Transplant Section - Allogeneic Hematopoietic Stem Cell Transplant

IMPORTANT REMINDER

This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status.

Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care.

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), 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).

Allogeneic stem cell transplantation may provide two theoretical advantages over autologous stem cell transplant:

• The potential for tumor contamination from autologous cells is eliminated; and
• There is the possibility of a beneficial graft-versus-tumor effect, in which the donor cells are believed to attack recipient cancer cells through an immune-mediated response.

Reduced intensity conditioning (RIC) allogeneic stem cell transplantation 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.

Safety

• Patients who undergo allogeneic SCT are susceptible to chemotherapy-related toxicities such as liver and kidney failure, pulmonary failure, or opportunistic infection.
• Compatibility between donor and patient is a critical factor for achieving good outcomes. 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 on autologous SCT or tandem transplants, refer to separate Regence Medical Policies:

POLICY/CRITERIA

Allogeneic stem cell transplant may be considered medically necessary for the diagnoses specified in the table below. Allogeneic 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 medical necessity 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. use as an allogeneic stem cell transplant in a related or unrelated recipient.)

POSITION SUMMARY

Effectiveness:

Acute Lymphoblastic Leukemia (ALL)                                Return to Table

Medically Necessary Indications

The evidence is sufficient to suggest that allogeneic SCT may be effective to treat the following in either childhood or adult ALL:

• ALL in first complete remission (CR1) in those at high risk for relapse (see table for high-risk factors)
• ALL in second or greater remission (>CR2)
• Refractory ALL
• For those in complete marrow and extramedullary CR1 or >CR2 who are unable to tolerate a standard myeloablative conditioning regimen, reduced intensity conditioning SCT may be considered.

Childhood ALL

• In childhood ALL, conventional chemotherapy is associated with complete remission rates of about 95%, with long-term durable remissions of 60%. Prognosis after a first relapse is related to the length of the original remission. For example, leukemia-free survival is 40-50% for children whose first remission was longer than three years, compared to only 10-15% for those with early relapse. Therefore, for patients in a first complete remission, stem-cell transplantation is considered necessary only in those at high risk of relapse, including those with short remissions. (1)
• Three reports describing the results of randomized controlled trials reported that overall outcomes after allogeneic SCT were generally equivalent to overall outcomes after conventional-dose chemotherapy in children being treated for high-risk ALL in CR1 or for relapsed ALL. Stem cell transplant administered in CR1 was associated with fewer relapses than conventional-dose chemotherapy however, it was also associated with more frequent deaths in remission (i.e., from treatment-related toxicity).  (21-23)
• A more recently published randomized trial (PETHEMA ALL-93) reported no significant differences in disease-free survival or overall survival rates at median follow-up of 78 months in 106 children with very high-risk ALL in CR1 who received allogeneic or autologous SCT versus standard chemotherapy with maintenance treatment. (24) Similar results were observed using either intention-to-treat or per-protocol analyses.
• These results and reviews of other studies suggest that while overall and event-free survival are not different after allogeneic SCT compared to conventional-dose chemotherapy, SCT remains an important therapeutic option in the management of childhood ALL, especially for patients considered at high risk of relapse. (25, 26)
• This conclusion is further supported by an evidence-based systematic review of the literature sponsored by the American Society for Blood and Marrow Transplantation (ASBMT), which reports for children in first complete remission, matched-related allogeneic SCT demonstrated benefit in very high-risk Philadelphia chromosome positive patients. (27) The review also reports matched related allogeneic SCT in second or subsequent remission has resulted in long-term survival that may be equivalent or better than chemotherapy.
• The National Comprehensive Cancer Network (NCCN) clinical practice guidelines do not specifically address acute lymphoblastic leukemia. However, since ALL is very similar to lymphoblastic lymphoma which originates in the lymph nodes as opposed to the blood or bone marrow, treatment strategies have generally been consistent for the two diseases. Current NCCN guidelines indicate that allogeneic SCT is appropriate for treatment of poor risk lymphoblastic lymphoma patients. (28)

Adult ALL

For adult patients, the decision between allogeneic SCT and conventional chemotherapy may reflect a choice between intensive therapy of short duration and longer but less-intensive treatment. (1)

An evidence-based systematic review of the literature sponsored by the ASBMT concluded that allogeneic SCT is superior to autologous SCT in adult patients in CR1, although available data did not permit separate analyses in high-risk versus low-risk patients. (32) This analysis was based on results from three randomized clinical trials. (29-31) The report recommends allogeneic SCT for adults with high-risk disease in CR1, but not for standard-risk patients and for patients in >CR2.

Partially conflicting results were reported in a multicenter randomized trial published after the ASBMT literature search. (33) Among 183 high-risk adult patients in CR1 receiving allogeneic, autologous or delayed intensification followed by maintenance chemotherapy, no statistically significant difference in outcomes between all three arms was detected at a median follow-up of 70 months. Both per-protocol and intention-to-treat analyses were completed.

More recently, a phase III randomized study of allogeneic or autologous SCT versus conventional consolidation and maintenance chemotherapy specific to adult ALL patients in CR1 reported a significant benefit of allogeneic SCT over chemotherapy or autologous SCT in patients with Philadelphia chromosome-negative high-risk ALL. (34)

The NCCN clinical practice guidelines do not specifically address acute lymphoblastic leukemia. However, since ALL is very similar to lymphoblastic lymphoma which originates in the lymph nodes as opposed to the blood or bone marrow, treatment strategies have generally been consistent for the two diseases. The NCCN guidelines for non-Hodgkin’s lymphoma indicate that allogeneic SCT is appropriate for treatment of poor risk lymphoblastic lymphoma patients. (28)

Reduced Intensity Conditioning Allogeneic SCT

Two studies were published on the use of reduced intensity conditioning (RIC) regimens for allogeneic SCT in patients with ALL. A multicenter single-arm study of 43 patients reported a three-year overall survival rate of 30%. (35) Another registry-based study reported three-year data on 97 adult patients in CR1, patients beyond CR1, and those with advanced/refractory ALL. The two-year overall survival was 31% with a non-relapse mortality of 28% and relapse rate of 51%. (36) In patients transplanted in CR1, overall survival was 52%; in CR2/CR3, it was 27%; in patients with advanced or refractory ALL, overall survival was 20%. These data suggest RIC allogeneic SCT has some efficacy as salvage therapy in high-risk ALL.

Investigational Indications

Available evidence is not sufficient to determine whether allogeneic SCT is effective as a salvage therapy to treat relapsing ALL after a prior autologous SCT. 

• A 2000 BlueCross BlueShield Technology Evaluation Center (TEC) Assessment focused on allogeneic SCT after a failed autologous SCT as a salvage therapy in the treatment of a variety of malignancies, including ALL. (19) Published evidence was limited to small, uncontrolled case series with short follow-up. In the only study that permitted direct comparison of outcomes between allogeneic or autologous SCT as a salvage treatment, there were no statistically significant differences between the two salvage therapies with respect to the probability of relapse or leukemia-free survival. However, the risk of early transplant-related mortality was much greater after salvage with allogeneic SCT than after salvage with autologous SCT (40% versus 7%). (19, 20)
• There are no evidence-based clinical practice guidelines that recommend allogeneic SCT after a failed prior autologous SCT as a salvage treatment for ALL.

