MP 8.01.20

Hematopoietic Stem-Cell Transplantation for Non-Hodgkin's Lymphomas

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Medical Policy
Section Therapy	Original Policy Date 12/1/99	Last Review Status/Date Reviewed with literature search/6:2008
Issue 6:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Hematopoietic Stem Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone-marrow-toxic doses of cytotoxic drugs, with or without whole-body radiation therapy. Bone-marrow stem cells may be obtained from the transplant recipient (i.e., autologous SCT) or from a donor (i.e., allogeneic SCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft vs. host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.
Immunologic incompatibility between infused stem cells and the recipient is not an issue in autologous SCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic SCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR loci on each leg of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci.
Conventional Preparative Conditioning for Hematopoietic Stem-Cell Transplantation
The conventional practice of allogeneic SCT involves administration of myelotoxic agents (e.g., cyclophosphamide, busulfan) with or without total-body irradiation at doses sufficient to cause bone marrow failure. The beneficial treatment effect in this procedure results from chemotherapeutic eradication of malignant cells with an associated immune-mediated graft-versus-malignancy effect. While such treatment may eliminate the malignant cells, patients are as likely to die from opportunistic infections, graft-versus-host disease, and/or organ failure as from the underlying malignancy.
Autologous SCT necessitates myeloablative chemotherapy to eradicate cancerous cells from the blood and bone marrow, thus permitting subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic progenitor cells. As a consequence, autologous SCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous SCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not graft-versus-host disease.
Reduced-Intensity Conditioning for Allogeneic Stem-Cell Transplantation
Reduced-intensity conditioning (RIC) refers to chemotherapy regimens that seek to reduce adverse effects secondary to bone marrow toxicity, while retaining the beneficial graft-versus-malignancy effect of allogeneic transplantation. These regimens do not eradicate the patient’s hematopoietic ability, thereby, allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less) even without a transplant. Patients who undergo RIC with allogeneic SCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. A number of different cytotoxic regimens, with or without radiotherapy, may be used for RIC allotransplantation. They represent a continuum in their effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation.
Non-Hodgkin’s Lymphomas (NHL)
NHL are a heterogeneous group of lymphoproliferative malignancies, which usually originate in lymphoid tissue. Historically, uniform treatment of patients with NHL was hampered by the lack of a uniform classification system. In 1982, the Working Formulation (WF) was developed to unify different classification systems into one. (1) The WF divided NHL into low-, intermediate-, and high-grade, with subgroups based on histologic cell type. Since our understanding of NHL has improved, the diagnosis has become more sophisticated and includes the incorporation of new immunophenotyping and genetic techniques. As a result, the WF has become outdated.
European and American pathologists proposed a new classification, the Revised European American Lymphoma (REAL) Classification (2), and an updated version of the REAL system, the new World Health Organization (WHO) classification. (3) The WHO/REAL classification recognizes 3 major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and Hodgkin lymphoma. Hodgkin lymphoma and SCT is addressed in policy No. 08.01.29.
Within the B-cell and T-cell categories, two subdivisions are recognized: precursor neoplasms, which correspond to the earliest stages of differentiation, and more mature differentiated neoplasms.
Updated REAL/WHO Classification
B-cell Neoplasms

T-cell and Putative NK-cell Neoplasms

1. Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL
2. Peripheral T-cell and NK-cell neoplasms
   •  T-cell chronic lymphocytic leukemia/prolymphocytic leukemia
   • T-cell granular lymphocytic leukemia
   • Mycosis fungoides/Sézary syndrome
   • Peripheral T-cell lymphoma, not otherwise characterized
   • Hepatosplenic gamma/delta T-cell lymphoma
   • Subcutaneous panniculitis-like T-cell lymphoma
   • Angioimmunoblastic T-cell lymphoma
   • Extranodal T-/NK-cell lymphoma, nasal type
   • Enteropathy-type intestinal T-cell lymphoma
   • Adult T-cell lymphoma/leukemia (human T-lymphotrophic virus [HTLV] 1+)
   • Anaplastic large cell lymphoma, primary systemic type
   • Anaplastic large cell lymphoma, primary cutaneous type
   • Aggressive NK-cell leukemia

