Transplant Section - Tandem Hematopoietic Stem Cell Transplant

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

When cancer patients receive high doses of chemotherapy, healthy bone marrow is destroyed in addition to cancer cells. Destruction of bone marrow cells is considered a lethal side effect of high-dose chemotherapy, so hematopoietic stem cells are infused or transplanted in order to restore bone marrow function. This process is known as stem cell transplantation (SCT).

In general, hematologic SCT may be performed when the patient’s disease is in complete remission as a consolidation therapy (i.e. to strengthen the remission), after initial chemotherapy treatment (called induction chemotherapy), or as a salvage therapy after relapse, or as an initial treatment in those not responding to standard chemotherapies.

Stem cells may be obtained from the patient’s own bone marrow (autologous SCT) or from a donor (allogeneic SCT). They can be harvested from bone marrow, peripheral blood, umbilical cord blood, or from the 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-versus-host disease.   

Immunologic compatibility between infused stem cells and the patient (recipient) is not an issue in autologous SCT since the cells are the patient’s own. However, immunologic compatibility between a 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) on the surface of the stem cells using cellular, serologic, or molecular techniques. Depending on the disease being treated, an acceptable donor will match the patient at all or most of the HLA loci. An HLA identical donor will match the recipient at all six HLA loci (A , B, C, DR, DP, and DQ).

Hematopoietic stem cell transplantation may be given either as a monotherapy (i.e. a single round of high-dose chemotherapy with either autologous or allogeneic SCT) or as a tandem transplantation. With tandem transplantation, the initial high-dose chemotherapy is followed by reinfusion of either autologous or allogeneic stem cells. This first stem cell transplant is closely followed (within 6 months) by a second round of chemotherapy and a second transplant.

Reduced intensity conditioning (RIC) allogeneic SCT may also be used in a tandem setting. RIC allogeneic SCT provides chemotherapy regimens that do not produce bone marrow failure (i.e. nonmyeloablative chemotherapy), thereby allowing for relatively prompt hematopoietic recovery (e.g., 28 days or less), even without a transplant.  RIC allogeneic SCT seeks to reduce adverse effects from chemotherapy while retaining the beneficial graft-versus-malignancy effect of allogeneic transplantation.

Tandem transplantations may include:

• autologous SCT followed by a second autologous SCT
• autologous followed by an allogeneic SCT
• autologous SCT followed by RIC allogeneic SCT
• allogeneic SCT followed by allogeneic SCT

Multiple cycles of high-dose chemotherapy with stem cell transplantation differs from tandem transplant in that more time is allowed between transplantation, to permit hematopoietic recovery.

Safety

• Patients who undergo autologous or allogeneic stem cell transplant are susceptible to chemotherapy-related toxicities such as liver and kidney failure, pulmonary failure, or opportunistic infection. 
  
• For marrow-based malignancies, such as multiple myeloma or chronic lymphocytic leukemia, reinfusion of autologous stem cells always carries the risk of reinfusion of the malignant stem cells.
• Compatibility between donor and patient is a critical factor for achieving good outcomes with allogeneic SCT. A poor donor match may cause graft rejection with loss of bone marrow function or lessen the graft versus tumor effect. 
• Graft versus host disease (GVHD) is a common and serious complication of allogeneic SCT which occurs when allogeneic donor cells recognize the patient’s organs and tissues as foreign and attack these cells. The most common areas affected by GVHD are the skin and visceral organs. GVHD may be either acute or chronic and can be a life-threatening complication. The risk of GVHD increases with greater HLA disparity and recipient age.

Note: For information and criteria specific to monotherapy with either autologous or allogeneic stem cell transplantation, refer to separate Regence Medical policies:

POLICY/CRITERIA

Tandem stem cell transplant may be considered medically necessary for the diagnoses specified in the table below. Tandem stem cell transplant is considered investigational for all other indications, including but not limited to those identified as investigational in the table. A link to the position summary for each indication is provided. For those indications which do not meet the medically necessary criteria, consider applying Regence Medical Policy, Medicine 74, Research Urgent Treatments.

