP [13]40
MRD (n = 37)

MUD (n = 2)

Other (n = 1)

Fludarabine-melphalan
12% (100-d)

25% (1-y)

NA32% (2-y)48% (2-y)
MDAH [14]40
MRD (n = 20)

MUD (n = 20)

Fludarabine/cyclophosphamide; fludarabine/melphalan
5% (100-d)

22% (18-mo)

55% (18-mo)32% (18-mo)61% (18-mo)
FHCRC and others [11]27
MRD (n = 18)

MUD (n = 9)

Low-dose TBI/fludarabine
11% (100-d)

39% (1-y)

47% (1-y)18% (1-y)51% (1-y)

⁎ EBMT indicates European Group for Blood and Marrow Transplantation; UKCG, United Kingdom Collaborative Group; SPCP, Spanish Prospective Cooperative Protocol; MDAH, MD Anderson Hospital; FHCRC, Fred Hutchinson Cancer Research Center; MRD, matched related donor; MUD, matched unrelated donor; DLI, donor leukocyte infusion; NA, not available; TRM, transplant-related mortality; PFS, progression-free survival; OS, overall survival; TBI, total body irradiation.

First, the common denominator of all these studies is the dramatic decrease in early (day 100) TRM, which has ranged from 4% to 17%. This is even more noteworthy in view of the fact some of these studies included a substantial number of patients who received transplants from a matched unrelated donor. It should be acknowledged that a decreased early TRM is largely expected if the intensity of the conditioning regimen is significantly reduced. However, compared with patients who undergo allografting with myeloablative regimens, even cumulative TRM has remained relatively low thus far (15% to 30%). A longer follow-up will be required to validate this conclusion.

Second, the willingness of investigators to include in their studies sizable numbers of patients receiving an allograft from a matched unrelated donor is important. If RIC allo-SCT is to gain a role in the management of these patients, the use of matched unrelated donors is essential to expand the number of patients eligible for the procedure. More stringent HLA-typing and -matching criteria for donors have certainly helped. Although the issue has not been formally examined, the outcome of these patients has not been, in our experience, dramatically different thus far from that of patients who underwent matched and related donor allo-SCT (Anderlini P, unpublished data, 2005). Peggs et al [8] did not report statistically significant differences in overall and progression-free survivals in patients who underwent allografting from matched related and unrelated donors.

Third, the incidence of disease progression/relapse remains high, presumably because of the advanced and refractory nature of the disease in these patients. At least 2 studies have emphasized the role of chemosensitivity before allo-SCT as a prognostic factor [8, 9], and it seems reasonable to make every effort to cytoreduce these patients effectively before transplantation. A double transplantation approach (auto-SCT followed by RIC allo-SCT) has been proposed as an effective way to accomplish this goal [10].

Fourth, RIC regimens can be very heterogeneous. Some are essentially devoid of any activity against the malignancy (such as fludarabine plus low-dose total body radiation) [11], whereas others have significant activity (such as fludarabine plus melphalan) [8, 12, 13, 14]. One study [14] has suggested that the intensity of the RIC regimen has an effect on patient outcome, and this area should be explored further. If one accepts the concept that a mounting an effective graft-versus-HL reaction may require several months, preventing early progression in these patients becomes essential. Interestingly, however, progression and relapse rates have been fairly consistent in all these studies (Table 2).

Fifth, at this time the data do not realistically help in addressing the issue of the existence of a graft-versus-HL effect. It is unclear whether GVHD had any correlation with patient outcome. The issue may be best approached from the donor leukocyte infusion (DLI) perspective, as described in more detail below.

Sixth, the jury is still out on what may be considered the ultimate test, namely progression-free survival and overall survival. Only longer follow-up will eventually answer the question. It should be pointed out that overall survival advantages can be hard to demonstrate in HL clinical trials because of the effectiveness of salvage treatment [15, 16]. A significant decrease in TRM may be relevant in its own right (regardless of progression-free survival and overall survival) because more patients would survive the procedure and would still be eligible to receive salvage therapies (including DLIs) after allo-SCT.