Acute Myleoid Leukemia (AML)                                Return to Table

Medically Necessary Indications

Available evidence suggests that high-dose chemotherapy with allogeneic stem cell transplant (SCT) may be effective for the treatment of acute myeloid leukemia (AML) in  remission, primary refractory AML, or relapsed AML including for those who relapse after a prior failed autologous SCT.

One randomized trial of 120 patients compared allogeneic SCT, high-dose cytarabine, and autologous SCT as post-remission treatment for AML. (39) The authors reported comparable survival outcomes, although the proportion of three-year failure-free survivors was larger in the allogeneic recipient group.

50% to 70% of patients are expected to relapse after attaining first complete remission from AML and conventional chemotherapy is generally not curative once relapse occurs. (40) Allogeneic SCT is associated with a prolonged disease-free survival in 30–40% of patients in first relapse or second complete remission. Due to the mortality associated with remission induction chemotherapy, allogeneic SCT may be considered the initial treatment of relapsed disease. (2)

The American Society for Blood and Marrow Transplantation published a systematic review on the role of cytotoxic therapy with SCT in pediatric patients with AML. (41) Patients in first complete remission who received allogeneic SCT showed superior overall survival and leukemia-free survival when compared to patients who received chemotherapy. Thus, allogeneic SCT is recommended in the first complete remission. For patients in second complete remission, the expert panel acknowledged a lack of evidence comparing matched related allogeneic donors versus chemotherapy; nonetheless, the panel consensus recommends the use of any suitable allogeneic matched related donor if one is available.

Allogeneic SCT is often performed as salvage for patients who have relapsed after conventional chemotherapy or autologous SCT.(158) Registry data show disease free survival rates of 35–40% using sibling transplants and 10% with matched unrelated donor transplants for patients with induction failure or in relapse following hematopoietic SCT.(12)

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines panel had reservations concerning allogeneic SCT to consolidate patients with good-risk cytogenetics because of prohibitive long-term toxicities associated with this procedure in the treatment of AML. (42) The guidelines find allogeneic SCT is appropriate when there is induction failure; for patients in first relapse; and as consolidation therapy in patients with intermediate or poor-risk cytogenetics, secondary AML, or prior myelodysplasia. For patients with secondary AML or prior myelodysplasia, the NCCN notes allogeneic SCT without induction chemotherapy may be appropriate due to the poor probability of attaining remission with induction chemotherapy.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Available evidence suggests that reduced intensity allogeneic SCT may be effective for those who are in complete marrow and extramedullary remission and who may not be able to tolerate a full myeloablative allogeneic SCT.

A growing body of evidence is accruing from clinical studies of RIC with allogeneic HSCT for AML.(153-158) Overall, these data suggest long-term remissions (2–4 years) can be achieved in patients with AML who because of age or underlying comorbidities would not be candidates for myeloablative conditioning regimens.  

The NCCN clinical practice guidelines panel recommends RIC allogeneic SCT in the context of a clinical trial for patients 60 years or older : 1) as a post-remission therapy for those achieving a complete response or 2) for treatment of induction failure only in those with low volume disease.(42)

Amyloidosis                                                                            Return to Table

Amyloidosis is a group of diseases in which protein is deposited in specific organs (localized amyloidosis) or throughout the body (systemic amyloidosis). Amyloidosis may be either primary (with no known cause) or secondary (caused by another disease, including some types of cancer). Generally, primary amyloidosis affects the nerves, skin, tongue, joints, heart, and liver; secondary amyloidosis often affects the spleen, kidneys, liver, and adrenal glands. (46)

Historically, this disease has had a poor prognosis, with a median survival from diagnosis of about 12 months, although outcomes have improved with the advent of combination chemotherapy with alkylating agents and autologous stem cell transplant (SCT). Emerging approaches include the use of immunomodulating drugs such as thalidomide or lenalidomide, and the proteasome inhibitor bortezomib. Regardless of the approach chosen, treatment of amyloidosis is aimed at rapidly reducing the production of amyloidogenic monoclonal light chain proteins by suppressing the underlying plasma cell imbalance, with supportive care to decrease symptoms and maintaining organ function. (3)

Investigational Indications

There is insufficient data to determine whether allogeneic SCT is effective as a treatment for primary systemic amyloidosis.

• Data on the use of allogeneic SCT to treat amyloidosis are sparse, with no systematic evaluation of this treatment in a clinical trial. (44) Concerns about the use of allogeneic SCT include high treatment-related mortality (more than 40%), morbidity secondary to graft-versus-host disease, and questions about the efficacy of a proposed graft-versus-malignancy effect on low-grade plasma cell dyscrasias.
• Comparisons of allogeneic SCT with autologous SCT or other standard treatments for amyloidosis have not been made.
• The current National Comprehensive Cancer Network clinical practice guidelines for multiple myeloma, which include guidelines for amyloidosis, recommend all treatment of amyloidosis should be in the context of a clinical trial since data are insufficient to determine optimal treatment. The guidelines do not list allogeneic stem cell transplant as a treatment option. (45)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for primary systemic amyloidosis.

• Data on the use of RIC allogeneic SCT to treat amyloidosis are sparse, with no systematic evaluation of this treatment in a clinical trial.

Autoimmune Diseases                                                           Return to Table

Investigational Indications

Available evidence has not established that allogeneic stem cell transplant (SCT) is effective for the treatment of any autoimmune disease including, but not limited to multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis/scleroderma.

• There are no randomized controlled trials that compare the use of allogeneic SCT with standard treatments for any autoimmune disease.
• Available evidence is from small case series and anecdotal reports of cure from autoimmune diseases after allogeneic SCT. (48-53) These data do not permit conclusions concerning the effectiveness of allogeneic SCT compared with other treatment strategies.
• Given the general complexity of the autoimmune diseases, the fluctuating nature of their clinical manifestations, and the wide variations in disease activity among patients with the same disease and in any one patient at various points in time, prospective, randomized controlled trials are needed to evaluate allogeneic SCT in an adequate number of patients for each disease indication. In addition, these trials should apply standardized patient selection criteria, disease severity stratification, treatment protocols, and clinical outcomes measurements.(47)
• Additionally, the increased risk of severe morbidity and mortality associated with allogeneic transplantation (10-30%) and the difficulty in distinguishing clinical features of graft-versus-host disease from those of recurrent autoimmune disease have made allogeneic transplantation a less-attractive strategy. (48)
• There are no evidence-based clinical practice guidelines that recommend allogeneic SCT as a treatment of any autoimmune disease.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for any autoimmune diseases.

• Data on the use of RIC allogeneic SCT to treat autoimmune diseases are sparse, with no systematic evaluation of this treatment in a clinical trial.