Note:  Collection and storage of cord blood from a neonate is considered not medically necessary when collected in advance for some unspecified future use (e.g. as an autologous stem-cell transplant in the original donor).

POSITION SUMMARY

Effectiveness:

Breast Cancer                                                                        Return to Table

Investigational Indications

There is insufficient evidence to determine whether high-dose chemotherapy with tandem stem cell transplantation (SCT) is effective to treat any stage of breast cancer.

• Data are limited from randomized studies that directly compare outcomes of tandem transplants with those of either single transplants or conventional-dose regimens. One randomized trial reported that tandem high dose chemotherapy cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single high dose chemotherapy in spite of a trend of improved progression-free survival. (8)
• Several uncontrolled pilot or phase II trials reported results after two or three sequential cycles of high-dose chemotherapy with autologous SCT for patients with metastatic, high-risk operable, or inflammatory breast cancer. (9-16) These studies do not permit conclusions regarding the efficacy of tandem transplant compared to conventional therapy because of small sample size or lack of comparison with standard therapies.
• The National Comprehensive Cancer Network practice guidelines for breast cancer do not address the use of tandem transplant for the treatment of breast cancer. (17)

Germ Cell Tumors (GCT)                                                      Return to Table

Germ-cell tumors (GCT) are composed primarily of testicular neoplasms (seminomas or nonseminomatous GCT) but also include ovarian and extragonadal GCTs (e.g., retroperitoneal or mediastinal tumors.

Therapy for GCT is generally dictated by stage, risk subgroup, and cell type. For example, primary therapy for early stage seminomas may rely on radiation therapy alone while more advanced stages of seminoma and non-seminomatous tumors ( stage ≥ IB) are given primary chemotherapy. Patients with stage IA non-seminomatous tumors may be managed initially by surgery, followed by adjuvant chemotherapy. First-line chemotherapy for good- and intermediate-risk patients with higher-stage disease is usually three or four cycles of a chemotherapeutic regimen followed by surgery to remove residual masses. Second-line therapy often consists of combined chemotherapy with agents not used for first-line treatment. The probability of long-term continuous complete remission diminishes with each successive relapse. (2) To determine the safety and efficacy of tandem transplantation, comparisons to these conventional treatments and single autologous SCT must be made.

Investigational Indications

There is insufficient evidence to determine the effectiveness of high dose chemotherapy with tandem transplantation for any type or stage of germ cell tumor.

• There are no controlled trials that demonstrate outcomes of tandem transplantation are superior to those of either standard chemotherapy or high-dose chemotherapy with single autologous SCT. (18-22, 24)
• One retrospective case series of 184 patients receiving two consecutive cycles of high dose chemotherapy and tandem transplantation showed encouraging results with 116 patients having complete remission at a median follow-up of 48 months. These results are from a highly specialized center and need to be confirmed in prospective studies from other centers. (23)
• There are no published evidence-based clinical practice guidelines that recommend tandem transplantation as a treatment of germ cell tumors.

Hodgkin Lymphoma (HL)                                                   Return to Table

Hodgkin lymphoma (HL) is a relatively uncommon B-cell lymphoma involving the lymph nodes and lymphatic system.  Initial treatment is with chemotherapy or combined modality therapy including radiation treatments. Treatment is followed by restaging to evaluate response. (25) More effective and less toxic chemotherapeutic regimens have made HL curable in most patients, with up to 80% of newly diagnosed patients curable using combination chemotherapy and/or radiation therapy. (25, 26)

Autologous stem cell transplant (SCT) is widely considered the therapy of choice for relapsed and refractory HL.(3, 25, 69) This therapy may not be an option for those with chronic bone marrow insufficiency or marrow malignancy. Limited treatment options exist for these patients, including palliative chemotherapy or occasionally, localized radiation therapy. (69) Those who prove refractory to initial therapy or who relapse after first-line therapy have a significantly worse prognosis. (3, 26) Therefore, tandem transplants have been investigated as an alternative treatment.

