Coverage Policy Manual
Policy #: 2000010
Category: Medicine
Initiated: January 1993
Last Review: June 2018
  HDC & Autologous Stem &/or Progenitor Cell Support-Non Hodgkin's Lymphomas

Description:
High dose chemotherapy (HDC) involves the administration of cytotoxic agents using doses several times greater than the standard therapeutic dose.  In some cases, whole body or localized radiotherapy is also given and is included in the term HDC when applicable.  HDC results in marrow ablation and thus HDC is accompanied by a reinfusion of stem cells in order to repopulate the bone marrow.  
 
Sources of Stem Cells:
    • Autologous stem cells may be harvested from the patient's bone marrow or peripheral blood.  Peripheral cells are harvested via one or more pheresis procedures.  Pretreatment with chemotherapy and/or hemapoietic growth factors can increase the number of circulating stem cells.
    • Syngeneic stem cells refer to genetically identical bone marrow or peripheral stem cells  harvested from an identical twin.  
 
Non Hodgkin's lymphomas (NHL) are neoplasms arising from lymphocytes arrested at various stages of maturation.  NHLs can be categorized according to their histologic type, grade, stage, on the basis of immunophenotyping, or a combination of these factors.  While use of immunophenotyping is rapidly evolving, the system most commonly used in the current literature is the International Working Formulation (IWF), summarized by IWF, Histologic Type, and Grade:
    • B, follicular, small cleaved cell, low;
    • C, follicular, mixed small cleaved and large cell, low;
    • D, follicular large cell, intermediate;
    • E, diffuse small cleaved cell, intermediate;
    • F, diffuse mixed small and large cell, intermediate;
    • G, diffuse large cell (histiocytic), intermediate;
    • H, large cell immunoblastic, high;
    • I, Lymphoblastic, high;
    • J, small non-cleaved cell (Burkitt's lymphoma),  high.
 
Follicular refers to an architectural pattern in which the neoplastic cells are arranged in nodules, or follicles, within the lymphocyte.  Follicular lymphomas arise from a B lymphocyte.  In diffuse lymphomas, the normal architecture of the lymph node is entirely effaced.  Diffuse lymphomas may arise from B or T cells.
 
Generally, intermediate and high- grade NHLs are considered unfavorable histologies that tend to progress rapidly.  However, these subtypes of NHL tend to more responsive to radiation and/or chemotherapy.  The low grade lymphomas are more indolent but are more rarely cured with conventional doses of radiation and/or chemotherapy.  When lymphomas relapse, the histologies tend to be similar to that of the original lymphoma.  However, relapsed lymphomas may also exhibit transformation, in which the histology transforms into a picture consistent with a higher grade lymphoma.  Transformed lymphomas are associated with a poor prognosis and constitute a separate category distinct from de novo high grade lymphomas.  Transformed lymphomas typically evolve from a nodular pattern to a diffuse pattern.
 
Reimbursement for high dose chemotherapy (HDC) with stem and/or progenitor cell transplant that has been pre-authorized is made as a global fee limited to the lesser of billed charges or the average allowable charge authorized by the Blue Quality Centers for Transplant in the geographic region where the transplant is performed.  This global payment includes all related transplant services including institutional, professional, ancillary, and organ procurement.  The global period begins one day prior to the date of the transplant and continues for 48 days after the transplant.  This covers the inpatient/outpatient stay and provides a per diem outlier payment if necessary.  This global fee also includes the cost of complications arising from the original procedure when services are rendered within the global postoperative period for the particular transplant.

Policy/
Coverage:
High dose chemotherapy with autologous bone marrow, stem cell or progenitor cell support for treatment of non-Hodgkin's lymphoma (NHL) meets primary coverage criteria for effectiveness and is covered:
 
International Working Formulation (IWF) subtypes intermediate or aggressive:
    • as salvage therapy for patients who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy;
    • to consolidate a first complete response for patients with an age-adjusted International Prognostic Index score that predicts a high- or high-intermediate risk of relapse; and
    • to achieve or consolidate CR for those in a chemosensitive first or subsequent relapse.
 