Breast Cancer                                                                        Return to Table

Investigational Indications

Available evidence does not demonstrate that allogeneic stem cell transplant (SCT) for the treatment of breast cancer results in improved health outcomes when compared to standard breast cancer treatments.

• There is no published data from controlled trials in which allogeneic SCT is compared to standard breast cancer treatments. Although several uncontrolled studies were published on the use of non-myeloablative (reduced intensity conditioning) regimens for allogeneic transplants, results from these studies were uncertain due to very small sample sizes and lack of control groups.(55-60)
• A 1999 BlueCross BlueShield Association Technology Evaluation Center (TEC) Assessment evaluated the use of high-dose chemotherapy with allogeneic SCT for breast cancer relapsing after a prior autologous SCT. No studies were identified that address this treatment strategy for relapsed breast cancer. (54)
• There are no evidence-based clinical practice guidelines that recommend allogeneic SCT for the treatment of breast cancer.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for breast cancer.

• There is no published data from controlled trials in which RIC allogeneic SCT is compared to standard breast cancer treatments. Data are sparse and consist primarily of small pilot studies or larger case series which do not permit conclusions to be made on health outcomes.(159)  
• The National Comprehensive Cancer Network clinical practice guidelines do not list either allogeneic or RIC allogeneic SCT as a treatment option for breast cancer.(162)

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)                                                                                       Return to Table

Treatment regimens used for CLL are generally the same as those used for SLL, and outcomes of treatment are comparable for the two diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses with median survivals of six to ten years, while the median survival of high-risk CLL or SLL may be only two years. Although typically responsive to initial chemotherapy (or chemo-immunotherapy), CLL and SLL are rarely cured, and nearly all patients ultimately die of their disease. (6)

See separate position statements for other non-Hodgkin lymphomas.

Investigational Indications

It is uncertain if allogeneic stem cell transplant (SCT) is effective for the treatment of CLL or SLL.

• There are no randomized controlled trials comparing allogeneic SCT with conventional-dose therapy for the treatment of CLL or SLL. Available evidence is only from uncontrolled case series and registry data. The data are not reliable as there is heterogeneity in patients and in disease characteristics. Additionally, small sample sizes with short duration of follow-up relative to the natural history of the disease do not permit conclusions concerning the effectiveness of this treatment strategy. (61)
• A direct comparative analysis from the International Bone Marrow Transplant Registry (IBMTR) was commissioned by the BlueCross BlueShield Association Technology Evaluation Center (TEC) to analyze allogeneic SCT compared with conventional chemotherapy. Fewer than twelve patients reported to the IBMTR had not received prior treatment for CLL making the sample size too small for analysis on newly diagnosed CLL patients. Analysis of data on patients receiving allogeneic SCT as a salvage therapy yielded inconclusive results, in part due to the small number of patients contributing to the last third of calculated survival curves. (61)
• Recent review articles discuss uncertainties with respect to the type of transplant, intensity of pretransplant conditioning, the optimal timing of transplantation in the disease course, the baseline patient characteristics that best predict likelihood of clinical benefit from transplant, and the long-term risks of adverse outcomes. (62-67) While allogeneic SCT may have curative potential for CLL or SLL, high rates (>10%) of treatment-related mortality discourage this approach in early or lower-risk disease. (65-67)
• A 2007 position statement from the European Group for Blood and Marrow Transplantation suggests allogeneic SCT with either myeloablative or reduced-intensity conditioning may be considered in the context of an approved clinical trial in younger, high-risk or unfavorable cases. (68)
• The National Cancer Institute Working Group has published guidelines for the diagnosis and treatment of CLL which the U.S. Food and Drug Administration (FDA) has also adopted. The 2008 version of these guidelines include allogeneic SCT only as a second-line treatment and in the context of a clinical trial. (69)
• The most recent National Comprehensive Cancer Network (NCCN) clinical practice guidelines indicate that allogeneic SCT (conditioning regimen unspecified) may be considered, preferably in a clinical trial, for patients younger than age 70 years with high-risk disease or as salvage treatment in those with progressive disease. (28) However, the NCCN recommendation is based on a single review article.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for CLL or SLL

• Data on the use of RIC allogeneic SCT to treat CLL and SLL are sparse, with no systematic evaluation of this treatment in clinical trials.
• The NCCN clinical practice guidelines do not list RIC allogeneic SCT as a treatment option for CLL or SLL.(28)

Chronic Myelogenous Leukemia (CML)                              Return to Table

Medically Necessary Indications

Available evidence is sufficient to demonstrate that allogeneic stem cell transplant (SCT) is effective for the treatment of CML.

• A BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment concluded that allogeneic SCT has emerged as the standard treatment for CML when a suitable stem-cell donor was available. (70) Patients in chronic phase receiving an HLA-matched sibling donor transplant are estimated to have a 45–75% probability of long-term disease-free survival, while those transplanted with more advanced disease have a 15%–40% long-term survival. (71) Young, good-risk patients transplanted early in the chronic phase from HLA-matched but unrelated donors reportedly have a 40–60% probability of long-term survival. (72, 73)
• Patients included in the TEC assessment were treated before the tyrosine kinase inhibitor, imatinib (Gleevec), became available. Since this drug has been shown to induce remissions, even among patients in accelerated phase and blast crisis (79-82), allogeneic SCT may be used less often to manage patients with CML, or may only be used when a complete molecular response to the drug fails or is not achieved. (74-76) Obvious limitations of allogeneic stem cells are the lack of a suitable donor for many patients and the increased morbidity of allogeneic transplant, especially in older patients.
• The most recent National Comprehensive Cancer Network (NCCN) practice guidelines recommend allogeneic SCT as an alternative treatment option in the following patients (77):
  • Those who do not achieve hematologic remission after three months of imatinib;
  • Those with no cytogenetic response or those in cytogenetic relapse at six, twelve, or 18 months, after achieving initial hematologic remission after three months of imatinib, and
  • Those progressing on imatinib to accelerated or blast crisis.
• Both the NCCN guidelines and the National Cancer Institute concur that allogeneic SCT remains the only potentially curative option for CML. (77, 78)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Based on the above assessments, reduced intensity conditioning (RIC) allogeneic SCT may be considered effective only for those who meet criteria for a myeloablative allogeneic SCT above, including eligibility on the basis of overall health status.  

• An underlying premise of this policy is that RIC allogeneic SCT is one of many conditioning regimens that can be used for which the evidence supports that allogeneic SCT improves health outcomes. The role of RIC allogeneic transplant in other settings is uncertain and requires direct comparative trials with adequate follow-up to analyze its safety and effectiveness. No such controlled trials were identified. (7,160,161)

Epithelial Ovarian Cancer                                                     Return to Table

Epithelial ovarian cancer accounts for 4% of all cancers in women and must be distinguished from the much less common germ cell tumor of the ovary. (8) In this policy the term ovarian cancer will refer exclusively to epithelial ovarian cancer. For germ cell tumors of the ovary, see separate position statements under germ cell tumors.