Medically Necessary Indications

Tandem Autologous SCT

Available evidence suggests that tandem autologous SCT may offer improved health outcomes for those with relapsed HL and poor-risk features* who do not obtain a complete response from cytoreductive chemotherapy prior to transplant. 

* Poor-risk relapsed HL may be defined as having two or more of the following risk factors at first relapse:  time to relapse less than 12 months, stage III or IV at relapse, and relapse within previously irradiated sites.

• There are no randomized controlled trials comparing single autologous SCT with tandem autologous SCT in the treatment of refractory HL. Given the low yearly incidence of poor-risk patients, randomized trials of single versus tandem autologous SCT are unlikely.(3, 67)
• One large multicenter prospective trial evaluated a risk-adapted salvage treatment with single or tandem autologous SCT in 245 patients with relapsed/refractory HL.(67)  Patients who were categorized as poor risk (n=150) were offered tandem autologous SCT.  Intermediate-risk patients (n=95), defined as having one risk factor at relapse, were eligible for a single autologous SCT. 
  • Outcome analysis based on the intent-to-treat sample showed five-year freedom from second failure and overall survival (OS) were 73% and 85% for the intermediate-risk group and 46% and 57% for the poor-risk group.
• Tandem autologous SCT showed a benefit in patients with chemotherapy-resistant HL and in partial responders to cytoreductive conditioning. Five-year OS rates for poor-risk patients were 79% for complete responders and 73% for partial responders. This represents improved outcomes for partial responders when compared to a previous trial of single autologous SCT which reported five-year OS rates of 86% and 37% for complete and partial responders, respectively (68).
• Additional case series data are characterized by small numbers of patients, disparate preparative regimens, and varying lengths of follow-up.  While unreliable, these trials also suggest a long-term benefit for use of tandem autologous SCT in those with refractory disease. (27-31)

Guidelines

The National Comprehensive Cancer Network guidelines for Hodgkin lymphoma recommend autologous SCT as the best option for patients with Hodgkin’s lymphoma that is incurable after primary treatment. The guidelines are silent on the use of tandem transplant as a treatment strategy. (25)

The evidence is insufficient to determine whether high-dose chemotherapy followed by tandem autologous and/or allogeneic SCT is effective for Hodgkin Lymphoma.

Multiple Myeloma (MM)                                                        Return to Table

Multiple myeloma (MM) is a systemic malignancy of relatively well-differentiated plasma cells. Management of myeloma is generally related to tumor mass. Patients with a high tumor mass undergo systemic cytotoxic chemotherapy. However, multiple myeloma rarely is cured with standard-dose chemotherapy and treatment options are evolving rapidly. (4)

Medically Necessary Indications

The current evidence suggests that high dose chemotherapy with stem cell transplantation (SCT) using either tandem autologous or tandem autologous followed by reduced-intensity conditioning (RIC) allogeneic regimens may be effective for the treatment of newly diagnosed MM.

