Transplant Section - Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas

IMPORTANT REMINDER

Regence Medical Policies are developed to provide guidance for members and providers regarding coverage in accordance with contract terms. Benefit determinations are based in all cases on the applicable contract language. To the extent there may be any conflict between the Medical Policy and contract language, the contract language takes precedence.

PLEASE NOTE: Contracts exclude from coverage, among other things, services or procedures that are considered investigational or cosmetic. Providers may bill members for services or procedures that are considered investigational or cosmetic. Providers are encouraged to inform members before rendering such services that the members are likely to be financially responsible for the cost of these services.

DESCRIPTION ^[1]

Hematopoietic Stem-Cell Transplantation

Hematopoietic stem-cell transplantation (HSCT) 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. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood 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-versus-host disease (GVHD).

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HSCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HSCT. 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 Class I and Class II loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci (with the exception of umbilical cord blood).

Conventional Preparative Conditioning for HSCT

The success of autologous HSCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow (myeloablative chemotherapy). This permits subsequent engraftment and repopulation of bone marrow space with presumably normal hematopoietic stem cells obtained from the patient prior to undergoing bone marrow ablation. As a consequence, autologous HSCT is typically performed as consolidation therapy (i.e., therapy that is intended to eliminate residual cancer cells after initial therapy) when the patient’s disease is in complete remission. Patients who undergo autologous HSCT are susceptible to chemotherapy-related toxicities and opportunistic infections prior to engraftment, but not GVHD.

Reduced-Intensity Conditioning for Allogeneic HSCT

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 initially eradicate the patient’s hematopoietic ability, allowing 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 myeloablation, to minimal myeloablation with lymphoablation.

For the purposes of this Policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be non-myeloablative, as opposed to fully myeloablative (traditional) regimens.

Tandem HSCT

Tandem transplants usually are defined as the planned administration of two successive cycles of high-dose myeloablative chemotherapy, each followed by infusion of autologous hematopoietic stem cells, whether or not there is evidence of persistent disease following the first treatment cycle. Sometimes, the second cycle may use non-myeloablative immunosuppressive conditioning followed by infusion of allogeneic stem cells.

Non-Hodgkin Lymphoma (NHL)

A heterogeneous group of lymphoproliferative malignancies, NHL usually originates 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.^[2] 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^[3], and an updated version of the REAL system, the new World Health Organization (WHO) classification.^[4] The WHO/REAL classification recognizes three major categories of lymphoid malignancies based on morphology and cell lineage: B-cell neoplasms, T-cell/natural killer (NK)-cell neoplasms, and lymphoma.

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

• Precursor B-cell neoplasm: precursor B-acute lymphoblastic leukemia/lymphoblastic lymphoma (LBL).
• Peripheral B-cell neoplasms
• B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (see Transplant No. 45.35)
• B-cell prolymphocytic leukemia
• Lymphoplasmacytic lymphoma/immunocytoma (see Transplant No. 45.40)
• Mantle cell lymphoma (MCL)
• Follicular lymphoma
• Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type
• Nodal marginal zone B-cell lymphoma (+/- monocytoid B-cells)
• Splenic marginal zone lymphoma (+/- villous lymphocytes)
• Hairy-cell leukemia
• Plasmacytoma/plasma cell myeloma
• Diffuse large B-cell lymphoma
• Burkitt lymphoma

T-Cell and Putative NK-Cell Neoplasm

• Precursor T-cell neoplasm: precursor T-acute lymphoblastic leukemia/LBL
• Peripheral T-cell (PTCL) 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 United States, B-cell lymphomas represent 80%–85% of cases of NHL, and T-cell lymphomas represent 15%–20%. NK lymphomas are relatively rare.^[5]

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.^[5]

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 has a relatively good prognosis, with a median survival of 10 years; however, it is not curable in advanced clinical stages.^[2] Early-stage indolent NHL (stage 1 or 2) may be effectively treated with radiation alone.^[2] Although indolent NHL is responsive to radiation and chemotherapy, a continuous rate of relapse is seen in advanced stages.^[2] These patients can often be re-treated 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 lymphoma^[6], 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 lymphoma.

Aggressive NHL has a shorter natural history; however, 30%–60% of these patients can be cured with intensive combination chemotherapy regimens.^[2] 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).^[7] Prior to the development of IPI in 1993, prognosis was predominantly based on 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 on 5 significant risk factors prognostic of OS:

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

Risk groups are stratified according to the number of adverse factors as follows: 0 or 1 is low risk, 2 is low intermediate, 3 is high intermediate, and 4 or 5 are high risk.