For patients with NHL subtypes the IWF scheme classified as indolent, and for new subtypes defined by the World Health Organization/Revised European American Lymphoma scheme
    • as salvage therapy for patients who do not achieve a complete remission (CR) after first-line treatment (induction) with a full course of standard-dose chemotherapy;
    • to achieve or consolidate CR for those in a first or subsequent chemosensitive relapse, whether or not their lymphoma has undergone transformation to a higher grade.
 
Tandem transplants are not covered for the treatment of Non-Hodgkin’s Lymphoma based on a specific exclusion in the member benefit contract.
 
High dose chemotherapy with autologous stem cell support for chronic lymphocytic leukemia/small lymphocytic lymphoma is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.  
 
For contracts without primary coverage criteria, high dose chemotherapy with autologous stem cell support for chronic lymphocytic leukemia/small lymphocytic lymphoma is considered investigational and is not covered.  Investigational services are exclusions in the member certificate of coverage.

Rationale:
The available evidence suggested that, based on total tumor response rates and complete response rates in patients with intermediate or high-grade lymphomas, the use of HDC with autologous stem-cell support produced outcomes comparable to salvage therapy for intermediate- and high-grade lymphomas.
 
The rationale for HDC and allogeneic stem-cell support in intermediate or high-grade lymphomas was based on the success seen with HDC and autologous stem-cell support, where the estimated 3- to 5-year survival was 40%–60%. However, some patients were not candidates for autologous stem-cell support due to chronic marrow hypocellularity or malignancy involving the bone marrow. Allogeneic stem-cell support provided an alternative. The data suggested that the 3- to 5-year survival rates associated with allogeneic stem-cell support were comparable to those associated with autologous stem-cell support.
    • Data were minimal concerning outcomes of allogeneic stem-cell support, and most reports focused on outcomes of HDC without regard to the source of stem cells. Thus, the literature reviewed only compared outcomes after HDC supported by any source of stem cells to outcomes after conventional-dose regimens. Whether there was a treatment advantage for allogeneic or autologous stem-cell support was unknown.
    • Data were inadequate to compare outcomes of high-dose therapy plus either allogeneic or autologous stem-cell support with conventional-dose alternatives for patients with low-grade or follicular NHL either as primary therapy or as salvage therapy after relapse and transformation to a higher grade NHL histology.
 
Sufficient data were reported to assess outcomes of HDC as salvage therapy for low-grade follicular lymphoma that had failed primary treatment without transformation to a higher grade. In this group of patients, the disease-free survival at 5 years was 10%–66% after HDC and only 2%–21% after conventional-dose alternatives. Given the natural history of this indolent disease, which is one of repeated relapses and progressively shorter durations of remission, improvement in disease-free survival was considered a good predictor of improvement in overall survival.
 
A review of the literature published between 1995 and 2000 on outcomes of HDC to treat follicular NHL did not alter the policy conclusions.  Specifically, review articles published in this interval concluded that evidence was still insufficient to support routine use of HDC to treat patients with follicular NHL in first remission. Morrison and Peterson stated that the available data were limited, follow-up was short, and no direct comparisons with conventional treatment were conducted in controlled trials. They concluded that the role of HDC with autologous stem-cell support to treat patients in first remission could not be determined based on the data available at that time. Blay and Phillip noted that it was unclear whether the reported results reflected improved health outcomes or patient-selection bias. These authors suggested that comparing outcomes of HDC plus autologous stem-cell support with those of alternatives required prospective, controlled trials.
 
Data available in 2000 also confirmed conclusions of the policy on use of HDC for patients with relapsed follicular NHL that had not undergone transformation. Evidence was consistent with earlier estimates of overall response, response duration, disease-free survival, overall survival, and treatment-related mortality. The University of Nebraska and Dana Farber published long-term follow-up data showing median overall survival of 6 years or more.  Subsequent data on overall tumor response (range: 82%–93%) and median response duration (3.1 years, over 4 years) continued to show an advantage of HDC over conventional chemotherapy.
 
Five-year disease-free survival was between 19% and 66%, which also was superior to conventional chemotherapy.
 
In 2000, one article and one abstract provided the only new evidence on outcomes of HDC for patients with transformed follicular NHL.  Considerable heterogeneity remained among patients in these series, and outcomes also were still quite variable. The published literature did not permit pooling of results by baseline characteristics to determine whether outcomes vary predictably. Thus, findings available at that time did not resolve uncertainty on outcomes of HDC plus stem-cell transplants for this indication.
 