All stages of ovarian cancer are first treated with cytoreductive surgery, including removal of the ovaries, fallopian tubes, and a total abdominal hysterectomy followed by combination chemotherapy. (83) The use of platinum and taxanes has improved progression-free survival and overall survival rates in advanced disease. (84) However, most of these women develop recurrences and die of their disease as chemotherapy drug resistance leads to uncontrolled cancer growth. (83) High-dose chemotherapy has been investigated as a way to overcome drug resistance.

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with allogeneic stem cell transplantation (SCT) is effective for the treatment of epithelial ovarian cancer.

• A 1998 Technology Evaluation (TEC) Assessment did not identify any studies reporting outcomes of allogeneic transplants for patients with ovarian cancer. (85) A separate 1999 TEC assessment evaluated the use of high dose chemotherapy with allogeneic stem-cell support as a salvage therapy after a failed prior course of high dose chemotherapy with autologous SCT. (86) There were no data regarding outcomes of this strategy as therapy for epithelial ovarian cancer.
• Experience with high-dose chemotherapy and allogeneic SCT in ovarian cancer comes primarily from registry data. (87, 88) Limited data exist on this treatment approach, and the ideal patient population and best regimen remain to be established. (83)
• The National Comprehensive Cancer Network (NCCN) clinical practice guidelines for ovarian cancer indicate that high-dose chemotherapy with SCT is considered investigational. (89)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for epithelial ovarian cancer.

• Data on the use of RIC allogeneic SCT to treat epithelial ovarian cancer are lacking, with no systematic evaluation of this treatment in clinical trials.
• The NCCN clinical practice guidelines do not list RIC allogeneic SCT as a treatment option for epithelial ovarian cancer.(89)

Ewing’s Sarcoma- Solid Tumor of Childhood                       Return to Table

Current therapy for Ewing’s sarcoma favors induction chemotherapy, with local control consisting of surgery and/or radiation (dependent on tumor size and location), followed by adjuvant chemotherapy. Multi-agent chemotherapy, surgery, and radiation therapy have improved the progression-free survival in patients with localized disease to 60%–70%. (90)

The presence of metastatic disease is the most unfavorable prognostic feature for Ewing’s sarcoma, and the outcome for patients presenting with metastatic disease is poor, with 20%–30% progression-free survival. Thirty to forty percent of patients experience disease recurrence, and patients with recurrent disease have a five-year event-free survival and overall survival rate of less than 10%. (92)

See separate policy statements for other primitive neuroectodermal tumors (PNETs) and Neuroblastoma.

Medically Necessary Indications

Evidence suggests that high-dose chemotherapy with allogeneic stem cell transplant (SCT) may be effective to consolidate remissions of high-risk Ewing’s sarcoma or as salvage therapy for those with residual, recurrent, or refractory disease.

• Even though it is associated with severe toxicity, high-dose chemotherapy with SCT has been shown to be effective in patients with relapsed or progressive Ewing’s sarcoma in several small studies. (9, 90, 91) Due to the poor prognosis of recurrent disease, this treatment may be considered an option.
• The National Comprehensive Cancer Network clinical practice guidelines for the treatment of Ewing sarcoma family tumors indicate the role of high dose chemotherapy and stem cell transplant for high-risk ESFT patients is yet to be determined in randomized controlled trials and patients with recurrent and metastatic ESFTs should be considered for investigational approaches. (91)
• A large Phase III trial (EURO-EWING 99) is underway, and will likely serve to guide future treatment options for Ewing sarcoma family tumors.(93)

Investigational Indications

There is insufficient data to determine whether high-dose chemotherapy with allogeneic SCT is effective as an initial treatment for Ewing’s sarcoma.

• No trials have been identified which directly compare high-dose chemotherapy with allogeneic SCT to multi-agent chemotherapy as initial treatment of Ewing’s sarcoma family tumors. Without such comparisons, it is not possible to determine if allogeneic SCT is as effective as or better than current standard treatment.
• The National Comprehensive Cancer Network clinical practice guidelines for bone cancer indicate primary treatment for all patients with Ewing’s sarcoma should include the following: 1) multi-agent chemotherapy along with appropriate growth factor support for 12-14 weeks; 2) local control therapy such as excision, with or without preoperative radiation therapy; and 3) adjuvant chemotherapy, including a combination of at least three standard chemotherapeutic agents. These guidelines indicate hematopoietic SCT has been shown to be effective in several small studies and patients with recurrent and metastatic disease should be considered for investigational treatments (91)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as an initial treatment for Ewing’s sarcoma.

• Data on the use of RIC allogeneic SCT as an initial treatment for Ewing’s sarcoma are lacking, with no systematic evaluation of this treatment in clinical trials.
• The National Comprehensive Cancer Network (NCCN) clinical practice guidelines do not list RIC allogeneic SCT as an initial treatment option for Ewing’s sarcoma.(91) These guidelines indicate hematopoietic SCT has been shown to be effective in several small studies in patients with recurrent and metastatic disease and patients with recurrent disease should be considered for investigational treatments.

Genetic Diseases and Acquired Anemias                             Return to Table

Medically Necessary Indications

High-dose chemotherapy with allogeneic stem cell transplant (SCT) is considered effective for the treatment of selected patients with the following disorders (10):

• Aplastic anemia, severe or very severe, including congenital (e.g. Fanconi’s anemia, Diamond-Blackfan syndrome, Familial hemophagocytic lymphohistiocytosis (HLH)) or acquired (secondary to drug or toxin exposure, e.g. acquired hemophagocytic lymphohistiocytosis). Appropriate patients include those with platelets less than 20 x 10⁹/L, granulocytes less than 0.5 x 10⁹/L, and reticulocytes less than 1% (corrected for hematocrit) and who have failed antithymocyte globulin therapy;
• Anemia, sickle cell, for children or young adults with either a history of prior stroke or at increased risk of stroke or end-organ damage, and with an HLA-identical, related donor. Factors associated with a high risk of stroke or end-organ damage include: recurrent chest syndrome, recurrent vaso-occlusive crises, red blood cell alloimmunization on chronic transfusion therapy;
• Homozygous beta-thalassemia (thalassemia major);
• Infantile malignant osteopetrosis (Albers-Schönberg disease or marble bone disease);
• Kostmann’s syndrome;
• Leukocyte adhesion deficiencies;
• Mucolipidoses (Gaucher’s disease, metachromatic leukodystrophy, globoid cell leukodystrophy, adrenoleukodystrophy) for patients who have failed conventional therapy, including diet and enzyme replacement and who are neurologically intact;
• Mucopolysaccharidoses (Hunter’s, Hurler’s, Sanfilippo, Maroteaux-Lamy variants) in patients who are neurologically intact;
• Severe combined immunodeficiencies;
• Wiskott-Aldrich syndrome;
• X-linked lymphoproliferative syndrome.

Four BlueCross BlueShield Association Technology Evaluation Center (TEC) assessments concluded that the evidence was sufficient to determine high-dose chemotherapy and allogeneic SCT is effective for certain genetically inherited diseases and acquired anemias. (94-97). Each TEC assessment determined there was an improvement in overall health outcomes for the above mentioned indications, especially for conditions where no alternative treatment is available.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Based on the above assessments, reduced intensity conditioning (RIC) allogeneic SCT may be considered effective only for those who meet criteria for a myeloablative allogeneic SCT above, including eligibility on the basis of overall health status.