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and overall survival (OS) at 5 years. Age-adjusted (aaIPI) and stage-adjusted modifications of this IPI are used for younger patients with localized disease.

Adverse risk factors for age-adjusted IPI include stage III or IV disease, elevated LDH and ECOG performance status >2, and can be calculated as follows: 0 is low risk, 1 is low intermediate, 2 is high intermediate, and 3 is high risk.

• Age older than 60 years
• Ann Arbor stage III-IV
• Hemoglobin level less than 12.0 g/dL
• More than four lymph node areas involved
• Elevated serum lactate dehydrogenase (LDH) level

These five factors are used to stratify patients into three categories of risk: low (0-1 risk factor), intermediate (2 risk factors), or poor (more than 3 risk factors).^[8]

Mantle Cell Lymphoma (MCL)

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.^[9] The number of therapeutic trials are not as numerous for MCL as for other NHL as it was not widely recognized until the REAL classification. MCL shows a strong predilection for elderly men, 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.^[10] 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^[11], 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.^[11] 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):

• Age
• ECOG performance status
• Serum LDH (calculated as a ratio of LDH to a laboratory’s upper limit of normal)
• White blood cell count (WBC)
• Zero points each are assigned for age younger than 50 years, ECOG performance 0–1, LDH ratio less than 0.67, WBC less than 6,700
• One point each for age 50–59 years, LDH ratio 0.67–0.99, 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 three groups with significantly different prognoses:^[11]

• 0–3 points=low risk, 44% of patients, median OS not reached and a 5-year OS rate of 60%
• 4–5 points=intermediate risk, 35% of patients, median OS 51 months
• 6–11 points=high risk, 21% of patients, median OS 29 months

Peripheral T-Cell Lymphoma (PTCL)

Immature T-cell lymphomas are generally treated on leukemia protocols, whereas mature (peripheral) T-cell lymphomas are usually treated with chemotherapy regimens similar to those used in DLBCL.

PTCLs are less responsive to standard chemotherapy than DLBCLs 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 two 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). The number of lymph node regions involved should be indicated by a subscript (e.g., II2)

• 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.

POLICY/CRITERIA

Note: HSCT in the treatment of Hodgkin lymphoma is addressed in Regence medical policy Transplant No. 45.30.
HSCT in the treatment of chronic lymphocytic leukemia and small lymphocytic lymphoma are considered separately in Regence Medical Policy Transplant No. 45.35
HSCT in the treatment of Waldenstrom macroglobulinemia, a lymphoplasmacytic lymphoma, is considered separately in Regence medical policy Transplant No. 45.40

NOTE: For those indications which do not meet the medical necessity criteria, consider applying Regence Medical Policy, Medicine 74, Research Urgent Treatments.

Policy Guidelines

Reduced-intensity conditioning (RIC) would be considered an option in patients who meet criteria for an allogeneic stem-cell transplant (SCT) but whose age (typically older than 55 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy) preclude use of a standard conditioning regimen.

SCIENTIFIC BACKGROUND

This policy was initially based on four TEC Assessments.^[12-15] Since that time, the classification of NHL has undergone significant changes, and several new and unique subtypes have emerged (e.g., MCL, PTCL).

Indolent Lymphomas

Stem-Cell Transplant (SCT) as First-Line Treatment for Indolent Non-Hodgkin Lymphoma (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.^[16] A total of 134 patients were enrolled to receive either rituximab-supplemented high-dose chemotherapy (HDC) and autologous SCS (R-HDC) or six courses of cyclophosphamide, doxorubicin (or Adriamycin), vincristine (Oncovin), and prednisolone (CHOP) followed by rituximab (CHOP-R). Of these patients 79% completed R-HDC and 71% completed 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 event-free survival (EFS) was 61% and 28% (R-HDC vs. CHOP-R), with no difference in overall survival (OS). Molecular remission (defined as negative results by polymerase chain reaction on two or more consecutive bone marrow samples spaced 6 months apart in patients who reached complete remission [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 who had a relapse, salvage R-HDC 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 follicular lymphoma initially with R-HDC, but that relapsed/refractory follicular lymphoma would be the most appropriate setting for this therapy.

In 2006, Sebban et al. reported the results of a randomized, multicenter study.^[17] A total of 209 patients received CHVP plus interferon (CHVP-I arm) and 131 patients 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 follicular lymphoma, 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.^[18] 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 EFS, there was no significant improvement in OS 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.^[19] Patients were randomized to receive either consolidative therapy with autotransplant or interferon therapy. The 5-year progression-free survival (PFS) 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 OS.