Literature was reviewed in 2000 that focused on HDC and allogeneic stem-cell support for patients with various hematologic malignancies, including NHL, that had failed a prior course of HDC and autologous stem-cell support.  The data were inadequate to permit conclusions on outcomes of this treatment strategy compared with alternatives.
 
This Policy was updated again in March 2003 based on literature published since 2000. The update focused on indications for HDC plus hematopoietic stem-cell transplants previously considered investigational, including consolidating a first CR, treating follicular NHL that relapsed with transformation; tandem transplants; and allotransplants for patients who have failed a prior autotransplant. In addition, evidence was sought on transplant outcomes for patients with distinct lymphoma subtypes defined by the WHO/REAL classification scheme but merged with others in the IWF scheme. Published results relevant to each of these indications are summarized below.
 
Consolidating a first CR. Several randomized trials compared outcomes of autotransplants used to consolidate a first CR in patients with intermediate or aggressive NHL, with outcomes of an alternative strategy that delayed transplants until relapse. As summarized in a recent editorial, the preponderance of evidence showed that consolidating first CRs with a stem-cell transplant did not improve overall survival for the full population of enrolled patients. However, a subgroup analysis at 8 years median follow-up focused on 236 patients at high- or high-intermediate risk of relapse (based on age-adjusted IPI scores) who were enrolled in the largest of these trials (the LNH87-2 protocol). The subgroup analysis reported superior overall (64% versus 49%; relative risk 1.51, p=0.04) and disease-free survival (55% versus 39%; relative risk 1.56, p=0.02) for patients at elevated risk of relapse who were consolidated with an autotransplant.
 
A large, multi-group, prospective, randomized phase III comparison of these strategies (the S9704 trial) is ongoing, to confirm results of the subgroup analysis in a larger population with diffuse large B-cell lymphoma at high- and high-intermediate risk of relapse. Nevertheless, many clinicians view the LNH87-2 subgroup analysis as sufficient evidence to support use of autotransplants to consolidate a first CR when risk of relapse is high. In contrast, editorials and recent reviews agree that available evidence shows no survival benefit from autotransplants to consolidate first CR in patients with intermediate or aggressive NHL at low or low-intermediate risk of relapse (using age-adjusted IPI score). Similarly, evidence remains insufficient to support routine use of transplants to consolidate a first CR for any patients with indolent (follicular) lymphomas.
 
Transformed follicular NHL. The literature search update found no randomized trials comparing autotransplants to alternative therapies for patients with follicular or other indolent NHL that has relapsed with transformation to a higher grade.  More recent retrospective data are available from a single institution series and a registry analysis. Although these studies lack controls treated with conventional-dose regimens, they directly compare outcomes of autotransplants for transformed NHL to outcomes of autotransplants for relapsed de novo intermediate or aggressive NHL.
 
The single-institution series reported similar event-free (38% for 18 transformed patients versus 37% for 100 de novo patients) and overall survival at 4 years (61% versus 53%, p not significant) for the 2 groups. Transplant-related mortality occurred in only 1 of 18 patients with transformed lymphoma. The registry analysis included 50 patients transplanted for follicular lymphoma that relapsed with transformation, 200 matched patients transplanted for follicular lymphoma that relapsed without transformation, and another 200 matched patients transplanted for de novo intermediate or aggressive lymphoma that relapsed.  Kaplan-Meier analyses showed no statistically significant differences in overall survival between the group transplanted for transformed NHL and either of the 2 matched comparison groups (p=0.939 versus non-transformed low-grade lymphoma; and p=0.438 versus de novo intermediate/aggressive lymphoma). Similar results were reported in single-institution retrospective series that lacked comparison groups.  Taken together, the new results indicate that autotransplants improve outcomes for patients with relapsed NHL whether it is de novo intermediate or aggressive disease, or indolent disease that has relapsed with or without transformation.
 