• An underlying premise of this policy is that RIC allogeneic SCT is one of many conditioning regimens that can be used for which the evidence supports that allogeneic SCT improves health outcomes. The role of RIC allogeneic transplant in other settings is uncertain and requires direct comparative trials with adequate follow-up to analyze its safety and effectiveness. Research is ongoing to determine the value of RIC allogeneic SCT for hemoglobinopathies and acquired anemias in other settings. (10, 177-181)

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). Germ cell tumors of the ovary should be distinguished from the more common epithelial ovarian tumors which are addressed separately in this policy. 

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. (11) To determine the safety and efficacy of high-dose chemotherapy with allogeneic SCT, comparisons to these conventional treatments must be made.

Investigational Indications

Available evidence does not demonstrate that high-dose chemotherapy with allogeneic stem cell transplant (SCT) is an effective treatment for germ cell tumors, including, but not limited to its use as therapy after a prior failed course of high-dose chemotherapy with autologous SCT.

• There are no randomized controlled trials comparing high-dose chemotherapy with allogeneic SCT with conventional therapy for the treatment of germ cell tumors.
• A 1999 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment evaluated outcomes of high-dose chemotherapy with allogeneic SCT as salvage therapy for germ-cell tumors after a failed prior course of autologous stem-cell transplant. The TEC review identified no references reporting survival outcomes of this approach for germ cell tumors. (98)
• Other studies are uncontrolled case series enrolling small numbers of patients, or retrospective reviews of larger cohorts treated at one or several institutions. None of the studies compared outcomes of high-dose chemotherapy to outcomes of conventional-dose chemotherapy in randomized or nonrandomized trials, and many included patients in multiple prognostic or risk categories. (11, 99-102)
• There are no published evidence-based clinical practice guidelines that recommend allogeneic SCT for the treatment of germ cell tumors.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for germ cell tumors.

• Data on the use of RIC allogeneic SCT to treat germ cell tumors are lacking, with no systematic evaluation of this treatment in clinical trials.
• There are no published evidence-based clinical practice guidelines that recommend RIC allogeneic SCT for the treatment of germ cell tumors.

Hodgkin’s Lymphoma (HL)                                                   Return to Table

Hodgkin Lymphoma (HL) is a relatively uncommon malignancy involving the lymph nodes and the lymphatic system. The use of more effective and less toxic chemotherapeutic regimens has made HL curable in most patients, with up to 80% of newly diagnosed patients curable using combination chemotherapy and/or radiation therapy. Patients who prove refractory or who relapse after first-line therapy have a significantly worse prognosis. (103, 106)

Autologous stem cell transplant (SCT) is widely considered the therapy of choice for relapsed and refractory HL. Limited treatment options exist for patients who relapse following an autologous SCT. (12) Options include single-agent palliative chemotherapy or occasionally, localized radiation therapy. (104) When a further remission may be attained with conventional-dose chemotherapy, it is rarely durable, with a median overall survival of less than one year. (105)

Medically Necessary Indications 

Available evidence suggests that high-dose chemotherapy with allogeneic SCT is effective for primary refractory* or relapsed Hodgkin’s lymphoma in certain patients.

*Primary refractory HL is defined as disease regression of less than 50% after four to six cycles of anthracycline-containing chemotherapy, disease progression during induction therapy, or progression within 90 days after the completion of first-line treatment. (106)

• 1990 Technology Evaluation Center (TEC) assessment concluded data showed improved outcomes after allogeneic SCT for certain patients with relapsed disease. (108) For those who would not be candidates for autologous SCT due to chronic marrow hypocellularity or malignancy involving the marrow, allogeneic SCT may be beneficial. Sufficient data was available to calculate the three year survival rate of 19%. While this was somewhat less than survival reported after autologous SCT, several studies reported comparable outcomes for either allogeneic or autologous SCT and ten patients were reported as being alive with no evidence of disease after allogeneic SCT. There was substantial mortality directly due to toxicity of allogeneic SCT (about 25%) however, it was determined the benefit outweighed the risk. Survival of patients who died of transplant-related complications was somewhat shorter, but not significantly so.
• The most recent National Comprehensive Cancer Network guidelines state that allogeneic transplant is an option in select patients with progressive or relapsed disease. (103)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Based on the above assessments, reduced intensity conditioning (RIC) allogeneic SCT may be considered effective only for those who meet criteria for a myeloablative allogeneic SCT above, including eligibility on the basis of overall health status.

• An underlying premise of this policy is that RIC allogeneic SCT is one of many conditioning regimens that can be used for which the evidence supports that allogeneic SCT improves health outcomes. The role of RIC allogeneic transplant in other settings is uncertain and requires direct comparative trials with adequate follow-up to analyze its safety and effectiveness.

Investigational Indications

The available evidence is not sufficient to determine whether high-dose chemotherapy with allogeneic SCT is effective as an initial therapy, for consolidation of a first complete remission of HL, or as a treatment of HL relapsing after a prior autologous SCT.

• There are minimal data that compare outcomes of high-dose chemotherapy with allogeneic SCT with conventional therapies as a first-line treatment for HL. To date, most allogeneic SCTs have been performed in patients who have failed a previous autologous SCT for primary refractory or relapsed HL. (12)
• No randomized trial has compared autologous SCT to allogeneic SCT prospectively. (109)
• A 2000 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment found data were inadequate to permit conclusions on the effectiveness of high-dose chemotherapy with allogeneic SCT as a salvage therapy after a failed autologous SCT. (107) No published studies were identified that reported outcomes exclusively for patients with HD. Three published case series included only 12 patients. Available registry data did not report treatment-related mortality outcomes. Additionally, the limited data available did not suggest that high-dose chemotherapy with allogeneic SCT was superior as a salvage treatment.
• The most recent National Comprehensive Cancer Network guidelines recommend chemotherapy and/or radiation as both first and second-line therapies for HL. Autologous SCT is recommended as the best option for HL incurable after primary treatment.  They indicate allogeneic transplant is an option in select patients with progressive or relapsed disease. However, this is a category 3 recommendation (based on any level of evidence but reflects major disagreement). (103)

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. (13)

While myeloablative allogeneic SCT may be potentially curative for MM, due in part to a graft-versus-myeloma effect, high transplant-related mortality is a major limitation to wider use of this modality. Mortality may be decreased through the use of reduced intensity conditioning allogeneic regimens; however this comes at a cost of higher rates of disease progression and relapse. In addition, the risk of chronic graft-versus-host disease is still significant with reduced intensity conditioning and allogeneic SCT. (110)

Investigational Indications

Data are insufficient to determine whether allogeneic stem cell transplant (SCT) as a monotherapy (i.e. outside a tandem transplant) is effective, either as an initial treatment for MM or as treatment after a prior failed course of autologous SCT.