In the U.S., B-cell lymphomas represent 80–85% of cases of NHL and T-cell lymphomas 15–20%. NK lymphomas are relatively rare. (4)
The International Lymphoma Classification Project identified the most common NHL subtypes as follows: diffuse large B-cell lymphoma (DLBCL) 31%, follicular lymphoma (FL) 22%, small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) 6%, mantle cell lymphoma (MCL) 6%, peripheral T-cell lymphoma (PTCL) 6%, and marginal zone B-cell lymphoma/mucosa-associated lymphoid tissue (MALT) lymphoma 5%. All other subtypes each represent less than 2% of cases of NHL. (4)
Several subtypes of NHL have emerged with the REAL/WHO classification with unique clinical and biologic features, and they will be addressed separately throughout the policy, when necessary (specifically MCL and PTCL).

In general, the NHL can be divided into two prognostic groups- indolent and aggressive. Indolent NHL have a relatively good prognosis with a median survival of 10 years; however, they are not curable in advanced clinical stages. (1) Early stage indolent NHL (stage 1 or 2) may be effectively treated with radiation alone. (1) Although indolent NHL are responsive to radiation and chemotherapy, a continuous rate of relapse is seen in advanced stages. (1) These patients can often be retreated, if their disease remains of the indolent type. Indolent NHL may transform into a more aggressive form, which is generally treated with regimens that are used for aggressive, recurrent NHL. Histologic transformation to higher grade lymphoma occurs in up to 70% of patients with low-grade lymphomas (5), and median survival with conventional chemotherapy is 1 year or less. FL is the most common indolent NHL (70–80% of cases), and often the terms indolent lymphoma and FL are used synonymously. Also included in the indolent NHL are SLL/CLL, lymphoplasmacytoid lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphomas.
The aggressive NHL have a shorter natural history; however, 30–60% of these patients can be cured with intensive combination chemotherapy regimens. (1) Aggressive lymphomas include DLBCL, MCL, PTCL, anaplastic large cell lymphoma, and Burkitt’s lymphoma.
Oncologists developed a clinical tool to aid in predicting the prognosis of patients with aggressive NHL (specifically DLBCL) referred to as the International Prognostic Index (IPI). (6) Prior to the development of IPI in 1993, prognosis was predominantly based upon disease stage.
Based on the number of risk factors present and adjusted for patient age, the IPI defines 4 risk groups: low, low intermediate, high intermediate, and high risk, based upon 5 significant risk factors prognostic of OS:

1. Age older than 60 years old
2. Elevated serum lactate dehydrogenase (LDH) level
3. Ann Arbor stage III or IV disease
4. ECOG (Eastern Cooperative Oncology Group) performance status of 2, 3, or 4
5. Involvement of more than 1 extranodal site

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at 5 years. Age-adjusted (aaIPI) and stage-adjusted modifications of this IPI are used for younger patients with localized disease.
With the success of the IPI, a separate prognostic index was developed for FL, which has multiple independent risk factors for relapse after a first CR. The proposed and validated Follicular Lymphoma International Prognostic Index (FLIPI) contains 5 adverse prognostic factors:

1.  Age older than 60 years
2. Ann Arbor stage III-IV
3. Hemoglobin level less than 12.0 g/dL
4. More than than 4 lymph node areas involved
5. Elevated serum LDH level

These 5 factors are used to stratify patients into 3 categories of risk: low (0-1 risk factor), intermediate (2 risk factors), or poor (more than 3 risk factors). (7)
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) comprises approximately 6-8% of NHL, and has been recognized within the past 15 years as a unique lymphoma subtype with a particularly aggressive course. MCL is characterized by a chromosomal translocation t(11;14) and the term “mantle cell lymphoma” was proposed in 1992 by Banks et al. (8) The number of therapeutic trials are not as numerous as for other NHL as it was not widely recognized until the REAL classification. MCL shows a strong predilection for elderly males, and the majority of cases (70%) present with disseminated (stage 4) disease and extranodal involvement is common. Localized MCL is quite rare. MCL has a median survival of approximately 2–4 years, and although most patients achieve remission with first line therapy, relapse inevitably occurs, often within 12-18 months. (9) MCL is rarely, if ever, cured with conventional therapy, and no standardized therapeutic approach to MCL is used.
There had been no generally established prognostic index for patients with MCL. Application of the IPI or FLIPI system to patients with MCL showed serious limitations (8), which included no separation of some important risk groups. In addition, some of the individual IPI and FLIPI risk factors, including number of extranodal sites and number of involved nodal areas showed no prognostic relevance, and hemoglobin showed no independent prognostic relevance in patients with MCL. (8) Therefore, a new prognostic index for patients with MCL was developed, and should prove useful in comparing clinical trial results for MCL.
MCL international prognostic index (MIPI):

