BlueCross and BlueShield of Montana Medical Policy/Codes
Stem-Cell Transplant for Non-Hodgkin Lymphomas
Chapter: Transplant
Current Effective Date: December 27, 2013
Original Effective Date: July 09, 2008
Publish Date: September 27, 2013
Revised Dates: March 1, 2010; April 2, 2012; September 16, 2013
Description

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.  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  As a result, the WF has become outdated.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, and an updated version of the REAL system, the new World Health Organization (WHO) classification.  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 Hodgkin 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 Revised European American Lymphoma (REAL)/ World Health Organization (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,
    • B-cell prolymphocytic leukemia,
    • Lymphoplasmacytic lymphoma/immunocytoma,
    • Mantle cell lymphoma (MCL),
    • Follicular lymphoma (FL),
    • 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 Natural Killer (NK) Cell Neoplasms

  • 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.

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%,
  • marginal zone B-cell lymphoma/mucosa-associated lymphoid tissue (MALT) lymphoma 5%.

All other subtypes each represent less than 2% of cases of NHL.

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.  Early-stage indolent NHL (stage one or two) may be effectively treated with radiation alone.  Although indolent NHL is responsive to radiation and chemotherapy, a continuous rate of relapse is seen in advanced stages.  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, and median survival with conventional chemotherapy is one 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, and 30%–60% of these patients can be cured with intensive combination chemotherapy regimens.  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).  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 four risk groups: low, low intermediate, high intermediate and high risk, based on five significant risk factors prognostic of overall survival (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, and
  • Involvement of more than 1 extranodal site.

Risk groups are stratified according to the number of adverse factors as follows: zero or one is low risk, two is low intermediate risk, three is high intermediate risk, and four or five are high risk.

Patients with two or more risk factors have a less than 50% chance of relapse-free survival and OS at five 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 greater than two, and can be calculated as follows: : zero is low risk, one is low intermediate risk, two is high intermediate risk, and three is high risk.

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 five adverse prognostic factors:

  • 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 (zero to one risk factor), intermediate (two risk factors), or poor (more than three risk factors).

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”, and the term mantle cell lymphoma was proposed in 1992 by Banks et al.  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 four) disease and extranodal involvement is common.  Localized MCL is quite rare.  MCL has a median survival of approximately two to four years, and although most patients achieve remission with first-line therapy, relapse inevitably occurs, often within 12–18 months.  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, 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.  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 (Eastern Cooperative Oncology Group) performance status,
  • Serum LDH, (lactate dehydrogenase) 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:

  • 0–3 points = low risk, 44% of patients, median overall survival (OS) not reached and a five 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 (diffuse large B-cell lymphoma) 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 (American Joint Committee on Cancer) Manual for Staging Cancer. Originally developed for Hodgkin's disease, this staging scheme was later expanded to include non-Hodgkin lymphoma.

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).

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

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Coverage

Coverage for evaluation of and subsequent single treatment by stem-cell transplant (SCT) (using bone marrow, peripheral blood, or umbilical cord blood as a stem-cell source), derived from a specific donor category, and following a chemotherapy regimen for treatment of non-Hodgkin lymphomas (NHL) is identified in the grid below.

Allogeneic

May be considered medically necessary for patients with NHL subtypes considered 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 CR (for patients with diffuse large B-cell lymphoma, only those with an age-adjusted International Prognostic Index (IPI) score that predicts a high- or high-intermediate risk of relapse); or
  • to achieve or consolidate CR for those in a chemo sensitive first or subsequent relapse.

May be considered medically necessary for patients with NHL subtypes considered indolent:

  • as salvage therapy for patients who do not achieve CR after first-line treatment (induction) with a full course of standard-dose chemotherapy; or
  • to achieve or consolidate CR for those in a first or subsequent chemo sensitive relapse, whether or not their lymphoma has undergone transformation to a higher grade.

Is considered experimental, investigational and unproven:

  • to treat NHL that progresses or relapses relatively soon after a prior course of high-dose chemotherapy with autologous stem-cell support;
  • 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 aggressive NHL subtypes and IPI scores that predict a low- or low-intermediate risk of relapse;
  • to consolidate a first CR for those with indolent NHL subtypes; or
  • for peripheral T-cell lymphoma (PTCL) at any stage of disease.