Allogeneic SCT as an initial therapy for MM

• No prospective, randomized studies directly compare the outcomes of allogeneic SCT alone with either conventional chemotherapy or autologous SCT.
• Indirect comparisons suggest that allogeneic SCT is associated with 39%–55% five-year survival. Comparable figures for autologous SCT are 36%–52%, and many conventional-dose regimens resulted in survival that was close to or within this range. However, treatment-related mortality after allogeneic SCT was 14-43% compared to 2-14% for autologous SCT and 0-12% for conventional dose SCT. (111, 112)
• Randomized trials are required to determine whether the above reported survival outcomes for allogeneic SCT are a true reflection of the treatment’s effectiveness or are due to patient selection bias. Candidates for allogeneic SCT tend to be younger than the average age of patients with multiple myeloma and are in better overall condition. They may have a better prognosis no matter what treatment they receive. (13)
• More recent evidence-based reviews summarize data comparing autologous SCT with allogeneic SCT for newly diagnosed or responsive multiple myeloma. (113, 114) Data summarized do not alter the conclusion that treatment-related toxicity after allogeneic SCT exceeds potential benefits from a graft-versus-myeloma effect with reported treatment-related mortality ranging from 16-20%. (113)
• Data from one retrospective case-matched analysis suggests outcomes of syngeneic (identical twin donor) allogeneic SCT are superior to those of autologous SCT. (117) Prospective studies are needed to confirm these encouraging results.
• The current American Society for Blood and Marrow Transplantation guideline concludes that autologous SCT is preferred over allogeneic SCT based on presently available evidence. (118)
• The National Comprehensive Cancer Network guidelines for multiple myeloma do not make a distinction between the myeloablative and non-myeloablative regimens and indicate that allogeneic SCT may be considered in a clinical trial. (45)

Allogeneic SCT after a prior failed autologous SCT

• A 2000 Technology Evaluation Center (TEC) assessment on allogeneic SCT after a prior failed course of autologous SCT concluded data were inadequate to permit conclusions about this modality. These results and more recently published outcomes are from small, nonrandomized studies which do not permit conclusions concerning this strategy since they lack control groups for comparison of outcomes. (113, 115, 116)
• The National Comprehensive Cancer Network guidelines for multiple myeloma support reduced intensity allogeneic SCT in a clinical trial setting or as a tandem transplant with autologous SCT. (45)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Note: See Regence Medical policy Transplant No. 44, Tandem Hemopoietic Stem Cell Transplant, for criteria concerning RIC allogeneic transplant as a tandem treatment for MM.

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT alone is effective as a treatment for Multiple myeloma.

• While mortality can be reduced through the use of RIC allogeneic regimens, this comes at a cost of higher rates of disease progression and relapse. Studies are ongoing in an attempt to improve overall outcomes of allogeneic SCT. In addition, the risk of chronic GVHD is significant with RIC-allo-SCT. (13)
• The National Comprehensive Cancer Network guidelines for multiple myeloma do not make a distinction between the myeloablative and non-myeloablative regimens and indicate that allogeneic SCT may be considered in a clinical trial. (45)

Myelodysplastic Syndrome (MDS) and Myeloproliferative Neoplasms (MPN)                                                                                      Return to Table

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal stem cell disorders characterized by impaired maturation of bone marrow stem cells and a tendency to transform into acute myeloid leukemia. (14)

The most widely accepted classification system for MDS is the French-American-British (FAB) system that identifies five types of MDS with increasing numbers of circulating blast cells as follows (14):

• Refractory anemia (RA),
• Refractory anemia with ringed sideroblasts (RARS),
• Refractory anemia with excess blasts (RAEB),
• Refractory anemia with excess blasts in transformation (RAEBT),
• Chronic myelomonocytic leukemia (CMML)

Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to acute myeloid leukemia (AML) than do other patients. Given the long natural history of MDS, allogeneic stem cell transplant (SCT) is typically considered in those with increasing numbers of blasts, signaling a possible transformation to acute myeloid leukemia. Subtypes falling into this category include RAEB, RAEBT, and CMML. Patients with RA and RARS may also be considered candidates for allogeneic SCT when chromosomal abnormalities are present or the disorder is associated with the development of significant decreases in blood cell counts. (e.g., neutrophils less 500/mm³, platelets less than 20,000/mm³). (14)

The myeloproliferative neoplasms are characterized by the slow but relentless growth of a particular clone of hematopoietic cells with the potential evolution into a blast crisis similar to acute myeloid leukemia.  Myeloproliferative disorders include the following (14):

• Polycythemia Vera (PV) - characterized by an expansion of the total red blood cell mass. Initial treatment focuses on phlebotomy to reduce red cell mass and viscosity. However, the disease inevitably progresses. After a medial survival of 15 years, patients typically succumb to thrombotic complications or leukemic evolution.
• Essential thrombocythemia (ET) - characterized by an isolated expansion of the megakaryocytic lineage (thrombocyte precursors). The median survival is 10 years with most deaths due to thrombotic complications.
• Agnogenic myeloid metaplasia (AMM) - also known as primary myelofibrosis or chronic idiopathic myelofibrosis is characterized by proliferation of abnormal bone marrow stem cells that replace bone marrow with fibrous connective tissue leading to fibrosis, splenomegaly, and extramedullary hematopoiesis. (14) The median survival is 3.5 to 5.5 years, but patients younger than 55 years have a median survival of 11 years. (121)

Patients with MPN may be considered candidates for allogeneic SCT when there is progression to myelofibrosis, or when there is evolution toward acute leukemia. In addition, allogeneic SCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. (14)

Medically Necessary Indications

Available evidence suggests that allogeneic SCT may be effective for the treatment of MDS and may improve health outcomes of selected patients when compared to conventional supportive treatments (e.g. transfusions, antibiotics, steroidal hormones, blood modifiers). The evidence also suggests that allogeneic SCT may be effective to treat MPN and may potentially be curative for a subset of agnogenic myeloid metaplasia patients.

• For MDS/AML patients treated with allogeneic SCT, the largest published study showed an overall survival of 45% at three years. Historically, such a population of patients treated by conventional means have an expected median overall survival of approximately one to two years with a three-year survival probability of 0-30%. (119)
• Data on therapy for MPN remain sparse and no therapy, other than allogeneic SCT, has yet been proven to be potentially curative or to prolong survival. (122-124) One review of a total of 29 patients with agnogenic myeloid metaplasia reported 16 patients were alive without evidence of relapsed disease between seven months and 15 years after transplant. (125)
• A 1998 review reported only nine patients with polycythemia vera (PV) had been treated with allogeneic SCT. (125) However, considering that PV represents an emerging malignant clone of cells, and given the success of allogeneic SCT in other hematopoietic disorders, it is reasonable to extrapolate the results of allogeneic SCT for myelodysplastic syndrome to PV.
• The 2009 National Comprehensive Cancer Network treatment guidelines for MDS suggest allogeneic SCT from an HLA-matched sibling donor is a preferred approach, in particular for those with high-risk disease. (120)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Available evidence suggests that reduced intensity allogeneic SCT may be effective for MDS and MPN for those  who are unable to tolerate a full myeloablative allogeneic SCT.