Back to Article Outline

Role of DLIs 

DLIs remain in many ways a gold standard to establish the presence of a graft-versus-HL effect. However, published data on DLIs in HL are even sketchier than those on RIC allo-SCT are. Porter et al [17] reported 4 cases of DLI after auto-SCT preceded by interferon treatment in 3 of them, with 1 complete response and 1 minor response. Peggs et al [8, 12] reported on 19 patients with HL (3 with preceding salvage chemotherapy) from a cohort of 41 originally transplant recipients who received DLIs for residual disease or disease progression (n = 16) or mixed chimerism (n = 3) after RIC allo-SCT. About 33% of patients developed GVHD, and DLI-related mortality was 11%. The response rate was 9 of 16 (56%) of evaluable patients. Two of these responders had received prior chemotherapy, although none of the 5 maintained responses was in chemotherapy-treated patients [8, 12]. Although this response rate is high, the investigators employed alemtuzumab-based conditioning in all patients, which may have increased the chance of response to the DLI. The frequent need for DLIs in this setting (characterized by profound B- and T-cell depletions in the infused graft) could be interpreted as indirect evidence in support of a graft-versus-HL effect. In the Spanish Prospective Cooperative Protocol, 11 patients received ≥1 DLI for persistent disease or disease progression [13]. In 3 cases the DLI was preceded by salvage chemotherapy. The response rate was 54% (complete in 3 patients and partial in 3 patients). Acute GVHD developed in 5 patients (46%).

Our experience in this area was recently reported [18]. Nine patients with HL who had undergone allo-SCT received DLIs for treatment of persistent or progressive disease. Fifteen DLIs were performed, with 4 patients receiving >1 DLI. In 4 patients prior salvage chemotherapy was administered. GVHD developed in all but 1 patient. The response rate was 4 of 9 (44%). Three of these 4 responders developed GVHD and 3 of 4 had received chemotherapy. No correlation was observed between CD3+ cell dose infused and disease response. At the most recent follow-up, 3 patients were alive and 6 had expired (progressive disease, n = 3; nonrelapse mortality, n = 3). The median response duration was 7 months (range, 4-9), with 1 response currently ongoing.

As a whole, these limited data suggest that DLIs for immunotherapy of recurrent HL have significant activity, although they frequently lead to GVHD. They clearly suggest, but do not prove, the existence of a graft-versus-HL effect. The durability of the responses has been variable depending on the clinical scenario, and the concomitant administration of chemotherapy in many patients has interfered with interpretation of the data.

Back to Article Outline

Conclusion 

RIC allo-SCT in HL is generating a lot of interest, but there are probably many more questions than answers at this stage. It should be recognized that this is an intrinsically very challenging area because of the nature of the patients involved and the refractoriness of their disease. The results reported thus far are clearly appealing, and RIC allo-SCT is currently being given serious consideration in subsets of patients with HL (such as those with primary refractory disease), where outcome with conventional salvage treatments (including high-dose chemotherapy and autologous SCT) is known to be poor. Because a prospective comparative study between the myeloablative and RIC approach is unlikely to occur, registry data should be reviewed in detail, and such an effort is currently ongoing (Anderlini P, Devetten M, personal communication, 2005). More patients treated, better patient selection, longer follow-up, and a more detailed analysis of the data may better define the role of RIC allo-SCT in HL.

Back to Article Outline

Acknowledgments 

We are indebted to Monica Phelps for secretarial assistance.

