Hematopoietic Cell Transplantation

HCT is a procedure in which hematopoietic stem cells are intravenously infused to restore bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allogeneic HCT [allo-HCT]). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Cord blood transplantation is discussed in detail in a separate policy on 'Placental and Umbilical Cord Blood as a Source of Stem Cells' (Policy #012 in the Surgery Section).

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex expressed at the HLA-A, -B, and -DR (antigen-D related) loci on each arm of chromosome six. An acceptable donor will match the patient at all or most of the HLA loci.

Conditioning for HCT

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without total body irradiation at doses sufficient to cause bone marrow ablation in the recipient. The beneficial treatment effect of this procedure is due to a combination of the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients who are sufficiently medically fit to tolerate substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Subsequent to graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease, which increases susceptibility to opportunistic infections.

The success of autologous HCT is predicated on the potential of cytotoxic chemotherapy, with or without radiotherapy, to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with presumably normal hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. Therefore, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are also susceptible to chemotherapy-related toxicities and opportunistic infections before engraftment, but not GVH disease.

Reduced-Intensity Conditioning Allo-HCT

RIC refers to the pretransplant use of lower doses of cytotoxic drugs or less intense regimens of radiotherapy than are used in traditional full-dose myeloablative conditioning treatments. Although the definition of RIC is variable, with numerous versions employed, all regimens seek to balance the competing effects of relapse due to residual disease and non-relapse mortality. The goal of RIC is to reduce disease burden and to minimize associated treatment-related morbidity and non-relapse mortality in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops. RIC regimens range from nearly total myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative.

HCT in Solid Tumors in Adults

HCT is an established treatment for certain hematologic malignancies. Its use in solid tumors is less well established, although it has been investigated for a variety of solid tumors. With the advent of nonmyeloablative allogeneic transplant, interest has shifted to exploring the generation of alloreactivity to metastatic solid tumors via a graft-versus-tumor effect of donor-derived T cells.^1,

HCT as a treatment for ovarian cancer, germ cell tumors, ependymoma, or malignant glioma is addressed separate medical policies. HCT as a treatment for breast cancer is not addressed. This policy collectively addresses other solid tumors of adults for which HCT has been investigated, including lung cancer, malignant melanoma, tumors of the gastrointestinal tract (affecting the colon, rectum, pancreas, stomach, esophagus, gallbladder, or bile duct), male and female genitourinary systems (eg, renal cell carcinoma, prostate cancer, cervical cancer, uterine cancer, fallopian tube cancer), tumors of the head and neck, soft tissue sarcoma, thyroid tumors, tumors of the thymus, and tumors of unknown primary origin.

Regulatory Status

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under Code of Federal Regulation, Title 21, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

Related Policies

• Placental and Umbilical Cord Blood as a Source of Stem Cells (Policy #012 in the Surgery Section)
• Hematopoietic Cell Transplantation for Epithelial Ovarian Cancer (Policy #042 in the Treatment Section)
• Hematopoietic Cell Transplantation for Central Nervous System Embryonal Tumors and Ependymoma (Policy #044 in the Treatment Section)
• Hematopoietic Cell Transplantation for Solid Tumors of Childhood (Policy #047 in the Treatment Section)
• Hematopoietic Cell Transplantation in the Treatment of Germ Cell Tumors (Policy #045 in the Treatment Section)

A. The law only applies to autologous bone marrow or peripheral stem cell transplant for the treatment of cancer. Medical necessity criteria must NOT be applied to these cases. They are automatically eligible for coverage under the law.

[INFORMATIONAL NOTE: Please note that self-insured accounts are exempt from the law. However, they have the option to adopt the law.

Policy Statement II of this policy deals with eligibility and medical necessity criteria which must be applied specifically to those self-insured accounts that opted NOT to adopt the law.]

B. In cases of multiple, repeat, or tandem autologous bone marrow or peripheral stem cell transplant procedures for the same member, the first or initial transplant is automatically covered under the law. However, subsequent transplant procedures are NOT automatically covered under the law but are subject to medical necessity criteria.

C. The law applies to contracts delivered, issued, executed or renewed in New Jersey. Services rendered outside New Jersey are covered by the law as long as the member has a contract that is written or issued in New Jersey and permits coverage for non-emergency services out-of-network.

D. Exclusions to the law:
Policy Statement II of this policy addresses medical necessity criteria as it applies to the following requests for:
• an allogeneic bone marrow or peripheral stem cell transplant.
• treatment of non-cancerous conditions even if it involves autologous bone marrow or peripheral stem cell transplant.
• mini-transplants or non-myeloablative transplants since they are allogeneic transplants.