Tandem transplants.
The updated literature search identified 2 uncontrolled pilot studies on outcomes of tandem transplants as part of initial therapy for patients with aggressive NHL. One study (n=36) was limited to patients at high- or high-intermediate risk for relapse after achieving a first CR.  The second (n=25) included 11 patients with low-intermediate risk and 14 patients at higher risk.  Note also that only 17 of the 25 patients in the second study were given full courses of induction therapy, and only 8 of these achieved a CR. Thus, patient populations in these studies differed with respect to disease status at transplant. Neither study included a control group of similar patients managed with a single transplant. Therefore, results reported by these studies did not provide convincing evidence that tandem transplants improved outcomes when compared with single transplants for patients with NHL. A recent review also concluded that available data were insufficient to determine whether outcomes of tandem transplants were superior to outcomes of single transplants for patients with NHL.
 
Allotransplants after a failed autotransplant.
The updated literature search found no prospective controlled studies comparing allotransplants to alternative strategies for managing failure (progression or relapse) after an autotransplant for NHL. Only 2 reports that included patients with NHL have been published since 2000.  One series included 4 NHL patients who relapsed after an autotransplant, while the second included 2 patients with mantle cell lymphoma that had relapsed after an autotransplant.  The scant new data clearly are insufficient to change conclusions of the previous policy. Note also that many patients with follicular NHL that has relapsed after an autotransplant reportedly respond to conventional dose treatment and achieve long-term survival.
 
The paucity of outcomes data for allotransplants after a failed autotransplant is not surprising. Patients are rarely considered eligible for this option either because their relapsed lymphoma progresses too rapidly, because their advanced physiologic age or poor health status increases the likelihood of adverse outcomes (e.g., from GVHD), or because they lack a well-matched donor. A few institutions have treated up to 15 or 20 such lymphoma patients (NHL plus Hodgkin’s disease) in the last 1 to 2 decades. Thus, it appears highly unlikely that adequately powered, randomized trials comparing this therapy to alternatives could ever be conducted, even by a multi-institutional group. Nevertheless, several institutions report that a minority of patients achieved long-term disease-free survival following an allotransplant for relapsed NHL after an autotransplant. Factors that apparently increase the likelihood of survival include a chemosensitive relapse, younger age, a long disease-free interval since the prior autotransplant, availability of an HLA-identical sibling donor, and fewer chemotherapy regimens prior to the failed autotransplant. Thus, clinical judgment, confirmed by external review, can play an important role to select patients for this treatment with a reasonable likelihood that potential benefits may exceed harms.
 
Newly defined NHL subtypes.
Many new NHL subtypes defined by the WHO/REAL classification scheme have not previously been classified as indolent, intermediate, or aggressive lymphomas. Data reported by the NHL Classification Project suggest that clinical characteristics, prognostic features, and survival rates for patients with some newly defined entities (e.g., mantle cell and peripheral T-cell lymphomas) may be closer to those of intermediate or aggressive NHLs than to the indolent lymphomas. Other new NHL subtypes (e.g., marginal zone B-cell lymphoma of extranodal mucosa-associated lymphoid tissue) are closer in these respects to indolent lymphomas. Limited evidence is available on autotransplant outcomes for homogeneous groups with these newly defined NHL subtypes.
 
The updated literature search identified 2 studies reporting outcomes of autotransplants for mantle cell lymphoma. A retrospective analysis on 40 patients transplanted between 1991 and 1998 reported that median overall survival was 47 months (65% alive at 2 years) and median event-free survival was 17 months (36% at 2 years).  However, only 5 (13%) of these patients were transplanted in a first CR, and outcomes were not reported separately for these patients. A second study reported 68% overall survival and 55% event-free survival at 3 years after treatment.  Autotransplants were part of first-line therapy for 9 of the 24 patients included in this study, and only 3 of the 9 were in first CR at the time of transplant. Two of the 3 died with mantle cell lymphoma at 4 and 47 months after transplant, while the third was alive at 24 months’ followup. A review that summarized data from 8 studies on previously treated patients and 3 studies on patients in first CR concluded that evidence was insufficient to clearly establish a role for autotransplants to consolidate a first CR in patients with mantle cell lymphoma.  Note that the review also concluded the available evidence did not demonstrate a clear survival advantage for autotransplants as salvage when compared with conventional-dose salvage.
 