Tandem Autologous Stem Cell Transplantation

• One randomized controlled trial comparing single autologous SCT with double autologous SCT reported seven years after diagnosis, patients randomized to tandem transplants had higher probabilities for event-free survival; (20% vs. 10%, p=0.03), relapse-free survival; (23% vs. 13%; p<0.01), and overall survival; (42% vs. 21%, p=0.010) than those randomized to single transplants. (33) Treatment-related mortality was 6% and 4% after tandem and single transplants, respectively (p=0.40). Second transplants apparently extended survival only for those who failed to achieve complete response or very good partial response after one transplant. The primary endpoint of this study was complete response rate.
• A second RCT reporting improved survival for patients receiving a higher dose of chemotherapy and single autologous SCT called into question whether the improved survival in the above tandem trial was related to tandem transplantation or to patients receiving a higher overall dose of chemotherapy (280 mg/m² vs 140 mg/m²  Melphalan). (34, 35) However, the evidence supporting improved outcomes with higher doses of Melphalan and single autologous SCT remains inconclusive. (36-40)
• Another randomized controlled trial comparing single with double autologous SCT (n=321) reported patients undergoing tandem autologous SCT were more likely than those with a single SCT to attain at least a near complete response (47% vs. 33%; p=0.008), to prolong relapse-free survival (median, 42 vs. 24 months; p<0.001), and extend event-free survival (median, 35 vs. 23 months; p=0.001). (41) There was a difference between single and double autologous SCT only for patients who initially responded to induction chemotherapy.
• Randomized controlled trials on stem cell transplantation were largely designed prior to the availability of the medications bortezomib, thalidomide or lenalidomide. Therefore, the role of SCT for MM may evolve in the future. (43) One study randomized 195 patients to receive either tandem autologous SCT transplantation up front or single autologous SCT followed by a maintenance therapy with thalidomide. (42) In both arms, autologous SCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells. With a median follow-up of 33 months, the three-year overall survival was 65% in the tandem arm and 85% in the single autologous SCT arm (P = .04). Additional trials with longer follow-up are needed to understand the role of tandem transplants in myeloma with the use of newer agents.
• The National Comprehensive Cancer Network states tandem autologous transplant for MM is an option for patients with partial response or stable disease to the first autologous transplant. (43)

Tandem Autologous/Reduced-Intensity Conditioning (RIC) Allogeneic SCT

• One trial used “genetic randomization” to allow patients with an HLA-identical sibling donor to choose either tandem autografts or tandem autologous followed by RIC allogeneic SCT for the treatment of MM. Results show the autograft/allograft group had a higher complete response rate (55%) than the autograft/autograft group (26%; p=0.004). (44) Analyzing the group with HLA-identical siblings versus those without, in a pseudo intention-to-treat analysis, event-free survival and OS were significantly longer in the group with HLA-identical siblings. The treatment-related mortality rate at two years was 2% in the double autograft group and 10% in the autograft/allograft group; 32% of the latter group has extensive, chronic GVHD.
• The National Comprehensive Cancer Network guidelines for Multiple Myeloma do not make a distinction between the myeloablative and non-myeloablative (RIC) regimens and indicate that tandem autologous/allogeneic SCT may be considered in a clinical trial. (43)

Neuroblastoma (peripheral)                                                    Return to Table

Neuroblastoma is the most common extracranial solid tumor of childhood. (45) These tumors originate where sympathetic nervous system tissue is present, within the adrenal gland or paraspinal sympathetic ganglia. They are remarkable for their broad spectrum of clinical behavior, with some undergoing spontaneous regression, others differentiating into benign tumors, and still others progressing rapidly and resulting in patient death. (5)

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and high) that determine treatment plans. (46) Risk variables include age at diagnosis, clinical stage of disease as defined by the International Neuroblastoma Staging System, tumor histology, and certain molecular characteristics, including the presence of the myelocytomatosis viral related (MYCN) oncogene.

High-risk neuroblastoma is characterized by an age older than one year, disseminated disease, MYCN oncogene amplification, and unfavorable histopathologic findings. (46) It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis (47), even in the setting of other coexisting favorable factors.

Conventional chemotherapy rarely results in long-term survival in the 60% of children with high-risk tumors. Therefore, research on high dose chemotherapy has focused on those with high-risk neuroblastoma.

Investigational Indications

There is insufficient evidence to determine whether multiple cycles of high-dose chemotherapy (i.e. tandem or multiple transplants) is effective to treat any stage of neuroblastoma.