A. This procedure is subject to the specific terms of the member's contract.
[Also refer to a separate policy on Transplant Donor and Recipient Policy (Policy #003) under the Surgery Section.]

B. Medical necessity is established based on review of the following information:
1. Stage to which the malignancy has progressed;
2. Clinical history of the member including results of diagnostic procedures performed (i.e., laboratory, pathology, radiology), and previous modes of therapy with results;
3. Treatment protocol of the facility where the procedure is being performed.

C. [INFORMATIONAL NOTE: Please note that there are separate policies which address other solid tumors (e.g., Breast Cancer, Epithelial Ovarian Cancer, Malignant Astrocytoma and Gliomas, Primitive Neuroectodermal Tumors and Ependymoma, Germ Cell Tumors, Solid Tumors of Childhood).]

Autologous or allogeneic hematopoietic cell transplant is considered investigational for the following malignancies in adults:
• Lung cancer, any histology
• Colon cancer
• Rectal cancer
• Pancreas cancer
• Stomach cancer
• Esophageal cancer
• Gallbladder cancer
• Cancer of the bile duct
• Renal cell cancer
• Cervical cancer
• Uterine cancer
• Cancer of the fallopian tubes
• Prostate cancer
• Nasopharyngeal cancer
• Paranasal sinus cancer
• Neuroendocrine tumors
• Soft tissue sarcomas
• Thyroid tumors
• Tumors of the thymus
• Tumors of unknown primary origin
• Malignant melanoma

Before making a determination that this procedure is investigational, please refer to Policy Statement I of this policy for the applicability of the New Jersey State Law on High Dose Chemotherapy (HDC) and Autologous Bone Marrow Transplant (BMT) or Peripheral Stem Cell Transplant (PSCT).

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2001 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 11, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, two domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

This policy was initially based on a 1995 TEC Assessment that focused on adult solid tumors other than breast cancer, epithelial ovarian cancer, germ cell tumors, and glial cell-derived brain cancers.^2, Literature on solid tumors identified in the Assessment included lung cancers, melanoma, tumors of gastrointestinal organs, genitourinary system tumors, tumors of the head and neck, soft tissue sarcomas of the extremities and torso, thyroid tumors, tumors of the thymus, undifferentiated tumors, and tumors of unknown primary. The Assessment offered the following conclusions:

• While 125 articles were identified that reported on the results of autologous hematopoietic cell transplantation (HCT) in a variety of solid tumors, only 17 included survival data from groups of patients with the same cancer. These studies reported on four indications: advanced small cell lung cancer (SCLC), advanced colorectal cancer (CRC), malignant melanomas, and inoperable gastric cancer.
• The evidence did not permit conclusions on the effect of autologous HCT on patient survival.

Autologous HCT in Solid Tumors

The evidence on the use of autologous HCT for the solid tumors of adults addressed in this policy consists primarily of small series.

Adult Soft Tissue Sarcomas

Clinical Context and Therapy Purpose

The purpose of autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with adult soft tissue sarcomas.

The question addressed in this policy is: Does HCT improve the net health outcome for adults with adult soft tissue sarcomas?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with adult soft tissue sarcomas.

Interventions

The therapy being considered is autologous HCT. Autologous HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators of interest include the standard of care.

Outcomes

The general outcomes of interest are overall survival (OS), disease-specific survival (DSS), treatment-related mortality (TRM), and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.
d. Studies with duplicative or overlapping populations were excluded.

In 2017, a Cochrane systematic review evaluated the use of autologous HCT following high-dose chemotherapy (HDC) for nonrhabdomyosarcoma soft tissue sarcomas.^8,One RCT (2012) assessing 83 patients was identified.⁹ In the RCT, OS did not differ statistically between autologous HCT following HDC and standard-dose chemotherapy (hazard ratio, 1.26; 95% confidence interval [CI], 0.70 to 2.29; p=0.44), and the point estimate for survival at 3 years was 32.7% compared with 49.4%. Peinemann and Labeit (2014) conducted another systematic review that included an RCT (described above) and 61 single-arm studies.^9, The pooled TRM rate across 61 single-arm studies was 15 (5.1%) of 294.