1. Age
2. ECOG performance index (MIPI):
3. serum LDH (calculated as a ratio of LDH to a laboratory's upper limit of normal)
4. White blood cell count (WBC)
   • Zero points each are assigned for age younger than 50 years, ECOG performance 0-1, LDH ration less than 0.67, WBC less than 6,700
   • One point each for age 50-59 years, LDH ratio 0.37-0.99, WBC 6,700-9,999.
   • Two points each for age 60-69 years, ECOG 2-4, LDH ratio 1.00-1.49, WBC 10,000-14,999
   • Three points each for age 70 years or older, LDH ratio 1.5 or greater, WBC 15,000 or more

MIPI allows separation of 3 groups with significantly different prognoses: (8)

Peripheral T-cell Lymphomas (PTCL)
The immature T-cell lymphomas are generally treated on leukemia protocols, whereas the mature (peripheral) T-cell lymphomas are usually treated with chemotherapy regimens similar to those used in DLBCL.
PTCL are less responsive to standard chemotherapy than DLBCL and therefore carry a worse prognosis. The poor results with conventional chemotherapy have prompted exploration of the role of HDC/SCT as first line consolidation therapy.

Staging
The Ann Arbor staging classification is commonly used for the staging of lymphomas and is the scheme defined in the AJCC Manual for Staging Cancer. Originally developed for Hodgkin's disease, this staging scheme was later expanded to include non-Hodgkin's lymphoma.
Staging of Lymphoma: Ann Arbor classification
Stage I
Involvement of a single lymph node region (I) or of a single extralymphatic organ or site (IE)
Stage II
Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of extralymphatic organ or site and of one or more lymph node regions on the same side of the diaphragm (IIE).
Stage III
Involvement of lymph node regions on both sides of the diaphragm (III) which may also be accompanied by localized involvement of extralymphatic organ or site (IIIE) or by involvement of the spleen (IIIS) or both (IIISE)
Stage IV
Diffuse or disseminated involvement of one or more extralymphatic organs or tissues with or without associated lymph node enlargement.
Note: Small lymphocytic lymphoma (SLL; IWF class A) may be considered a node-based variant of chronic lymphocytic leukemia (CLL). Therefore, SLL is considered along with CLL in policy No. 8.01.15.

Policy

For patients with NHL subtypes considered aggressive, either autologous or allogeneic stem-cell support may be considered medically necessary:

For patients with NHL subtypes considered indolent, either autologous or allogeneic stem-cell support may be considered medically necessary:

• 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.

Either autologous or allogeneic stem-cell support is considered investigational:

• as initial therapy (i.e., without a full course of standard-dose induction chemotherapy) for any NHL;
• to consolidate a first CR for patients with aggresive NHL subtypes and IPI scores that predict a low- or low-intermediate risk of relapse; and
• to consolidate a first CR for those with indolent NHL subtypes; and 
• for peripheral T-cell lymphoma (PTCL) at any stage of disease.

Tandem transplants are considered investigational to treat patients with any stage, grade, or sub-type of NHL.

Allogeneic stem-cell support is considered investigational to treat NHL that progresses or relapses relatively soon after a prior course of high-dose chemotherapy with autologous stem-cell support. (Note: This policy statement is based on a strict evidence-based analysis on outcomes of allotransplants after a failed autotransplant. However, see further discussion in the Policy Guidelines and Rationale sections.)

Policy Guidelines

Two general categories of patients are considered candidates for reduced-intensity conditioning (RIC) allotransplants: those who would otherwise be considered candidates for a conventional myeloablative allotransplant, and those who would not. In the first category, RIC allotransplants could be considered as a variant of a standard chemotherapy conditioning regimen. In the latter category, they would be considered a novel approach, either for patients whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy) preclude a standard myeloablative conditioning regimen, or in those with malignancies that have not been shown to be effectively treated with conventional myeloablative allogeneic transplants.