Autologous

 

May be considered medically necessary for patients with NHL subtypes considered 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 CR (for patients with diffuse large B-cell lymphoma, only those with an age-adjusted International Prognostic Index (IPI) score that predicts a high- or high-intermediate risk of relapse); or
  • to achieve or consolidate CR for those in a chemo sensitive first or subsequent relapse.

May be considered medically necessary for patients with NHL subtypes considered indolent:

  • as salvage therapy for patients who do not achieve CR after first-line treatment (induction) with a full course of standard-dose chemotherapy; or
  • to achieve or consolidate CR for those in a first or subsequent chemo sensitive relapse, whether or not their lymphoma has undergone transformation to a higher grade.

Is considered experimental, investigational and unproven:

  • 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 aggressive NHL subtypes and IPI scores that predict a low- or low-intermediate risk of relapse;
  • to consolidate a first CR for those with indolent NHL subtypes; or
  • for peripheral T-cell lymphoma (PTCL) at any stage of disease.

Tandem or Triple Stem-Cell Transplant

Is considered experimental, investigational and unproven. 

Donor Leukocyte Infusion

Is considered experimental, investigational and unproven. 

Rationale

The quality of life after high-dose chemotherapy (HDC) followed by hematopoietic stem-cell (HSC) (i.e., blood or marrow) transplant is of utmost importance.  In aplastic anemia and malignancies, there is the expectation of improved status after HDC and HSC.  Conversely, quality of life outcomes (measured by growth, skeletal development dysfunction, and neuropsychological) for patients with storage diseases is gradually being defined.  Because of these long-term problems, non-malignant or maldevelopment indications for HDC and HSCs should not be reviewed with criteria similar to that for malignancies.

This policy is based on several Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessments; 1987, 1990, 1995, and 2000.  Since these assessments, 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.  A total of 134 patients were enrolled to receive either rituximab-supplemented HDC and autoSCT (R-HDC) or six courses of cyclophosphamide, doxorubicin (or adriamycin), vincristine (oncovin), and prednisolone (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 four 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 two or more consecutive bone marrow samples spaced six months apart negative by polymerase chain reaction 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% three 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.  Two hundred and nine patients received CHVP (cyclophosphamide, hydroxydaunomycin, vm 26, prednisone) plus interferon (CHVP-I arm) and 131 received CHOP followed by HDC with total body irradiation and autoSCT (CHOP-HDC 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 auto transplants as initial therapy in 172 patients with FL, 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 three involved nodal sites, massive splenomegaly, or a variety of other indicators of high tumor burden.  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 FL (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 FL, mantle cell lymphoma (MCL), or lymphoplasmacytoid lymphoma.  Patients were randomized to receive either consolidative therapy with autotransplant or interferon therapy.  The five 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.

Stem Cell Transplant (SCT) for Relapsed, Indolent Non-Hodgkin Lymphoma (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.  In the European same chemotherapy (C), high-dose therapy followed by autologous unpurged (U) or purged (P) stem-cell transplantation (CUP) trial, 89 patients with relapsed, non-transformed FL 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 autoSCT (n=33), or HDC with purged autoSCT (n=32).  Overall survival (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 auto-transplant arms.  Although several studies have consistently shown improved disease-free survival (DFS) with autoSCT for relapsed FL, this study was the first to show a difference in OS benefit. 

Aggressive Lymphomas

Stem Cell Transplant (SCT) for First-Line Therapy for Aggressive Non-Hodgkin Lymphoma (NHL)

Several randomized trials reported on between 1997 and 2002 compared outcomes of autotransplants used to consolidate a first complete remission (CR) in patients with intermediate or aggressive NHL, with outcomes of an alternative strategy that delayed transplants until relapse.  As summarized in an editorial, the preponderance of evidence showed that consolidating first CRs with SCT did not improve OS for the full population of enrolled patients.  However, a subgroup analysis at eight 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% 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.

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 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).