SCT for Relapsed, Indolent NHL

The majority of patients with follicular lymphoma relapse, and with relapsed disease, cure is very unlikely, with a median survival of 4.5 years after recurrence.^[20] 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: three additional cycles of conventional chemotherapy (n=24), HDC and unpurged autologous SCS (n=33), or HDC with purged autologous SCS (n=32). OS at four 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 autotransplant arms. Although several studies have consistently shown improved disease-free survival (DFS) with autologous HSCT for relapsed follicular lymphoma, this study was the first to show a difference in OS benefit.^[6]

Aggressive Lymphomas

HSCT for First-Line Therapy for Aggressive NHL

Several randomized trials reported on between 1997 and 2002 compared outcomes of autotransplants used to consolidate a first CR in patients with intermediate or aggressive non-Hodgkin lymphoma (NHL), with outcomes of an alternative strategy that delayed transplants until relapse.^[21-24] As summarized in an editorial^[25], the preponderance of evidence showed that consolidating first CRs with HSCT did not improve OS 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 International Prognostic Index [IPI] scores) who were enrolled in the largest of these trials (the LNH87-2 protocol; reference 19). The subgroup analysis reported superior overall (64% vs. 49%; relative risk 1.51, p=0.04) and DFS (55% vs. 39%; relative risk 1.56, p=0.02) for patients at elevated risk of relapse who were consolidated with an autotransplant.^[26]

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^[27] as sufficient evidence to support use of autotransplants to consolidate a first CR when risk of relapse is high. In contrast, editorials^[25,27] and recent reviews^[28-30] 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 showed 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 HDC with SCS as first-line treatment in patients with aggressive NHL improves survival compared to patients treated with conventional chemotherapy.^[31] 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 HDC/SCS group (p=0.004). However, HDC 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 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 III multicenter, randomized trial comparing sequential HDC with SCS (SHiDo) to standard CHOP as first-line therapy in 129 patients with aggressive NHL.^[32] 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 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 on the results of a prospective RCT comparing HDC and autologous HSCS to conventional chemotherapy as frontline therapy in 56 patients with high-risk aggressive NHL.^[33] 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 HDC/SCS and conventional groups, respectively; p=0.02.)

Olivieri et al. reported on 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).^[34] In the conventional group, 29 patients achieved a partial response 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 patients with aggressive NHL do not benefit from upfront HDC/SCS.

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.

SCT for Relapsed, Aggressive NHL

Autologous SCT is the treatment of choice for relapsed or refractory aggressive NHL.^[2,5]

Tandem Transplants

A pilot study in 2005 included 41 patients with poor-risk NHL and Hodgkin’s disease that were given tandem HDC with autologous HSCS.^[35] 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 on a multicenter, nonrandomized, prospective trial consisting of 112 patients with previously untreated diffuse large B-cell lymphoma and age-adjusted IPI score of 2-3.^[36] All patients received rituximab-supplemented, early-intensified HDC with multiple autologous HSCS. 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

An 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 TEC Assessment.^[14]

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 graft-versus-host-disease), or because they lack a well-matched donor. Nevertheless, several institutions report that a minority of patients achieved long-term DFS 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 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 mantle cell lymphoma, several Phase II trials investigated the efficacy of autologous HSCT, with published results differing substantially.^[11,37] Some studies found no benefit to HSCT, and others suggested an EFS advantage, at least in a subset of patients.^[11] The differing results in these studies were likely due to different time points of transplant (first vs. second remission) and other patient selection criteria.^[37]
  
  In 2005, the results of the first randomized trial were reported by Dreyling and colleagues of the European MCL Network.^[37] A total of 122 patients with mantle cell lymphoma 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.
  
  Jantunen et al. investigated the feasibility and efficacy of autologous HSCT in patients with MCL older than 65 years. In the retrospective comparison, there were no differences in relapse rate, PFS, or OS between patients with MCL under 65 years of age and the seventy-nine patients ≥65 years of age.^[38]

• The literature regarding allogeneic transplantation in mantle cell lymphoma is limited. This is due, in part, to the fact that the average age of patients at diagnosis is 65 years, making them unsuitable for allogeneic transplant. Although a graft-versus-tumor effect has been demonstrated ^[39], there is currently no conclusive evidence that allogeneic transplantation is curative in mantle cell lymphoma.^[40]
  
  In an International Bone Marrow Transplant Registry (IBMTR) study, 212 patients (median age 50 years) received allogeneic transplants.^[41] At two years, OS 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.^[42]