Two retrospective studies reported autotransplant outcomes for groups with a variety of peripheral T-cell lymphomas. Blystad et al. treated 40 patients with chemosensitive disease, of whom 17 were in a first complete or partial remission and 23 were in a second or third complete or partial remission. With a median 36 months’ follow-up, overall survival was 58% at 3 years, event-free survival was 48%, and relapse-free survival was 56%. Rodriguez et al. reported on 36 patients, all with recurrent, relapsed, or refractory disease (i.e., none in a first CR). Overall survival at 3 years was 36% and progression-free survival was 28%. Taken together, these reports are insufficient to determine whether autotransplants improve outcomes for peripheral T-cell lymphoma patients in a first complete remission.
 
2012 Update
This policy is being updated with results from a literature search conducted using the MEDLINE database.  The studies identified did not prompt a change in the coverage statement.
 
Indolent Lymphomas
In 2008, Ladetto et al. reported the results of a Phase III, randomized, multicenter trial of patients with high-risk follicular lymphoma (FL), treated at diagnosis (Ladetto, 2008).  A total of 134 patients were enrolled to receive either rituximab-supplemented high-dose chemotherapy and autologous HSCT or 6 courses of cyclophosphamide, doxorubicin (or Adriamycin®), vincristine (Oncovin®), and prednisolone (CHOP) followed by rituximab (CHOP-R). Of these patients, 79% completed HSCT and 71% completed CHOP-R. Complete remission was 85% with HSCT and 62% with CHOP-R. At a median follow-up of 51 months, the 4-year event-free survival (EFS) was 61% and 28% (HSCT vs. CHOP-R, respectively), with no difference in overall survival (OS). Molecular remission (defined as negative results by polymerase chain reaction (PCR) on 2 or more consecutive bone marrow samples spaced 6 months apart in patients who reached complete remission was achieved in 80% of HSCT and 44% of CHOP-R patients and was the strongest independent outcome predictor. In 71% of the CHOP-R patients who had a relapse, salvage HSCT was performed and achieved an 85% CR rate and a 68% 3-year EFS. The authors concluded that there was no OS advantage to treating high-risk FL initially with HSCT but that relapsed/refractory FL would be the most appropriate setting for this therapy.
 
 
Aggressive Lymphomas
Between 2005 and 2008, several reports of randomized trials have shown no survival benefit to HSCT as first-line therapy for aggressive lymphomas, as summarized below:
 
Greb et al. undertook a systematic review and meta-analysis to determine whether high-dose chemotherapy with autologous HSCT as first-line treatment in patients with aggressive NHL improves survival compared to patients treated with conventional chemotherapy (Greb, 2008).   Fifteen randomized, controlled trials (RCTs) including 3,079 patients were eligible for the meta-analysis. Thirteen studies with 2,018 patients showed significantly higher CR rates in the autologous HSCT group (p=0.004). However, autologous HSCT did not have an effect on OS when compared to conventional chemotherapy. According to the IPI, subgroup analysis of prognostic groups showed no survival differences between autologous HSCT and conventional chemotherapy in 12 trials, and EFS also was not significantly different between the two groups. The authors concluded that despite higher CR rates, there is no benefit with autologous HSCT as first-line treatment in aggressive NHL.
 
Betticher et al. reported the results of a Phase III multicenter, randomized trial comparing sequential high-dose chemotherapy with autologous HSCT to standard CHOP as first-line therapy in 129 patients with aggressive NHL (Bettichler, 2006).   Remission rates were similar in the two groups, and after a median observation time of 48 months, there was no difference in OS with 46% in the sequential autologous HSCT group and 53% in the group that received CHOP (p=0.48). The authors concluded that sequential autologous HSCT did not confer any survival benefit as initial therapy in patients with aggressive NHL.
 
Baldissera et al. reported on the results of a prospective RCT comparing high-dose chemotherapy and autologous HSCT to conventional chemotherapy as frontline therapy in 56 patients with high-risk aggressive NHL (Baldissera, 2006).   The 5-year actuarial OS and PFS were not statistically different between the two study groups; only DFS was statistically different (97% vs. 47%, for the autologous HSCT and conventional groups, respectively; p=0.02.)
 