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 SCT as first-line treatment in patients with aggressive NHL improves survival compared to patients treated with conventional chemotherapy.  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/SCT 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 III multicenter, randomized trial comparing sequential HDC with SCS (SHiDo) to standard CHOP as first-line therapy in 129 patients with aggressive NHL.  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 randomized controlled trial comparing HDC and autoSCT to conventional chemotherapy as frontline therapy in 56 patients with high-risk aggressive NHL.  The five 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 autoSCT versus conventional chemotherapy (plus HDC/SCT in cases of failure).  Twenty-nine patients in the conventional group achieved a partial response or no response, and went on to receive HDC and SCT.  With a median follow-up of 62 months, there was no difference in seven 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/SCT.

Stem Cell Transplant (SCT) for Relapsed, Aggressive Non-Hodgkin Lymphoma (NHL)

AutoSCT is the treatment of choice for relapsed or refractory aggressive NHL.

Tandem Transplants

A 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 autoSCT.  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 (DLBCL) and age-adjusted IPI score of two to three.  All patients received rituximab-supplemented, early-intensified HDC with multiple autoSCT.  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 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 BCBSA TEC Assessments. 

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 disease-free survival (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, 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 Non-Hodgkin Lymphoma (NHL) Subtypes by the Revised European American Lymphoma (REAL)/ World Health Organization (WHO) Classification

Mantle Cell Lymphoma (MCL)

In an attempt to improve the outcome of MCL, several Phase II trials investigated the efficacy of autoSCT with published results differing substantially.  Some studies found no benefit to SCT, and others suggested an event-free survival (EFS) advantage, at least in a subset of patients.  The differing results in these studies were likely due to different time points of transplant (first vs. second remission) and other patient selection criteria.  Most of the studies with autoSCT in MCL show no plateau in the survival curve, with late relapses despite the achievement of CR (complete remission).  Overall, HDC with autoSCT appears to improve time to treatment failure, but the impact on survival remains to be proven.

In 2005, the results of the first randomized trial were reported by Dreyling and colleagues of the European MCL Network.  One hundred twenty-two patients with MCL received either autoSCT or interferon as consolidation therapy in first complete or partial remission.  Among these, 43% had a low-risk, 11% had a high-intermediate risk, and 6% had a high-risk profile.  AutoSCT resulted in a partial response rate of 17% and CR of 81% (vs. partial response of 62% and CR of 37% with interferon).  Survival curves for time to treatment failure (TTF) after randomization showed that autoSCT was superior to interferon (p=0.0023).  There was significant improvement in three year PFS (progression-free survival) demonstrated in the autoSCT versus interferon arm (54% and 25%, respectively; p=0.01).  At the time of the reporting, there was no advantage seen in OS (overall survival), with a three year OS of 83% versus 77%.  The trial also suggested that the impact of autoSCT 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 partial response.

The literature regarding alloSCT in MCL is limited.  This is due, in part, to the fact that the average age of MCL patients at diagnosis is 65 years, making them unsuitable for allogeneic transplant.  Although a graft-versus-tumor effect has been demonstrated, there is currently no conclusive evidence that alloSCT is curative for MCL.

In an International Bone Marrow Transplant Registry (IBMTR) study, 212 patients (median age 50 years) received allogeneic BMTs (bone marrow transplants).  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.

There have been several studies regarding reduced-intensity chemotherapy (RIC) and alloSCT. Khouri et al. reported on results of RIC alloSCT in 18 patients with MCL, and after a median follow-up of 26 months, the actuarial probability of EFS was 82% at three years.  Maris et al. evaluated alloSCT in 33 patients with relapsed and recurrent MCL.  At two years, the relapse and non-relapse mortality rates were 9% and 24%, respectively, and the OS and DFS were 65% and 60%, respectively.  

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 CR (autologous or allogenic) rather than in the relapsed setting.

Updated 2008 National Comprehensive Cancer Network (NCCN) recommendations for MCL are for first-line consolidation with HDC and autoSCT, and second-line consolidation with HDC with non-myeloablative or myeloablative SCT. 

Peripheral T-Cell Lymphoma (PTCL)

The role of SCT 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 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 II trial by Rodriguez et al. showed that autoSCT as first-line consolidation therapy improved treatment outcome in patients responding to induction therapy.  Nineteen of 26 patients that showed CR or partial response to induction therapy received an autotransplant.  At two years post-transplant, OS, PFS, and DFS were 84%, 56%, and 63%, respectively.