• There have been several studies regarding reduced-intensity chemotherapy (RIC) and allogeneic HSCT.^[40] Khouri et al. reported on results of RIC allogeneic HSCT in 18 patients with mantle cell lymphoma, and after a median follow-up of 26 months, the actuarial probability of EFS was 82% at 3 years.^[43] Maris et al. evaluated allogeneic HSCT in 33 patients with relapsed and recurrent mantle cell lymphoma. At 2 years, the relapse and nonrelapse mortality rates were 9% and 24%, respectively, and the OS and DFS were 65% and 60%, respectively.^[44] Cook et al. retrospectively evaluated outcomes of RIC allogeneic HSCT in 70 MCL patients. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 37% and 14% respectively. The 1- and 5-year non-relapse mortality (NRM) was 18% and 21% respectively.^[45]

• Till et al. reported the results of the outcomes of 56 patients with mantle cell lymphoma, treated with high-dose induction chemotherapy with cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with or without rituximab followed by autologous SCT in first CR or PR (n=21), cyclophosphamide, doxorubicin (or Adriamycin), vincristine (Oncovin), and prednisolone (CHOP) with or without rituximab followed by autologous HSCT in first CR or PR (n=15), or autologous HSCT following disease progression (n=20).^[46] OS and PFS at 3 years among patients transplanted in CR or PR were 93% and 63% compared with 46% and 36% 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=.0006).
  
  Geisler et al. reported on 160 previously untreated patients with mantle cell lymphoma with dose-intensified induction immunochemotherapy.^[47] Responders received HDC 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 mantle cell lymphoma who received intensive induction chemotherapy, with an overall response rate of 74%.^[48] Seventeen patients received a consolidative autologous (n=13) or allogeneic (n=4) SCT. 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 SCT was 54% and 75%, respectively.
  
  Budde et al. evaluated outcomes of 118 consecutive patients with MCL who received a high-dose induction regimen before autologous HSCT.  The authors report that the intensive induction regimen was not associated with improved survival in the overall study population or any of the subgroups (i.e., patients who underwent autologous HSCT as initial consolidation, or patients under 60 years of age).^[49]
  
  A  review article summarizes the literature on high-dose therapy for mantle cell lymphoma, and a repeat finding in several studies has been a superior result of transplantation in first CR (autologous or allogeneic) rather than in the relapsed setting.^[11]

Peripheral T-Cell Lymphoma

The role of SCT in peripheral T-cell lymphoma is not well defined. Few studies have been conducted, mostly retrospectively and with small numbers of patients.^[50-54] This is partly due to the rarity and heterogeneity of this group of lymphomas.

There have been no randomized studies comparing chemotherapy regimens solely in patients with peripheral T-cell lymphoma (i.e., some randomized studies have included peripheral T-cell lymphoma with aggressive B-cell lymphomas).

A prospective Phase II trial by Rodriguez et al. showed that autologous HSCT as first-line consolidation therapy improved treatment outcome in patients responding to induction therapy.^[55] Nineteen of 26 patients who showed CR or partial response to induction therapy received an autotransplant. At 2 years post-transplant, OS, PFS, and DFS were 84%, 56%, and 63%, respectively.

Clinical Practice Guidelines

The National Comprehensive Cancer Network (NCCN) guidelines state that autologous HSCT may be considered as a consolidation treatment for various relapsed or refractory NHLs. Allogeneic HSCT may be considered as a treatment option for certain relapsed, refractory, or progressive NHLs. The guidelines support the use of high-dose therapy/autologous HSCT as a first-line and allogeneic HSCT (myeloablative or RIC) as a second-line consolidation treatment for MCL. Further, high-dose therapy with autologous HSCT may be considered as first-line consolidation for PTCL, except in low risk patients. In addition, consolidation therapy with allogeneic or high-dose therapy/autologous HSCT “is recommended for those [PTCL patients] with a CR or PR.”^[56]

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CROSS REFERENCES

Research Urgent Treatments, Regence Medical Policy Manual, Medicine, Policy No. 74

Donor Lymphocyte Infusion for Malignancies Treated with an Allogeneic Hematopoietic Stem-Cell Transplant, Regence Medical Policy, Transplant, Policy No. 45.03

Placental and Umbilical Cord Blood as a Source of Stem Cells, Regence Medical Policy, Transplant, Policy No. 45.16

Hematopoietic Stem Cell Transplantation for Hodgkin Lymphoma, Regence Medical Policy Manual, Transplant, Policy No. 45.30

Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma, Regence Medical Policy Manual, Transplant, Policy No. 45.35

Hematopoietic Stem-Cell Transplantation for Primary Amyloidosis or Waldenstrom Macroglobulinemia, Regence Medical Policy Manual, Transplant, Policy No. 45.40

Transplant Section Table of Contents