Benefit Application

Rationale

This policy was initially based on 4 TEC Assessments. (10-13) Since that time, the classification of NHL has undergone significant changes, and several new and unique subtypes have emerged (e.g., MCL, PTCL). The 2008 changes in the body of the policy reflect this, but the policy itself remains essentially unchanged.
Indolent Lymphomas
SCT as First-line Treatment for Indolent NHL
In 2008, Ladetto et al. reported the results of a Phase III, randomized, multicenter trial of patients with high-risk follicular lymphoma, treated at diagnosis. (14) A total of 134 patients were enrolled to receive either rituximab-supplemented high-dose chemotherapy (HDC) and autologous SCS (R-HDC) or 6 courses of CHOP followed by rituximab (CHOP-R). Seventy-nine percent of patients completed R-HDC and 71% CHOP-R. Complete remission was 85% with R-HDC and 62% with CHOP-R. At a median follow-up of 51 months, the 4-year EFS was 61 and 28% (R-HDC versus CHOP-R), with no difference in OS. Molecular remission (defined as 2 or more consecutive bone marrow samples spaced 6 months apart negative by PCR, in patients that reached CR), was achieved in 80% of R-HDC and 44% of CHOP-R patients, and was the strongest independent outcome predictor. In 71% of the CHOP-R patients that relapsed, salvage R-HDC was performed, and had an 85% CR rate and 68% 3-year EFS. The authors concluded that there was no overall survival advantage to treating high-risk FL initially with R-HDC, but that relapsed/refractory FL would be the most appropriate setting for this therapy.
In 2006, Sebban et al. reported the results of a randomized, multicenter study. (15) Two-hundred-nine patients received CHVP plus interferon (CHVP-I arm) and 131 received CHOP followed by HDC with total body irradiation and autologous SCT (CHOP-HDT arm). Response rates were similar in both groups (79% and 78% after induction therapy, respectively). After a median follow-up of 7.5 years, intent-to-treat analysis showed no difference between the two arms for OS (p=0.53) or EFS (p=0.11). The authors concluded that there was no statistically significant benefit to first-line, high-dose therapy in patients with FL, and that high-dose therapy should be reserved for relapsing patients.
Deconinck and colleagues investigated the role of autotransplants as initial therapy in 172 patients with follicular lymphoma, considered at high risk due to the presence of either B symptoms (i.e., weight loss, fever, or night sweats), a single lymph node larger than 7 cm, more than 3 involved nodal sites, massive splenomegaly, or a variety of other indicators of high tumor burden. (16) The patients were randomized to receive either an immunochemotherapy regimen or a high-dose therapy followed by purged autotransplant. While the autotransplant group had a higher response rate and longer median event-free survival, there was no significant improvement in overall survival rate, due to an excess of secondary malignancies. The authors concluded that autotransplant cannot be recommended as the standard first-line treatment of follicular lymphoma with a high tumor burden.
In 2004, Lenz and colleagues reported on the results of a trial of 307 patients with advanced stage lymphoma in first remission, including follicular lymphoma, mantle cell lymphoma or lymphoplasmacytoid lymphoma. (17) Patients were randomized to receive either consolidative therapy with autotransplant or interferon therapy. The 5-year progression-free survival rate was considerably higher in the autotransplant arm (64.7%) compared to the interferon arm (33.3%). However, the median follow-up of patients is still too short to allow any comparison of overall survival.