The 2008 NCCN (National Comprehensive Cancer Network) 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.

Donor Leukocyte Infusion (DLI) for NHL is considered experimental, investigational, and unproven due to lack of adequate evidence of safety and effectiveness documented in published, peer-reviewed medical literature.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply, drug or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Coding

Disclaimer for coding information on Medical Policies           

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy.  They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers.  Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

ICD-9 Codes

41.00, 41.01, 41.02, 41.03, 41.04, 41.05, 41.06, 41.07, 41.08, 41.09, 41.91, 99.25, 99.74, 99.79, 200.00, 200.01, 200.02, 200.03, 200.04, 200.05, 200.06, 200.07, 200.08, 200.10, 200.11, 200.12, 200.13, 200.14, 200.15, 200.16, 200.17, 200.18, 200.20, 200.21, 200.22, 200.23, 200.24, 200.25, 200.26, 200.27, 200.28, 200.30, 200.31, 200.32, 200.33, 200.34, 200.35, 200.36, 200.37, 200.38, 200.40, 200.41, 200.42, 200.43, 200.44, 200.45, 200.46, 200.47, 200.48, 200.50, 200.51, 200.52, 200.53, 200.54, 200.55, 200.56, 200.57, 200.58, 200.60, 200.61, 200.62, 200.63, 200.64, 200.65, 200.66, 200.67, 200.68, 200.70, 200.71, 200.72, 200.73, 200.74, 200.75, 200.76, 200.77, 200.78, 200.80, 200.81, 200.82, 200.83, 200.84, 200.85, 200.86, 200.87, 200.88, 202.00, 202.01, 202.02, 202.03, 202.04, 202.05, 202.06, 202.07, 202.08, 202.80, 202.81, 202.82, 202.83, 202.84, 202.85, 202.86, 202.87, 202.88 

