The quality of life after high-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant is of utmost importance. In aplastic anemia and malignancies, there is the expectation of improved status after HDC and HSC. Conversely, quality of life outcomes (measured by growth, skeletal development dysfunction, and neuropsychological) for patients with storage diseases is gradually being defined. Because of these long-term problems, non-malignant or maldevelopment indications for HDC and HSCs should not be reviewed with criteria similar to that for malignancies.
This policy is based on a 1987 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment that focused on high-dose therapy plus autologous stem-cell support and a 1990 BCBSA TEC Assessment that focused on high-dose therapy plus allogeneic stem-cell support. Each report concluded that data showed longer survival of patients with relapsed disease after transplants than after standard therapy.
A 2000 BCBSA TEC Assessment focused on HDC and myeloablative allogeneic stem-cell support after a prior failed course of high-dose chemotherapy and autologous stem-cell support as treatment for various malignancies including Hodgkin’s disease. The TEC Assessment found that data were inadequate to permit conclusions about outcomes of this treatment strategy.
The following data reflects the most current literature and treatment strategies, including the results of the relatively recent uses of RIC (reduced-intensity conditioning)-alloSCTs.
Autologous Stem Cell Transplant (autoSCT) for Hodgkin Lymphoma (HL)
AutoSCT is widely considered the therapy of choice for relapsed and refractory HL. Two randomized, controlled studies showed benefit in using autoSCT in these patients:
- The British National Lymphoma Investigation (BNLI) study was the first to show a progression-free survival benefit with autoSCT over conventional chemotherapy in relapsed or refractory HL patients. Forty patients with relapsed or refractory HL were given chemotherapy without transplant (n=20) or autologous transplant after high-dose chemotherapy (n=20). A significantly better event-free survival at three years of 53% versus 10% was reported in the patients who underwent transplant versus the group that did not.
- Subsequently, these findings were confirmed in a larger trial by the GHSG (German Hodgkin Study Group) and European Group for Blood and Marrow Transplantation (EBMT). Patients relapsing after initial chemotherapy were randomized to chemotherapy without transplant or to autoSCT. In the final analysis of 144 patients, freedom from treatment failure at three years was 55% in the transplanted group, versus 34% in the non transplanted group. This benefit was maintained in subgroup analysis, regardless of early or late relapse and the results were confirmed in follow-up data at seven years.
Several large retrospective studies have reported event-free survival rates ranging from 25–60%, with overall survival rates from 35–66%, showing that disease status before autoSCT was the most important prognostic factor for the final outcome.
Limited treatment options exist for patients who relapse following an autoSCT, and include single-agent palliative chemotherapy or occasionally, localized radiation therapy. When a further remission may be attained with conventional-dose chemotherapy, it is rarely durable, with a median overall survival of less than one year. There is limited experience with second autoSCTs, and treatment-related mortality is high (25–40%).
Allogeneic Stem Cell Transplant (alloSCT) for Hodgkin Lymphoma (HL)
The application of alloSCT to the treatment of patients with HL initially appeared limited due to a procedure-related mortality rate of approximately 50% associated with the myeloablative conditioning regimen. A small number of studies have investigated the role of RIC (reduced-intensity conditioning)-alloSCT in refractory and relapsed HL, and the preliminary results have been encouraging, as detailed below. To date, most of the RIC-alloSCTs have been performed in patients who have failed a previous autoSCT for primary relapsed/refractory HL.
Peggs et al. investigated outcomes with RIC-alloSCT and T-cell depletion in multiply relapsed patients. Forty-nine patients were enrolled, 90% of whom had failed a previous autologous transplant. Primary study endpoints were engraftment, toxicity, non-relapse-related mortality and graft-versus-host-disease incidence. All patients achieved engraftment. Thirty-one patients had an HLA-matched donor and 18 an unrelated donor. The cumulative incidence of non-relapse-related mortality was 4.1% at 100 days post-transplant and 16.3% at 730 days post-transplant. Patients with unrelated donors had a significantly higher non-relapse-related mortality, 34% versus 7% at 730 days. Projected four year overall survival and progression-free survival were 56% and 39%, respectively.
Alvarez et al. reported the results of a Spanish Cooperative Protocol using RIC/alloSCT in 40 patients with relapsed or refractory HL. Seventy-three percent of patients had failed a previous autoSCT. Thirty-eight patients received hematopoietic cells from an HLA-identical sibling. One-year treatment-related mortality was 25%. Overall and progression-free survival was 48 and 32%, at two years, respectively. For patients who had failed a previous autoSCT, two year overall and progression-free survival was 75 and 70% in the subset that relapsed more than 12 months after autoSCT.
Todisco et al. evaluated the efficacy of RIC-alloSCT in 14 patients with refractory or progressive HL after high-dose chemotherapy (HDC) and autoSCT. All of the patients had received at least one prior course of HDC, and 50% had undergone two previous. The median time from the first and second courses of HDC and the RIC-alloSCT was 15 and eight months, respectively (range 2–34 and 2–31 months). With a median follow-up of 21 months post RIC-alloSCT (range 3–74 months), 10 of the 14 patients were alive. Estimated overall survival at one and two years was 93% and 73%, respectively, for the entire population, 83% and 44%, respectively, for patients with chemo resistant disease, and 100% for those with chemo sensitive disease.
No randomized trial has been found that compared autoSCT to alloSCT prospectively.
In summary, the studies using RIC-alloSCT in relapsed/refractory HL are characterized by small numbers of patients, disparate preparative and graft-versus-host disease prophylaxis regimens, and varying lengths of follow-up. Nonetheless, they demonstrate reduced non-relapse mortality and some suggest a graft-versus-HL effect with favorable disease control in these poor-prognosis patients. The results seem to be more favorable in patients with chemo sensitive disease, with related donors, and in the subset of patient who have undergone a previous autoSCT; those who experience disease relapse more than 12 months after transplant.
Prospective, larger, comparative studies are needed to clarify the role RIC-alloSCT will play in the treatment of patients with HL.
Autologous SCT for front-line therapy of Hodgkin Disease (HD)
A study published by Federico and colleagues concluded that HDC with autoSCT offered no benefit in outcomes over conventional chemotherapy in front-line therapy for advanced Hodgkin lymphoma patients. This supports the above policy statement indicating HDC as initial or upfront therapy is investigational.
NCCN Guidelines and PDQ® Physician Data Query Database
The 2006 National Comprehensive Cancer Network (NCCN) guidelines on HL recommend HDC with autoSCT for relapsed or refractory disease consistent with this policy. However, the NCCN guidelines are silent on the use of alloSCT. The NCCN guidelines also specifically indicate that “up-front” HDC is not indicated, citing evidence that this approach offers no benefit over conventional therapy, as noted here.
The 2008 NCCN guidelines state that autoSCT is the best option for patients with HL that is incurable with primary treatment, even though it does not improve overall survival. The 2008 NCCN guidelines state that allogeneic transplant is an option in select patients with progressive or relapsed disease.
The National Cancer Institute’s PDQ database identified two active phase III randomized studies of SCT which include patients with HL:
- Phase II/III study of standard and novel conditioning therapy and allogeneic blood or marrow transplantation in patients with severe aplastic anemia or hematologic malignancy (Protocol IDs RPCI-RP-9815, NCT00003816, NCI-V99-1527);
- Phase III randomized study of nonmyeloablative conditioning comprising low-dose total-body irradiation with versus without fludarabine followed by HLA-matched related allogeneic hematopoietic stem cell transplantation in patients with hematologic malignancies at low or moderate risk for graft rejection (Protocol IDs FHCRC-1813.00, NCT00075478).
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