SCT for Relapsed, Indolent NHL
The majority of patients with FL relapse, and with relapsed disease, cure is very unlikely, with a median survival of 4.5 years after recurrence. (18) In the European CUP trial, 89 patients with relapsed, nontransformed follicular lymphoma with partial or complete response after standard induction chemotherapy were randomized to one of three arms: 3 additional cycles of conventional chemotherapy ('n=24), HDC and unpurged autologous SCS ('n=33), or HDC with purged autologous SCS ('n=32). (18) OS at 4 years for the chemotherapy versus unpurged versus purged arms was 46, 71 and 77%, respectively. Two-year PFS was 26, 58 and 55%, respectively. No difference was found between the two auto-transplant arms. Although several studies have consistently shown improved disease-free survival with autoSCT for relapsed FL, this study was the first to show a difference in OS benefit. (5)
Aggressive Lymphomas
SCT for First-line Therapy for Aggressive NHL
Several randomized trials were reported between 1997 and 2002 that 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. (19-22) As summarized in an editorial (23), 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; reference 19). The subgroup analysis reported superior overall (64% versus 49%; relative risk 1.51, p=0.04) and disease-free survival (55% vs. 39%; relative risk 1.56, p=0.02) for patients at elevated risk of relapse who were consolidated with an autotransplant. (24)
A large, multigroup, 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 (24) as sufficient evidence to support use of autotransplants to consolidate a first CR when risk of relapse is high. In contrast, editorials (23, 25) and recent reviews (26-28) 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).
Between 2005 and 2008, several reports of randomized trials have shown no survival benefit to SCT as first-line therapy for aggressive lymphomas, as summarized below:
Greb et al. undertook a systematic review and meta-analysis to determine whether HDC with SCS as first-line treatment in patients with aggressive non-Hodgkin lymphoma improves survival compared to patients treated with conventional chemotherapy. (29) Fifteen randomized controlled trials including 3,079 patients were eligible for the meta-analysis. Thirteen studies with 2,018 patients showed significantly higher CR rates in the HDC/SCS group ('p=0.004). However, HDC did not have an effect on OS, when compared to conventional chemotherapy. Subgroup analysis of prognostic groups according to the IPI did not show any survival differences between HDC 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 for HDC with SCS as first-line treatment in aggressive NHL.
Betticher et al. reported the results of a phase 3 multicenter, randomized trial comparing sequential HDC with SCS (SHiDo) to standard CHOP as first line therapy in 129 patients with aggressive NHL. (30) Remission rates were similar in the two groups, and after a median observation time of 48 months, there was no difference in overall survival with 46% in the SHiDo group and 53% in the group that received CHOP ('p=0.48). The authors concluded that SHiDo did not confer any survival benefit as initial therapy in patients with aggressive NHL.
Baldissera et al. reported the results of a prospective randomized controlled trial comparing HDC and autologous SCS to conventional chemotherapy as frontline therapy in 56 patients with high-risk aggressive NHL. (31) The 5-year actuarial OS and PFS were not statistically different between the two study groups; only DFS was statistically different ('97% versus 47%, for the HDC/SCS and conventional groups, respectively; p=0.02.)
Olivieri et al. reported a randomized study of 223 patients with aggressive NHL using upfront HDC with autologous SCS versus conventional chemotherapy (plus HDC/SCS in cases of failure). (32) Twenty-nine patients in the conventional group achieved a PR or no response, and went on to receive HDC and SCS. 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) between the two groups. The authors concluded that aggressive NHL patients do not benefit from upfront HDC/SCS.
The results of the ongoing S9704 trial will likely be important in the future direction of SCT as frontline therapy in patients with aggressive NHL and high- to high-intermediate risk of relapse.
SCT for Relapsed, Aggressive NHL
Auto-SCT is the treatment of choice for relapsed or refractory aggressive NHL. (1,4)
Tandem Transplants
The updated 2008 literature search did not identify any prospective controlled studies comparing tandem with single transplants.
A pilot study in 2005 included 41 patients with poor-risk NHL and Hodgkin’s disease that were given tandem HDC with autologous SCS. (33) Thirty-one patients (76%) completed both transplants. Overall toxic death rate was 12%. The study evaluated the maximum tolerated dose of the chemotherapeutic regimen, and did not compare tandem versus single transplants for NHL.
Tarella et al. reported a multicenter, nonrandomized, prospective trial consisting of 112 patients with previously untreated DLBCL and age-adjusted IPI score of 2-3. (34) All patients received rituximab-supplemented, early-intensified HDC with multiple autologous SCS. Although the study concluded the treatment regimen improved patients’ life expectancy, the comparisons were made with historic controls that had received conventional chemotherapy.