• There are no randomized controlled trials that directly compare outcomes of tandem transplants with those of either single transplants or conventional-dose regimens.
• Several uncontrolled pilot or Phase II trials reported results after tandem cycles of high-dose chemotherapy with autologous SCT for the treatment of neuroblastoma. These small, non-randomized studies do not permit conclusions regarding the efficacy of tandem transplant compared to conventional therapy. (48-50)
• Future studies for high-risk neuroblastoma include a phase III randomized study of single versus tandem myeloablative consolidation therapy followed by peripheral blood SCT. Results of this and other randomized trials may determine whether high-dose chemotherapy with tandem SCT improves event-free or overall survival in patients with neuroblastoma. (51)
• There are no published treatment guidelines which address the use of high-dose chemotherapy with tandem SCT for the treatment of neuroblastoma.

Non-Hodgkin’s Lymphoma (NHL)                                         Return to Table

Non Hodgkin's lymphomas (NHL) are hematologic (blood, bone marrow, or lymph node) cancers arising from lymphocytes arrested at various stages of maturation. In general, NHL can be divided into two prognostic groups, indolent and aggressive. (53)

Indolent NHL has a relatively good prognosis with a median survival of ten years; however, it is not curable in advanced clinical stages. (53) Follicular lymphoma is the most common indolent NHL (70%–80% of cases), and often the terms indolent lymphoma and follicular lymphoma are used synonymously. Also included in the indolent NHLs are small lymphocytic lymphoma/chronic lymphocytic leukemia*, lymphoplasmacytoid lymphoma, marginal zone lymphomas, and cutaneous T-cell lymphoma.(44)

* Small lymphocytic lymphoma and chronic lymphocytic leukemia are addressed in separate policies: Transplant 42, Autologous Hematopoietic Stem Cell Transplant and Transplant 43, Allogeneic Hematopoietic Stem Cell Transplant.

Aggressive NHL has a shorter natural history; however, 30%–60% of these patients can be cured with intensive combination chemotherapy regimens. (53) Aggressive lymphomas include diffuse large B-cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, and Burkitt’s lymphoma.

Investigational Indications

There is insufficient data to determine whether tandem stem cell transplantation is effective for the treatment of non-Hodgkin’s lymphoma (NHL).

• There are no prospective controlled studies comparing tandem transplantation with single transplants for the treatment of NHL. (6)
• Available evidence remains insufficient to determine the effectiveness of this treatment strategy. Studies are small case series that do not make direct comparisons of tandem transplantation with either conventional chemotherapy or single transplants. (54, 55).
• The 2008 National Comprehensive Cancer Network guidelines are silent on the use of tandem transplant as a treatment of NHL. (52)

Embryonal tumors of the CNS include medulloblastoma, medulloepithelioma, supratentorial primitive neuroectodermal tumors (PNETs, e.g., pineoblastoma, cerebral neuroblastoma, ganglioneuroblastoma), ependymoblastoma, and atypical teratoid/rhabdoid tumor (AT/RT).  The most common CNS embryonal tumor is medulloblastoma which accounts for 20% of all childhood CNS embryonal tumors, and thus, most studies focus on this diagnosis. (7, 56)

Initial therapy of CNS embryonal tumors focuses on neurosurgical resection, plus radiation therapy with or without adjuvant conventional-dose chemotherapy. Treatment protocols are based on risk stratification, as average or high risk. (7) Conventional treatment regimens have resulted in five-year overall survival rates of 80% or better for those with average-risk disease. (7, 65)  For those with high-risk medulloblastoma the average five-year event-free survival is much lower, ranging from 34% to 40% across studies, and fewer than 55% of children with high-risk disease survive longer than five years. (7, 66) 

The treatment of newly diagnosed medulloblastoma continues to evolve. Therapeutic approaches have attempted to delay and sometimes avoid the use of radiation because of the harmful effects radiation may have on the developing brain. (7, 56) For this reason, autologous stem cell transplant (SCT) has been used as a means of minimizing the need for radiation therapy.  Recurrent childhood CNS embryonal tumor is not uncommon, and depending on which type of treatment was initially received, autologous SCT may be considered for those with recurrent disease. (7, 56) Tandem SCT has also been investigated as an alternative to autologous SCT for those with new and relapsed disease.  