ICD-10 Codes
C82.00-C82.99, C83.00-C83.99, C84.40-C84.49, C85.10-C85.19, 30230G0, 30230X0, 30230Y0, 30230G1, 30230X1, 30230Y1, 30233G0, 30233X0, 30233Y0, 30233G1, 30233X1, 30233Y1, 30250G0, 30250X0, 30250Y0 30250G1, 30250X1, 30250Y1, 30253G0, 30253X0, 30253Y0, 30253G1, 30253X1, 30253Y1, 6A550ZT, 6A550ZV, 6A551ZT, 6A551ZV 
Procedural Codes: 36511, 38204, 38205, 38206, 38207, 38208, 38209, 38210, 38211, 38212, 38213, 38214, 38215, 38220, 38221, 38230, 38232, 38240, 38241, 38242, 38243, 81265, 81266, 81267, 81268, 81370, 81371, 81372, 81373, 81374, 81375, 81376, 81377, 81378, 81379, 81380, 81381, 81382, 81383, 86805, 86806, 86807, 86808, 86812, 86813, 86816, 86817, 86821, 86822, 86825, 86826, 86849, 86950, 86985, 88240, 88241, S2140, S2142, S2150
References
  1. Autologous Bone Marrow Transplantation for the Treatment of Non-Hodgkin's Lymphoma. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center (1987 May):61-9.
  2. Allogeneic Bone Marrow Transplantation (BMT) in the Treatment of Hodgkin’s Disease (Lymphoma) and Non-Hodgkin’s Lymphoma. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center (1990 August):178-211.
  3. Banks, P.M., Chan, J., et al. Mantle cell lymphoma. A proposal for unification of morphologic, immunologic, and molecular data. American Journal of Surgical Pathology (1992) 16(7):637-40.
  4. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. New England Journal of Medicine (1993) 329,987-94.
  5. Harris, N.L., Jaffe, E.S., et al. A revised European-American classification of lymphoid neoplasms: A proposal from the international lymphoma study group. Blood (1994) 84(5):1361-92.
  6. High-Dose Chemotherapy with Autologous or Allogeneic Stem-Cell Support for Follicular Non-Hodgkin's Lymphomas. Chicago, Illinois: Blue Cross Blue Shield Association – Technology Evaluation Center Assessment Program (1996 March) 10(28):1-29.
  7. Haioun, C., Lepage, E., et al. Benefit of autologous bone marrow transplantation over sequential chemotherapy in poor-risk aggressive non-Hodgkin's lymphoma: updated results of the prospective study LNH87-2. Groupe d'Etude des Lymphomes de l'Adulte. Journal of Clinical Oncology (1997) 15(3):1131-7.
  8. Khouri, I.F., Lee, M.S., et al. Allogeneic hematopoietic transplantation for mantle-cell lymphoma: molecular remissions and evidence of graft-versus-malignancy. Annals of Oncology (1999)10:1293-99.
  9. Harris, N.L., Jaffe, E.S., et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting-Arlie House, Virginia, 1997. Journal of Clinical Oncology (1999); 17(12):3835.
  10. Salvage HDC/AlloSCS for Relapse or Incomplete Remission Following HDC/AuSCS for
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  12. Hale, G.A. and G.L. Phillips. Allogeneic stem cell transplantation for the non-Hodgkin’s lymphomas and Hodgkin’s disease. Cancer Treatment Reviews (2000 December) 26(6):411-27.
  13. Vandenberghe, E., Ruiz de Elvira, C., et al. Does transplantation improve outcome in mantle cell lymphoma (MCL)?: a study from the EBMT. Blood (2000) 96:482a.
  14. Haioun, C., Lepage, E., et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a Groupe d'Etude des Lymphomes de l'Adulte study. Journal of Clinical Oncology (2000) 18(16):3025-30.
  15. Mink, S.A. and J.O. Armitage. High-dose therapy in lymphomas: A review of the current status of allogeneic and autologous stem cell transplantation in Hodgkin’s disease and non-Hodgkin’s lymphoma. Oncologist (2001) 6(3):247-56.
  16. Fisher, R.I. Autologous bone marrow transplantation for aggressive non-Hodgkin’s lymphoma: lessons learned and challenges remaining. Journal of the National Cancer Institute (2001) 93(1):4-5.
  17. Kimby, E., Brandt, L., et al. A systematic overview of chemotherapy effects in aggressive non-Hodgkin's lymphoma. Acta Oncologica (2001) 40(2-3):198-212.
  18. Hahn, T., Wolff, S.N., et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of diffuse large cell B-cell non-Hodgkin's lymphoma: an evidence-based review. Biology of Blood and Marrow Transplant (2001) 7(6):308-31.
  19. Sweetenham, J.W., Santini, G., et al. High-dose therapy and autologous stem-cell transplantation versus conventional-dose consolidation/maintenance therapy as postremission therapy for adult patients with lymphoblastic lymphoma: results of a randomized trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group. Journal of Clinical Oncology (2001) 19(11):2927-36.
  20. Kluin-Nelemans, H.C., Zagonel, V., et al. Standard chemotherapy with or without high-dose chemotherapy for aggressive non-Hodgkin's lymphoma: randomized phase III EORTC study. Journal of the National Cancer Institute (2001) 93(1):22-30.
  21. Kaiser, U., Uebelacker, I., et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. Journal of Clinical Oncology (2002) 20(22):4413-9.
  22. Fisher, R.I. Autologous stem-cell transplantation as a component of initial treatment for poor-risk patients with aggressive non-Hodgkin's lymphoma: resolved issues versus remaining opportunity. Journal of Clinical Oncology (2002) 20(22):4411-2.