Back to Article Outline

References 

  1. Champlin R , Khouri I , Kornblau S , et al.   Allogeneic hematopoietic transplantation as adoptive immunotherapy, induction of graft-versus-malignancy as primary therapy . Hematol Oncol Clin North Am . 1999;13:1041–1057
  2. Martino R , Sierra J . Allogeneic hematopoietic stem cell transplantation after immunosuppressive but non-myeloablative conditioning (“miniallografts” are no small matter) . Haematologica . 1998;83:865–867
  3. Gajewski JL , Phillips GL , Sobocinski KA , et al.   Bone marrow transplants from HLA-identical siblings in advanced Hodgkin’s disease . J Clin Oncol . 1996;14:572–578
  4. Anderson JE , Litzow MR , Appelbaum FR , et al.   Allogeneic, syngeneic and autologous marrow transplantation for Hodgkin’s disease (the 21-year Seattle experience) . J Clin Oncol . 1993;11:2342–2350
  5. Milpied N , Fielding AK , Pearce R , et al.  European Group for Blood and Marrow Transplantation   Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin’s disease . J Clin Oncol . 1996;14:1291–1296
  6. Akpek G , Ambinder RF , Piantadosi S , et al.   Long-term results of blood and marrow transplantation for Hodgkin’s lymphoma . J Clin Oncol . 2001;19:4314–4321
  7. Peniket AJ , Ruiz de Elvira MC , Taghipour G , et al.   An EBMT registry matched study of allogeneic stem cell transplants for lymphoma (allogeneic transplantation is associated with a lower relapse rate but a higher procedure-related mortality rate than autologous transplantation) . Bone Marrow Transplant . 2003;31:667–678
  8. Peggs KS , Hunter A , Chopra R , et al.   Clinical evidence of a graft-versus-lymphoma effect after reduced-intensity allogeneic transplantation . Lancet . 2005;365:1906–1908
  9. Robinson SP , Taghipour G , Sureda A . Reduced-intensity allogeneic stem cell transplantation for Hodgkin’s disease (Outcome depends primarily on disease status at the time of transplantation) . (abstract) Blood . 2004;104:639a
  10. Carella AM , Cavaliere M , Lerma E , et al.   Autografting followed by non-myeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin’s disease and non-Hodgkin’s lymphoma . J Clin Oncol . 2000;18:3918–3924
  11. Burroughs LM , Maris MB , Sandmaier BM , et al.   HLA-matched related or unrelated donor non-myeloablative conditioning and hematopoietic cell transplant for patients with advanced Hodgkin’s disease . Biol Blood Marrow Transplant . 2004;10(suppl 1):73
  12. Peggs KS , Thomson K , Chopra R , et al.   Long term results of reduced intensity transplantation in multiply relapsed and refractory Hodgkin’s lymphoma (evidence of a therapeutically relevant graft-versus-lymphoma effect) . (abstract) Blood . 2003;102:198a
  13. Alvarez I , Sureda A , Caballero MD , et al.   Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed Hodgkin lymphoma (results of a Spanish Prospective Cooperative Protocol) . Biol Blood Marrow Transplant . 2006;12:172–183
  14. Anderlini P , Saliba R , Acholonu S , et al.   Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin’s disease (low transplant-related mortality and impact of intensity of conditioning regimen) . Bone Marrow Transplant . 2005;35:943–951
  15. Linch DC , Winfield D , Goldstone AH , et al.   Dose intensification with autologous bone marrow transplantation in relapsed and resistant Hodgkin’s disease (results of a BNLI randomised trial) . Lancet . 1993;341:1051–1054
  16. Schmitz N , Pfistner B , Sextro M , et al.   Aggressive conventional chemotherapy compared with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease (a randomized trial) . Lancet . 2002;359:2065–2071
  17. Porter DL , Luger SM , Duffy KM , et al.   Allogeneic cell therapy for patients who relapse after autologous stem cell transplantation . Biol Blood Marrow Transplant . 2001;7:230–238
  18. Anderlini P , Acholonu SA , Okoroji GJ , et al.   Donor leukocyte infusions in relapsed Hodgkin’s lymphoma following allogeneic stem cell transplantation (CD3+ cell dose, GVHD and disease response) . Bone Marrow Transplant . 2004;34:511–514

PII: S1083-8791(06)00292-8

doi:10.1016/j.bbmt.2006.03.013

Biology of Blood and Marrow Transplantation
Volume 12, Issue 6 , Pages 599-602, June 2006

Article Tools