Olivieri et al. reported on a randomized study of 223 patients with aggressive NHL using upfront high-dose chemotherapy with autologous HSCT versus conventional chemotherapy (plus autologous HSCT in cases of failure) (Olivieris, 2005).  In the conventional group, 29 patients achieved a PR or no response and went on to receive high-dose chemotherapy and autologous HSCT. With a median follow-up of 62 months, there was no difference in 7-year probability of survival (60% and 57.8%; p=0.5), DFS (62% and 71%; p=0.2), and PFS (44.9% and 40.9%; p=0.7, all respectively) between the two groups. The authors concluded that patients with aggressive NHL do not benefit from upfront autologous HSCT.
 
The results of the ongoing S9704 trial will likely be important in the future direction of HSCT as frontline therapy in patients with aggressive NHL and high- to high-intermediate risk of relapse.
 
 
Mantle Cell Lymphoma
In an attempt to improve the outcome of mantle cell lymphoma (MCL), several Phase II trials investigated the efficacy of autologous HSCT, with published results differing substantially (Hoster, 2008) (Dreyling, 2005).  Some studies found no benefit to HSCT, and others suggested an EFS advantage, at least in a subset of patients (Holster, 2008).  The differing results in these studies were likely due to different time points of transplant (first vs. second remission) and other patient selection criteria (Dreyling, 2005).   
 
In 2005, the results of the first randomized trial were reported by Dreyling and colleagues of the European MCL Network (Dreyling, 2005).   A total of 122 patients with MCL received either autologous HSCT or interferon as consolidation therapy in first CR or PR. Among these patients, 43% had a low-risk, 11% had a high-intermediate risk, and 6% had a high-risk profile. Autologous HSCT resulted in a PR rate of 17% and a CR rate of 81% (versus PR of 62% and CR of 37% with interferon). Survival curves for time to treatment failure (TTF) after randomization showed that autologous HSCT was superior to interferon (p=0.0023). There also was significant improvement in the 3-year PFS demonstrated in the autologous HSCT versus interferon arm (54% and 25%, respectively; p=0.01). At the time of the reporting, no advantage was seen in OS, with a 3-year OS of 83% versus 77%. The trial also suggested that the impact of autologous HSCT could depend on the patient’s remission status prior to the transplant, with a median PFS of 46 months in patients in CR versus 33 months in patients in PR.
 
Till et al. reported the results of the outcomes of 56 patients with MCL treated with induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) with or without rituximab followed by autologous HSCT in first CR or PR (n=21), CHOP with or without rituximab followed by autologous HSCT in first CR or PR (n=15), or autologous HSCT following disease progression (n=20) (Till, 2008).  OS and PFS at 3 years among patients transplanted in CR or PR were 93% and 63% compared with 46% and 36%, all respectively, for patients transplanted with relapsed/refractory disease. The hazard of mortality among patients transplanted with relapsed or refractory disease was 6.1 times that of patients transplanted in first CR or PR (p=0.0006).
 
Geisler et al. reported on 160 previously untreated patients with MCL with dose-intensified induction immunochemotherapy (Geisler, 2008).   Responders received high-dose chemotherapy with in vivo purged autologous HSCT. Overall and CR was achieved in 96% and 54%, respectively. The 6-year OS, EFS, and PFS were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years.
 
Evens et al. reported on 25 untreated patients with MCL who received induction chemotherapy, with an overall response rate of 74% (Evens, 2008).  Seventeen patients received a consolidative autologous (n=13) or allogeneic (n=4) HSCT. Five-year EFS and OS for all patients was 35% and 50%, respectively. After a median follow-up of 66 months, the 5-year EFS and OS for patients who received autologous HSCT was 54% and 75%, respectively.
 