  23. Philip, T., Biron, P. High-dose chemotherapy and autologous bone marrow transplantation in diffuse intermediate- and high-grade non-Hodgkin lymphoma. Critical Reviews in Oncology/ Hematology (2002) 41(2):213-23.
  24. Armitage, J.O. Allotransplants for mantle cell lymphoma. Annals of Oncology (2002) 13(suppl 2):9a.
  25. Schouten, H.C., Qian, W., et al. High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s lymphoma:  Results from the randomized European CUP trial.  Journal of Clinical Oncology (2003 November 11) 21(21):3918-27.
  26. Khouri, I.F., Lee, M.S., et al. Nonablative allogeneic stem-cell transplantation for advanced/recurrent mantle-cell lymphoma. Journal of Clinical Oncology (2003) 21:4407-12.
  27. Maris, M.B., Sandmaier, B.M., et al. Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood (2004) 104:3535-42.
  28. Solal-Celigny, P., Roy, P., et al. Follicular lymphoma international prognostic index. Blood (2004) 104(5):1258-65.
  29. Lenz, G., Dreyling, M., et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low Grade Lymphoma Study Group. Blood (2004) 104(9):2667-74.
  30. Deconinck, E., Foussard, C., et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood (2005) 105(10):3817-23.
  31. Donor Leukocyte Infusion for Hematologic Malignancies that Relapse after Allogeneic Stem Cell Transplant. BCBSA Medical Policy Reference Manual (2005 September) Medicine: 2.03.03.
  32. Dreyling, M., Lenz, G., et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL network. Blood (2005) 105(7):2677-84.
  33. Olivieri, A., Santini, G., et al. Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Annals of Oncology (2005) 16(12):1941-8.
  34. Papadopoulos, K.P., Noguera-Irizarry, W., et al. Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma. Bone Marrow Transplant (2005) 36(6):491-7.
  35. Zelenetz, A.D. Mantle cell lymphoma: an update on management. Annals of Oncology (2006)17(S4):iv12-14.
  36. Betticher, D.C., Martinelli, G., et al. Sequential high dose chemotherapy as initial treatment for aggressive sub-types of non-Hodgkin lymphoma: results of the international randomized phase III trial (MISTRAL). Annals of Oncology (2006) 17(10):1546-52.
  37. Baldissera, R.C., Nucci, M., et al. Frontline therapy with early intensification and autologous stem cell transplantation versus conventional chemotherapy in unselected high-risk, aggressive non-Hodgkin's lymphoma patients: a prospective randomized GEMOH report. Acta Haematologica (2006) 115(1-2):15-21.
  38. Laport, G.G. The role of hematopoietic cell transplantation for follicular non-Hodgkin’s lymphoma. Biology of Blood and Marrow Transplant (2006) 12:59-65.
  39. Sebban, C., Mounier, N., et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood (2006) 108:2540-44.
  40. Villanueva, M.L., Vose, J.M. The role of hematopoietic stem cell transplantation in non-Hodgkin lymphoma. Clinical Advances in Hematology and Oncology (2006) 4(7):521-30.
  41. Rodriguez, J., Conde, E., et al. Frontline autologous stem cell transplantation in high-risk peripheral T-cell lymphoma: a prospective study from The Gel-Tamo Study Group. European Journal of Haematology (2007) 79(1):32-8.
  42. Tarella, C., Zanni, M., et al. Prolonged survival in poor-risk diffuse large B-cell lymphoma following front-line treatment with rituximab-supplemented, early-intensified chemotherapy with multiple autologous hematopoietic stem cell support: a multicenter study by GITIL (Gruppo Italiano Terapie Innovative nei Linfomi). Leukemia (2007) 21(8):1802-11.
  43. Kasamon, Y.L. Blood or marrow transplantation for mantle cell lymphoma. Current Opinions in Oncology (2007) 19:128-35.
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  45. Greb, A., Bohlius, J., et al. High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive non-Hodgkin lymphoma (NHL) in adults. Cochrane Database of Systemic Reviews. (2008) Jan 23 (1):CD004024.
  46. Hoster, E., Dreyling, M., et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood (2008) 111:558-65.
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  48. Ladetto, M., De Marco, F., et al. for Gruppo Italiano Trapianto di Midollo Osseo (GITMO): Intergruppo Italiano Linfomi (IIL). Prospective, multicenter randomized GITMO/IIL trial comparing intensiveR-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood (2008) 111(8):4004-13.
History
April 2012 Name change from: Transplant: High-Dose Chemotherapy and Hematopoietic Stem-Cell Support to Treat Hodgkin's and Non-Hodgkin's Lymphomas to Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas. Divided policy into Hodgkin's and Non-Hodgkin's Lymphoma. updated rationale, references, and policy statements to reflect specific policy.
September 2013 Policy formatting and language revised.  Title changed from "Hematopoietic Stem-Cell Transplantation for Non-Hodgkin Lymphomas" to "Stem-Cell Transplant for Non-Hodgkin Lymphomas".
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Stem-Cell Transplant for Non-Hodgkin Lymphomas