Therefore, the data on tandem transplants is insufficient to determine outcomes with this type of treatment.
Allotransplant after a Failed Autotransplant
The updated literature search found no prospective randomized controlled studies comparing allotransplants to alternative strategies for managing failure (progression or relapse) after an autotransplant for NHL. The scant data are insufficient to change conclusions of the previous Assessment. (13)
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. 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.
NHL Subtypes Newly Defined by the REAL/WHO Classification
Mantle Cell Lymphoma
In an attempt to improve the outcome of MCL, several phase 2 trials investigated the efficacy of autologous SCT with published results differing substantially. (9, 35) Some studies found no benefit to stem cell transplantation, and others suggested an EFS advantage at least in a subset of patients. (9) The differing results in these studies were likely due to different time points of transplant (first versus second remission) and other patient selection criteria. (35) Most of the studies with autologous SCT in MCL show no plateau in the survival curve, with late relapses despite the achievement of CR. (9) Overall, HDC with ASCT appears to improve time to treatment failure, but the impact on survival remains to be proven. (36)
In 2005, the results of the first randomized trial were reported by Dreyling and colleagues of the European MCL Network. (35) One-hundred twenty-two patients with mantle cell lymphoma received either autologous stem-cell transplant (ASCT) or interferon as consolidation therapy in first complete or partial remission. Among these, 43% had low-risk, 11% high-intermediate risk, and 6% a high-risk profile. ASCT resulted in a PR rate of 17% and CR 81% (versus PR of 62% and CR 37% with interferon). Survival curves for time to treatment failure (TTF) after randomization showed ASCT was superior to interferon ('p=0.0023). There was significant improvement in 3-year PFS demonstrated in the ASCT versus interferon arm ('54% and 25%, respectively; p=0.01). At the time of the reporting, there was no advantage seen in OS with 3-year OS 83 versus 77%. The trial also suggested that the impact of ASCT could depend upon 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.
The literature regarding allogeneic transplantation in MCL is limited. This is due, in part, to the fact that the average age of MCL patients at diagnosis is 65, making them unsuitable for allogeneic transplant. Although a graft-versus-tumor effect has been demonstrated (37), there is currently no conclusive evidence that allo-SCT is curative for MCL. (38)
In an International Bone Marrow Transplant Registry (IBMTR) study, 212 patients (median age 50) received allogeneic BMTs. (39) OS at 2 years was only 40%. In a study by the European Bone Marrow Transplant Group, 22 allogeneic transplant patients had EFS and OS rates of 50% and 62%, respectively, but the follow-up was too short. (40)
There have been several studies regarding reduced intensity chemotherapy (RIC) and allo-SCT. (38) Khouri et al. reported results of RIC allo-SCT in 18 patients with MCL, and after a median follow-up of 26 months, the actuarial probability of EFS was 82% at 3 years. (41) Maris et al. evaluated allo-SCT in 33 patients with relapsed and recurrent MCL. At 2 years the relapse and nonrelapse mortality rates were 9 and 24%, respectively, and the OS and DFS were 65 and 60%, respectively. (42)
A recent review article summarizes the literature on high-dose therapy for MCL, and a repeat finding in several studies has been the superior result of transplantation in first complete remission (auto or allo) rather than in the relapsed setting. (9)
Updated 2008 National Comprehensive Cancer Network (NCCN) recommendations for MCL are for first-line consolidation with HDC and auto-SCT, and second-line consolidation with HDC with nonmyeloablative or myeloablative SCT. (4)
Peripheral T-cell Lymphomas (PTCL)
The role of stem cell transplant in PTCL is not well defined. Few studies have been conducted, mostly retrospectively and with small numbers of patients. This is partly due to the rarity and heterogeneity of the PTCL.
There have been no randomized studies comparing chemotherapy regimens solely in patients with PTCL (i.e. some randomized studies have included PTCL with aggressive B-cell lymphomas).
A prospective phase 2 trial by Rodriguez et al. showed that auto-SCT as first-line consolidation therapy improved treatment outcome in patients responding to induction therapy. (43) Nineteen out of 26 patients that showed CR or PR to induction therapy received an autotransplant. At 2 years post-transplant, OS, PFS and DFS were 84%, 56% and 63%, respectively.
2008 NCCN guidelines recommend clinical trials as the preferred treatment option for all patients with PTCL since there is no standardized treatment for this group of lymphomas. The guidelines also state that HDC/SCT as first line consolidation is a reasonable treatment option only in patients showing good response to induction therapy.
A search of the 2008 National Cancer Institute database returned no Phase III trials involving PTCL and SCT.

 

References:

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Index

Policy History

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