• Evidence from more than 30 largely heterogeneous uncontrolled studies of RIC with allogeneic SCT shows long-term remissions (i.e., longer than 4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS/AML who otherwise would not be candidates for myeloablative conditioning regimens. (153-156, 163-170)
• Conventional chemotherapy alone has been the standard of care for those who are unable to tolerate a myeloablative allogeneic SCT. While no randomized trials have been published in which RIC allogeneic SCT has been compared with conventional chemotherapy alone, given the absence of curative therapies for these patients and the accumulation of encouraging results noted above, RIC with allogeneic SCT may be considered an effective treatment for this group of patients.(14)
• The 2009 National Comprehensive Cancer Network treatment guidelines indicate allogeneic SCT is preferred in patients with high-risk disease and RIC conditioning regimens are becoming an option at some centers. The timing of SCT relative to remission induction using chemotherapy is unsettled. (14,120)

Neuroblastoma (peripheral)                                                    Return to Table

Neuroblastoma is the most common extracranial solid tumor of childhood. (126) 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. (15)

Patients with neuroblastoma are stratified into prognostic risk groups (low, intermediate, and high) that determine treatment plans. (128) Risk variables include age at diagnosis, clinical stage of disease as defined by the International Neuroblastoma Staging System (INSS), 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. (128) It is well established that MYCN amplification is associated with rapid tumor progression and a poor prognosis (129), 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.

See separate position statements for central nervous system primitive neuroectodermal tumors (PNETs) or Ewing’s sarcoma

Investigational Indications

There is insufficient evidence to determine whether high dose chemotherapy with allogeneic stem cell transplant is effective either as an initial treatment of low- to intermediate-risk patients or as a salvage therapy after a prior failed autologous stem cell transplant for the treatment of neuroblastoma.

• There are no randomized trials that address the use of allogeneic SCT either as an initial therapy or as a salvage therapy after a prior failed autologous SCT.
• In general, most patients with low-stage disease have excellent outcomes with minimal therapy. With INSS stage 1 disease, most patients can be treated by surgery alone. (126) Most infants, even with disseminated disease, have favorable outcomes with chemotherapy and surgery. (126)
• While myeloablative consolidation with autologous SCT has been shown to improve event-free survival in three randomized trials and one randomized trial showed improved overall survival, there are no randomized trials that compare allogeneic SCT with autologous SCT as a treatment of neuroblastoma. (130-132)
• There are no published treatment guidelines which address the use of high-dose chemotherapy with allogeneic SCT for the treatment of neuroblastoma.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for neuroblastoma.

• There are no randomized trials that address the use of RIC allogeneic SCT either as an initial therapy or as a salvage therapy for the treatment of neuroblastoma. Studies consist of small pilot trials which do not permit conclusions on the effectiveness of this procedure on health outcomes.
• There are no published treatment guidelines which address the use of RIC allogeneic 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. (133)

Indolent NHL has a relatively good prognosis with a median survival of ten years; however, it is not curable in advanced clinical stages. (133) 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. (16)

* Small lymphocytic lymphoma and chronic lymphocytic leukemia are addressed separately in this policy.  Add link here to separate policy statement

Aggressive NHL has a shorter natural history; however, 30%–60% of these patients can be cured with intensive combination chemotherapy regimens. (133) Aggressive lymphomas include diffuse large B-cell lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, and Burkitt’s lymphoma.

Medically Necessary Indications

Evidence suggests that allogeneic stem cell transplant (SCT), other than as an initial therapy, may be effective for the treatment of NHL.

• Treatment of intermediate or high-grade lymphomas with high-dose chemotherapy with allogeneic SCT is based on the success seen with autologous SCT, where the estimated three- to five-year survival is 40%-60%. Some patients are not candidates for autologous SCT due to chronic marrow cell depletion or malignancy involving the bone marrow. For these patients, allogeneic SCT provides an alternative. The data suggests that the three- to five-year survival rates associated with allogeneic SCT are comparable to those associated with autologous SCT. (134)
• A 1995 BlueCross BlueShield Association Technology Evaluation Center (TEC) assessment compared outcomes after high-dose chemotherapy supported by autologous or allogeneic SCT to outcomes after conventional dose regimens for follicular lymphomas. The disease-free survival at five years was 10%-66% after high-dose chemotherapy and only 2%-21% after conventional-dose alternatives when used as salvage therapy to treat low-grade follicular lymphoma that had failed primary therapy without transformation to a higher grade. Given the natural history of this indolent disease, which is one of repeated relapses and progressively shorter durations of remission, improvement in disease-free survival was considered a good predictor of improvement in overall survival. (135)
• The 2008 National Comprehensive Cancer Network guidelines for non-Hodgkin’s lymphoma recommend allogeneic SCT as a treatment for certain relapsed or refractory NHLs. (28)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

Available evidence suggests that reduced intensity allogeneic SCT may be effective for those  who may be unable to tolerate a full myeloablative allogeneic SCT.

• Several nonrandomized studies using RIC allogeneic SCT for mantle cell and peripheral T-cell lymphomas show encouraging long-term results with event-free survival rates ranging from 60 to 82% and overall survival rates of up to 60%. (171-174)
• RIC allogeneic SCT 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.(16)
• In patients who qualify for a myeloablative allogeneic hematopoietic SCT on the basis of overall health and disease status, allogeneic SCT using either myeloablative or RIC may be considered. However, a myeloablative conditioning regimen with allogeneic SCT may benefit younger patients with good performance status and minimal comorbidities more than allogeneic SCT with RIC.(16)
• The 2008 National Comprehensive Cancer Network recommendations for mantle cell lymphoma are for first-line consolidation with high dose chemotherapy (HDC) and autologous SCT, and second-line consolidation with HDC with RIC allogeneic or myeloablative SCT. (28)

Investigational Indications

Evidence does not demonstrate that high-dose chemotherapy with allogeneic stem cell transplant (SCT) is effective as initial therapy for NHL (i.e., without a full course of standard-dose induction chemotherapy).