Tam and colleagues reported a retrospective study which included all patients with MCL who had undergone HSCT in sequential phase 2 protocols (autologous or nonmyeloablative allogeneic) at the University of Texas M.D. Anderson Cancer Center between February 1990 and June 2007 (Tam, 2009).   The approach to transplantation was risk-adapted and based primarily on the patient’s treatment status. Autologous HSCT was performed as consolidation therapy for patients in first remission after chemotherapy (1990-2001). From 2001 onward, because of the favorable clinical outcomes found with rituximab (R)-hyperCVAD chemotherapy, autologous HSCT was performed only in patients not in CR after R-hyperCVAD and in patients who had received less-intensive induction chemotherapy (e.g., CHOP-R). For patients with relapsed or primary refractory MCL, autologous HSCT was performed before the use of nonmyeloablative allogeneic in 1997. After 1997, nonmyeloablative allogeneic was performed whenever a histocompatible donor was available. Patients generally underwent autologous HSCT up to the age of 70 and RIC-allogeneic up to the age of 65 years. Since 2004, patients up to the age of 75 years could receive an autologous transplant. The study included 121 patients with MCL: 50 who underwent autologous HSCT in first CR (46%) or PR (54%) (AUTO1), 36 who underwent autologous HSCT for relapsed or refractory disease (AUTO2), and 35 who underwent nonmyeloablative allogeneic for relapsed or refractory disease (NST). The ages at transplantation were similar in all 3 groups (median, 57 years [range: 38–73 years] for AUTO1; median, 59 years [range: 42–76 years] for AUTO2; and median, 58 years [range: 43–68 years] for NST).
 
For the AUTO1 group, at a median follow-up of 6 years, the actuarial PFS and OS were 39% and 61%, respectively, with median PFS and OS durations of 42 months and 93 months. Of the AUTO2 patients, 31% did not experience a response to initial chemotherapy but did experience a PR or better to salvage therapy with hyperCVAD (n=6), R-hyperCVAD (n=4), or methotrexate and ara-C (n=1). Seventeen patients (47%) were in their second remission, 3 (8%) were in their third or subsequent remission, and 5 (14%) had chemorefractory relapse and were transplanted in less than partial remission. The actuarial 6-year PFS and OS rates were 10% and 35%, respectively (p=0.01 and 0.02 compared with AUTO1), and the median PFS and OS durations were 27 and 52 months, respectively. These inferior results for both PFS and OS compared with AUTO1 patients were maintained in a multivariate analysis that accounted for differences in baseline factors.
 
Of the patients who underwent nonmyeloablative allogeneic HSCT for relapsed or refractory MCL, 20% did not experience a response to initial chemotherapy but experienced a PR or better to salvage therapy with R-hyperCVAD. Thirty-one percent were in their second remission, 31% were in their third or subsequent remission, and 17% had refractory relapse and received a transplant in less than partial remission. With a median follow-up of 56 months (range, 19-110 months), the median PFS duration was 60 months, and the median OS had not yet been reached. The 6-year actuarial PFS rate was 46%, and the 6-year actuarial OS rate was 53%. Plateaus in the survival curves were observed for both PFS and OS, with no relapses or deaths occurring in 9 patients followed between 63 and 110 months. These outcomes were significantly superior to that of AUTO2 patients, whereby relapses and deaths occurred in a continuous fashion (p=0.01 for PFS; p=0.005 for OS [4-year landmark for OS]). Compared with AUTO1 patients, the RIC-allogeneic HSCT patients had an initially lower OS; however, this reversed at 8 years because of the lack of late deaths among nonmyeloablative allogeneic patients.
 
The authors concluded that their study provides early evidence that MCL may be curable in both the frontline and salvage settings. In chemotherapy-naïve patients, their results showed that rituximab-containing autologous HSCT in first remission may result in long-term disease control, with only 1 relapse occurring among 11 patients followed between 2 and 8 years, in contrast to that of autologous transplantation without rituximab, in which relapses occurred in a continuous fashion. In contrast to frontline transplantation, the outcomes of autologous transplantation in patients with relapsed or refractory MCL remain unsatisfactory, with no evidence of a cured fraction on survival curves.
 
The authors also summarize the two recent major therapeutic advances that have substantially altered the outlook of patients with MCL: 1) the introduction of rituximab, which in combination with chemotherapy, has improved the results of both frontline and salvage treatments for MCL, and 2) the combination of rituximab and hyperCVAD, which is capable of achieving CR rates of up to 90% in the frontline setting, with a prolonged 5-year failure-free survival of 60% in younger patients.
 
