High-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) transplant (HSCT) or stem-cell support (SCS) (i.e., blood or marrow) transplant is an effective treatment modality for many patients with certain malignancies and non-malignancies. The rationale of this treatment approach is to provide a very dose-intensive treatment in order to eradicate malignant cells followed by rescue with peripheral blood, umbilical cord blood, or bone marrow stem-cells.
A 2002 International Workshop summarized clinical experience (combined n=49) using autologous stem-cell support (AutoSCS) for Waldenstrom macroglobulinemia (WM). (1) These were all small feasibility studies that reported response rates but lacked data on survival and other long-term outcomes. A total of 9 (18%) achieved complete response (CR) and 39 (80%) achieved partial response (PR), but data on the durability of these responses were unavailable.
A consensus panel from the Second International Workshop on WM recommended that AutoSCS may be considered for selected patients with refractory or relapsing disease, but allogeneic stem-cell support (AlloSCS) should be used only in the context of a clinical trial. (2) Another recent review agreed that the role of AutoSCS for WM was not fully defined, although its empirical use might be appropriate for some patients with relapsed or refractory disease. (3) This review also considered AlloSCS for WM to be investigational therapy.
In 2004, a consensus panel from the Third International Workshop on WM suggested AutoSCS may be considered for eligible patients with primary refractory or relapsing disease but that AlloSCS should be cautiously approached, only in the context of a clinical trial. (4) However, the review article does not cite evidence to support the recommendations. The panelists also concluded that it was not possible to recommend a particular first-line therapeutic approach; rather, the choice should be made on the basis of individual patient considerations. A retrospective Center for International Blood and Marrow Transplant Research (CIBMTR) registry analysis of SCS (autologous, n=10, allogeneic, n=26) for WM reported 3-year overall survival (OS) rates of 46% (95% confidence interval [CI]: 27–65%) for AlloSCS recipients and 70% (95% CI: 40–93%) for AutoSCS patients. (5) Although the CIBMTR results appear favorable, it should be noted that patients in this report were heavily pretreated, highly heterogeneous in terms of disease characteristics and risk factors, and received a variety of conditioning regimens, including myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), between 1986 and 2002. These data, taken together, are insufficient to form conclusions about the potential clinical efficacy of SCS for WM. Subsequent additional review articles are in general agreement with this position. (6, 7)
Kyriakou et al. reported on 158 adult patients with WM reported to the European Group for Blood and Marrow Transplantation (EBMT) between January 1991 and December 2005. (8) Median time from diagnosis to AutoSCS was 1.7 years (range, 0.3 to 20.3 years), 32% of the patients experienced treatment failure with at least 3 of therapy, and 93% had sensitive disease at the time of SCS. Median follow-up for surviving patients was 4.2 years (range: 0.5 to 14.8 years). Nonrelapse mortality (NRM) was 3.8% at 1 year. Relapse rate was 52.1% at 5 years. Progression-free survival (PFS) and OS were 39.7% and 68.5%, respectively, at 5 years and were significantly influenced by number of lines of therapy and chemo-refractoriness at SCS. The authors conclude that AutoSCS is a feasible procedure in young patients with advanced WM but that it should not be offered to patients with chemoresistant disease and to those who received more than 3 lines of therapy.
Kyriakou and colleagues also reported on a retrospective analysis of a smaller group of patients who had AlloSCS for WM. (9) A total of 86 patients received AlloSCS by using either MAC (n=37) or RIC (n=49) regimens. The median age was 49 years (range: 23 to 64 years); 47 patients had received 3 or more previous lines of therapy, and 8 patients had experienced failure on a prior AutoSCS. A total of 59 patients (68.6%) had chemotherapy-sensitive disease at the time of AlloSCS. Median follow-up of the surviving patients was 50 months. The overall response rate was 75.6%. The relapse rates at 3 years were 11% for MAC and 25% for RIC. Overall survival at 5 years was 62% for MAC and 64% for RIC, respectively. The occurrence of chronic graft-versus-host disease (GVHD) was associated with a lower relapse rate. The authors concluded that AlloSCS can induce durable remissions in a selected population of young and heavily pretreated patients who have WM.
Little additional published evidence is available on use of AutoSCS for WM, as summarized in 2 recent review articles.(10, 11) No randomized trials have been reported.
Clinical Guidelines and Trials for WM:
National Comprehensive Cancer Network Guidelines:
The 2013 National Comprehensive Cancer Network (NCCN) guidelines indicate that selected cases of WM may be treated with AutoSCS or AlloSCS, but the latter only in a clinical trial. (12)
National Cancer Institute (NCI) Clinical Trial Database (PDQ®):
No current study is specifically focused on SCS for WM. Five Phase III studies are active that may involve patients with WM
Additional Infusion Treatments for NHL
Tandem or triple stem-cell transplant and donor leukocyte infusion (DLI) for WM are considered experimental, investigational and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
As with DLI, hematopoietic progenitor cell (HPC) boost has a positive response rate for relapse following AlloSCS. (16) The boost of stem-cells, a second dose, may be helpful to reduce the graft failure process, avoiding the risk of serious bleeding and/or infection. However, the data is insufficient for the use of HPC Boost following AlloSCS for treatment of non-hematological malignancies to lessen post-transplant graft failures. (13, 14, 15, 16)
Short Tandem Repeat (STR) Markers
Following SCS therapy, it is important to determine whether the new blood forming system is of the donor or the recipient, based upon the proportion of donor and recipient cells. The characteristics of the engraftment are analyzed, which is called chimerism analysis. Using STR marker assay to characterize the hematological course and to evaluate the usefulness of the blood forming system (particularly for hematological malignancies, myelodysplastic/myeloproliferative processes, or certain genetic or metabolic disorders) has been tested initially after the SCS, when the patient is declared as disease-free, and at the point of the confirmed stable engraftment of only the donor pattern of the blood forming system. (17, 18) Without further randomized trials using STR markers prior to or post SCS therapy for treatment of WM, the data is insufficient to determine the outcome/effect of stem-cell engraftment. (17, 18, 19, 20, 21, 22)
Based on the literature and clinical input, AutoSCS may be considered medically necessary as salvage therapy for chemosensitive WM. AlloSCS for WM is considered experimental, investigational and unproven.
Based on a search of scientific literature in the MedLine database through March 2013, HPC boost to reduce the graft failure process and STR markers to monitor engraftment chimerism for the treatment of WM are considered experimental, investigational, and unproven due to the lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.
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