• There are no randomized controlled trials that directly compare survival outcomes for high-dose chemotherapy and allogeneic SCT as an initial treatment of NHL to survival outcomes of alternate treatment strategies.
• There are no evidence-based clinical practice guidelines that recommend allogeneic SCT as initial therapy for NHL. The 2008 National Comprehensive Cancer Network guidelines for NHL suggest this treatment may possibly be used for induction therapy of Burkitt’s lymphoma, but only within the context of a clinical trial. (28)

Primitive Neuroectodermal Tumors (PNETs)                      Return to Table

Primitive Neuroectodermal Tumors (PNETs) arise from neuroepithelial cells and include medulloblastoma, neuroblastoma arising in the central nervous system, ependymoblastoma, or pinealoblastoma. All show similar histology and are distinguished by their site of origin, biologic behavior, and different genetic alterations. (136) Many studies include PNETs in general and do not make a distinction between the sites of origin. (136) The most common central nervous system (CNS) PNET is medulloblastoma, and thus, most studies focus on this diagnosis. (17)

Initial therapy of CNS PNETs focuses on neurosurgical resection, plus radiation therapy with or without adjuvant conventional-dose chemotherapy; 60% of children survive five years or more with this approach. In patients with residual tumor or recurrent disease, further surgery or radiation therapy usually is not an option, and conventional chemotherapy rarely is successful. The use of radiotherapy in children may be limited by its adverse neurodevelopmental effects. Studies of allogeneic SCT for CNS PNETs have focused primarily on residual or recurrent disease. (17)

Other CNS tumors include astrocytoma, oligodendroglioma, and glioblastoma multiforme. However, these tumors arise from glial cells and not neuroepithelial cells.  These CNS tumors are addressed in a separate policy, Transplant 42, Autologous Hematopoietic Stem Cell Transplant.

Due to their neuroepithelial origin, peripheral neuroblastoma and Ewing’s sarcoma may be considered PNETs. See separate policy statements concerning neuroblastoma (peripheral) and Ewing sarcoma.

Investigational Indications

Available evidence is not sufficient to determine if allogeneic stem cell transplant (SCT) is effective for the treatment of PNETs.

• Data are lacking concerning the effectiveness of high-dose chemotherapy with allogeneic stem cell transplant for PNET tumors. There are no published randomized controlled trials comparing the use allogeneic SCT to standard therapies.
• Other CNS PNETs (pinealoblastoma, ependymoblastoma, and central neuroblastoma) are uncommon. There are few data regarding allogeneic SCT for these rare tumors. (17)
• The National Comprehensive Cancer Network guidelines do not address allogeneic stem cell support for CNS PNETs. (137)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for primitive neuroectodermal tumors

• Data on the use of RIC allogeneic SCT to treat primitive neuroectodermal tumors are lacking, with no systematic evaluation of this treatment in clinical trials.
• There are no published evidence-based clinical practice guidelines that recommend RIC allogeneic SCT for the treatment of CNS PNETs.

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. (136) 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). 

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. (17) Given the poor response to conventional-dose chemotherapy, high dose chemotherapy with autologous stem cell transplant (SCT) has been investigated as a possible salvage therapy.

Investigational Indications

Available evidence is not sufficient to determine if allogeneic stem cell transplant (SCT) is effective for the treatment of ependymoma.

• There are no published randomized, controlled trials comparing allogeneic 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. (139, 140). For example, Mason and colleagues reported on a case series of 15 patients with recurrent ependymoma. (139) Similarly, Grill and colleagues reported a disappointing experience in 16 children. (140)
• There are no evidence-based clinical practice guidelines which recommend allogeneic SCT as a treatment option for primitive neuroectodermal tumors or ependymoma.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for Ependymoma.

• Data on the use of RIC allogeneic SCT to treat ependymoma are sparse, with no systematic evaluation of this treatment in a clinical trial.

Solid Tumors -Investigational Indications                             Return to table

Investigational

Available evidence does not demonstrate that high-dose chemotherapy with allogeneic stem cell transplant (SCT) is effective as a treatment of solid tumors, including but not limited to the following:

• Data on the use of allogeneic SCT for the treatment of solid tumors consists mainly of anecdotal reports and small case series. (141-144, 146)
• To date, no randomized controlled trials have been published for any of the above listed solid tumors comparing the effectiveness of allogeneic SCT to standard therapies. Without randomized trials, it is not known if allogeneic SCT results in improved overall or progression-free survival compared to standard therapies.
• A 1999 Technology Evaluation Center (TEC) Assessment evaluated the use of high-dose chemotherapy with allogeneic SCT as a salvage therapy after a failed prior course of high-dose chemotherapy and autologous SCT for solid tumors. (145) Data were inadequate to permit conclusions. A single case report was identified which used allogeneic SCT as a salvage treatment for solid tumors.
• One very small case series published after the TEC assessment demonstrated a graft-versus-tumor effect of allogeneic SCT in patients with metastatic renal cell carcinoma. (144) However, most other pilot trials for this indication have shown lower response rates with overall response rates around 25% and complete response rates of about 8%. (142). Prospective, randomized trials are needed to assess the net impact of this strategy on the survival of patients with renal cell carcinoma. (142)
• There are no evidence-based clinical practice guidelines that recommend high-dose chemotherapy and allogeneic SCT for the treatment of the solid tumors listed above.

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for the above solid tumors.

• Data on the use of RIC allogeneic SCT to treat solid tumors are sparse, with no systematic evaluation of these tumors in clinical trials.
• Results from small trials using RIC allogeneic SCT for renal cell carcinoma have been inconsistent. (175-176) Overall response rates have been about 25%, with complete response rates of about 8%. (175) Prospective, randomized trials are needed to assess the net impact of RIC allogeneic SCT on the survival of patients with cytokine-refractory RCC. (175)
• There are no evidence-based clinical practice guidelines that recommend RIC allogeneic SCT for the treatment of the solid tumors listed above.

Waldenstrom’s Macroglobulinemia (WM)                             Return to table

Investigational

There is insufficient data to determine whether allogeneic stem cell transplant (SCT) is effective as a treatment for Waldenström’s macroglobulinemia (WM).

• A consensus panel from the Second and Third International Workshops on WM recommended that allogeneic SCT should be used only in the context of a clinical trial. (147, 148) Another recent review also considered allogeneic SCT for WM to be investigational therapy. (148)
• A retrospective analysis of registry data conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) reported three-year overall survival rates of 46% (95% CI: 27–65%) for WM patients treated with allogeneic SCT (n=26). (150) Although the CIBMTR results appear favorable, it should be noted that patients in this report were heavily pretreated, highly heterogeneous in terms of disease characteristics and risk factors, and received a variety of conditioning regimens, including myeloablative and reduced intensity conditioning.
• Taken together, data are insufficient to form conclusions about the potential clinical efficacy of allogeneic stem cell transplantation for Waldenström’s macroglobulinemia. Subsequent review articles are in general agreement with this position. (151, 152)
• The current National Comprehensive Cancer Network clinical practice guidelines for multiple myeloma, which include guidelines for Waldenström’s macroglobulinemia, recommend stem cell transplantation (type not specified) as salvage therapy for WM only in a clinical trial. (45)

Reduced Intensity Conditioning (RIC) Allogeneic SCT

There is insufficient data to determine whether reduced intensity conditioning allogeneic SCT is effective as a treatment for Waldenstrom’s macroglobulinemia.

• Data on the use of RIC allogeneic SCT to treat Waldenstrom’s macroglobulinemia are sparse, with no systematic evaluation of this treatment in a clinical trial.
• There are no evidence-based clinical practice guidelines that recommend RIC allogeneic SCT for the treatment of Waldenstrom’s macroglobulinemia.

References

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Cross References

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

Tandem Hematopoietic Stem Cell Transplant, Regence Medical Policy, Transplant, Policy No. 44

Transplant Section Table of Contents