As noted in the Tam et al. study, (Tam, 2009)  recent review articles on high-dose therapy for MCL reiterate the finding in several studies of a superior result of transplantation in first CR (autologous or allogeneic) rather than in the relapsed setting, and that intensive immunochemotherapy as induction therapy preceding high-dose therapy plus autologous HSCT is indicated  (Holster, 2008) (Geisler, 2009).
 
2013 Update
A literature search was conducted using the MEDLINE database through May 2013. There was no new information identified that would prompt a change in the coverage statement. The following is a summary of the key identified literature.
 
In 2012, Al Khabori et al. performed a systematic review and meta-analysis of the use of autologous HSCT in untreated, advanced follicular lymphoma (Al Khabori, 2012). Four randomized controlled trials (RCTs) comparing autologous HSCT to conventional chemotherapy in 941 patients were included. Three trials reported overall survival (OS); moderate quality evidence from these trials did not show an improved OS with the use of HSCT as part of the initial treatment of FL. Adverse outcomes including treatment-related mortality and the development of myelodysplastic syndrome, acute myeloid leukemia, and solid tumors, were not different between the two arms.
 
In 2012, Schaaf et al. performed a systematic review with meta-analysis of RCTs comparing autologous HSCT with chemotherapy or immuno-chemotherapy in patients with previously untreated or relapsed FL with respect to OS, progression free survival (PFS), treatment related mortality, adverse events and secondary malignancies (Schaaf, 2012). Five RCTs involving 1,093 patients were included; four trials in previously untreated patients and one trial in relapsed patients. The quality of the five trials was judged to be moderate. There was a statistically significant increase in PFS in previously untreated FL patients in the HSCT arm (HR = 0.42 (95% confidence interval (CI) 0.33 to 0.54; P < 0.00001). However, there was not a statistically significant OS advantage (HR = 0.97; 95% 0.76 to 1.24; P = 0.81). In the four trials in previously untreated patients there was no statistically significant differences between HSCT and the control-arm in terms of treatment related mortality (RR = 1.28; 95% CI 0.25 to 6.61; P = 0.77), secondary acute myeloid leukemia/myelodysplastic syndromes (RR = 2.87; 95% CI 0.7 to 11.75; P = 0.14) or solid cancers (RR = 1.20; 95% CI 0.25 to 5.77; P = 0.82). Adverse events were rarely reported and were more frequent in patients who underwent HSCT. For patients with relapsed FL, there was some evidence from one trial with 70 patients that HSCT was advantageous in terms of PFS and OS (PFS: HR = 0.30; 95% CI 0.15 to 0.61; OS: HR = 0.40; 95% CI 0.18 to 0.89). No results were reported from this trial for treatment related mortality, adverse events or secondary cancers.
 
2014 Update
 
A literature search conducted through May 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Results of a phase III multicenter randomized trial (SWOG-9704) of autologous HSCT as consolidation for aggressive (high-intermediate or high-risk) diffuse B-cell NHL were published in October 2013 (Crocchiolo, 2013). In this trial, 253 patients received 5 cycles of induction chemotherapy (CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone with [n=156, 47%] or without rituximab). Those who had at least a partial response to 5 cycles of induction therapy were randomly assigned to receive 3 additional cycles of CHOP (n=128) or 1 additional cycle of CHOP followed by autologous HSCT (n=125). The primary efficacy end points of the trial were 2-year PFS and OS. Two-year PFS rates were 69% and 55% in the HSCT and control group, respectively (HR control vs HSCT=1.72; 95% CI, 1.18 to 2.51; p=0.005). The 2-year OS rates in the HSCT and control group were 74% and 71%, respectively (HR=1.26; 95% CI, 0.82 to 1.94; p=0.30). Unplanned exploratory analyses showed a differential treatment effect according to disease risk level. Among high-risk patients, the 2-year OS rate was 82% in the HSCT group and 64% in the control group (log-rank test p=0.01). The main results of this trial comport with earlier study results in not discerning a significant effect of early autologous HSCT on OS among a group of patients with high-, intermediate-, and high-risk diffuse B-cell NHL. However, it appears that the survival curve shows a plateau among the high-risk HSCT patients out to perhaps 10 years after study registration. Although this evidence was from exploratory subset analysis, it further supports the medical necessity of this approach in such cases compared with nontransplant strategies.
 
2015 Update
 
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement.
  
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
 

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