Investigational Indications

Available evidence is not sufficient to determine whether multiple-cycle high-dose chemotherapy is effective to treat CNS embryonal tumors.

• Data are lacking concerning the effectiveness of tandem stem cell transplant for CNS embryonal tumors. There are no published randomized controlled trials comparing this treatment strategy to standard therapies.
• Several small case series have reported favorable outcomes concerning multiple cycle or tandem autologous SCT for the treatment of medulloblastoma. (57-59) While these results suggest tandem transplantation may improve the survival of children with newly diagnosed high-risk medulloblastomas, the data are unreliable due to very small sample sizes, heterogeneity of patient population, and lack of randomization. Further study is needed to establish the role of the tandem approach.  
• Other CNS PNETs are uncommon and include pinealoblastoma, ependymoblastoma, and central neuroblastoma. There were few data regarding high-dose therapy for these rare tumors, although it was thought that the results with medulloblastoma may be extrapolated to other PNETs. (7)
• The National Comprehensive Cancer Network guidelines do not address tandem stem cell support for CNS embryonal tumors. (60)

Ependymoma                                                                            Return to table

Ependymoma is a neuroepithelial tumor that arises from the ependymal lining cell of the ventricles of the brain and is therefore usually contiguous with the ventricular system. Ependymomas are distinct from ependymoblastomas (a primitive neuroepithelial cell tumor) due to their more mature histologic differentiation. For this reason, ependymomas are not formally considered primitive neuroectodermal tumors (PNETs). (56,61)

Initial treatment of ependymoma consists of maximal surgical resection followed by radiotherapy. Chemotherapy usually does not play a role in the initial treatment of ependymoma. However, disease relapse is common, typically occurring at the site of origin. Treatment of recurrence is problematic as further surgical resection or radiation therapy is usually not possible. (7)

Investigational Indications

Available evidence is not sufficient to determine if multiple-cycle high-dose chemotherapy with or without associated radiotherapy (i.e., tandem or multiple transplants) is effective for the treatment of ependymoma.

• There are no published randomized, controlled trials comparing tandem SCT with standard treatments for patients with ependymoma.
• Literature published regarding SCT for ependymoma consists primarily of small case series using autologous stem cell transplants. (62-64) For example, Mason and colleagues reported on a case series of 15 patients with recurrent ependymoma. (62) Similarly, Grill and colleagues reported a disappointing experience in 16 children. (63) Results of these series, although limited in size, further suggest high-dose chemotherapy with SCT is not superior to other previously reported chemotherapeutic approaches.
• There are no evidence-based clinical practice guidelines which recommend tandem SCT as a treatment option for ependymoma.

References

1. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.27 High-Dose Chemotherapy with Hematopoietic Stem-Cell Support for Breast Cancer
2. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.35, High-Dose Chemotherapy and Hematopoietic Stem-Cell Support as a Treatment of Germ-Cell Tumors
3. BlueCross BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.29 Hematopoietic Stem-Cell Transplantation for Hodgkin Lymphoma
4. BlueCross and BlueShield Association Medical Policy Reference Manual, Policy No. 8.01.17, Hematopoietic Stem-Cell Transplantation for Multiple Myeloma
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40. Goldschmidt H, Cremer FW, Hegenbart U et al. Comparison of 3 high-dose regimens with autologous peripheral blood stem cell transplantation for multiple myeloma: a single center experience in 261 patients. Proc VII Int Multiple Myeloma Workshop 1999. Abstract 117a
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Cross References

Autologous Hematopoietic Stem Cell Transplant, Regence Medical Policy, Transplant, Policy No. 42

Allogeneic Hematopoietic Stem Cell Transplant, Regence Medical Policy, Transplant, Policy No. 43

Transplant Section Table of Contents