A small number of studies not included in the Cochrane review have described outcomes after HCT for soft tissue sarcoma. Kasper et al (2010) reported the results of a prospective, single-institution phase 2 study that enrolled 34 patients with advanced and/or metastatic soft tissue sarcoma.^10, After four courses of chemotherapy, nine patients with at least a partial response underwent HDC and autologous HCT. All other patients continued chemotherapy for two more cycles. Median PFS for patients treated with HCT was 11.6 months (range, 8-15 months) and 5.6 months for patients treated with standard chemotherapy (p=0.047); median OS for the 2 groups was 23.7 months (range, 12-34 months) and 10.8 months (range 0-39 months; p=0.027), respectively.

Hartmann et al (2013) reported on results from a phase 2 study of HDC with ifosfamide, carboplatin, and etoposide followed by peripheral blood stem cell transplantation in patients with grade 2 or 3 histologically proven soft tissue sarcoma considered unresectable or marginally resectable.^11, After a median follow-up of 50 months (range, 26-120 months) in surviving patients, median PFS for all patients was 21 months (range, 1-94 months) and median OS was 37 months (range, 3-120 months), corresponding to 5-year PFS and OS rates of 39% and 48%, respectively.

A 2014 case report on the use of autologous HCT for treatment of an adult histiocytic sarcoma was identified, in which the patient was alive with no evidence of disease 30 months posttreatment.^12,

Section Summary: Adult Soft Tissue Sarcomas

Overall, one RCT and several, small phase 2 studies have reported outcomes after autologous HCT in adults with soft tissue sarcoma. Although one small phase 2 study reported longer survival for patients treated with HCT than with standard chemotherapy, the available RCT did not show a survival benefit with autologous HCT.

Small Cell Lung Cancer

Clinical Context and Therapy Purpose

The purpose of autologous HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with SCLC.

The question addressed in this policy is: Does HCT improve the net health outcome for patients with SCLC?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with SCLC.

Interventions

The therapy being considered is autologous HCT. Autologous HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, TRM, and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described above.

The interest in treating SCLC with autologous HCT stems from the extremely high chemosensitivity and poor prognosis of this tumor type. A phase 3 trial (2005) randomized 318 patients with SCLC to standard chemotherapy or to HCT.^13, No statistically significant difference in response rates was seen between the 2 groups (response rate, 80% in standard arm group vs 88% in HCT group; difference, 8%; 95% CI, -1% to 17%; p=0.09). There was no statistically significant difference in OS between groups, with a median OS of 13.9 months in the standard arm (95% CI, 12.1 to 15.7 months) and 14.4 months in the HCT arm (95% CI, 13.1 to 15.4 months; p=0.76). One smaller, randomized study and several single-arm studies of HCT and autologous HCT for SCLC are summarized in a 2007 review article.^14, Overall, most of the data from these studies, including the randomized study, showed no increase in OS with autologous HCT.

Jiang et al (2009) performed a meta-analysis of English-language studies through October 2008 using intensified chemotherapy with autologous hematopoietic progenitors to treat SCLC.^15, The meta-analysis consisted of 5 RCTs (3 phase 3 trials, 2 phase 2), with a total of 641 patients. Reviewers found no significant increase in the odds ratio for response rate with autologous transplant vs control chemotherapy (odds ratio, 1.29; 95% CI, 0.87 to 1.93; p=0.206). No statistically significant increase in OS was seen among the autologous transplant patients compared with control regimens (hazard ratio =0.94; 95% CI, 0.80 to 1.10; p=0.432). Reviewers concluded that current evidence did not support the use of intensified chemotherapy and autologous HCT for treating SCLC.

Section Summary: SCLC

Treatment of SCLC with autologous HCT has been studied in a meta-analysis, RCTs, and small series. None of these studies showed a survival benefit with autologous HCT.

Other Tumors

Uncontrolled pilot studies of autologous HCT for patients with refractory urothelial carcinoma^16, and recurrent or advanced nasopharyngeal carcinoma^17, has not demonstrated adequate evidence of improved outcomes to alter previous conclusions. In a 2014 small series (n=8) of bilateral retinoblastoma survivors with secondary osteosarcoma, 2 patients (of 7 treated with multimodal chemotherapy) received HDC with autologous peripheral blood stem cell support.^18, The 2 HCT-treated patients were alive with no evidence of disease at 33.4 and 56.4 months of follow-up.

Allogeneic HCT in Solid Tumors

The evidence base for the treatment of patients with types of solid tumors using allo-HCT consists of single-case reports and small series.^1,19,20,

Renal Cell Carcinoma

Clinical Context and Therapy Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with RCC.

The question addressed in this policy is: Does allo-HCT improve the net health outcome for patients with RCC?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with RCC.

Interventions

The therapy being considered is allo-HCT. Allo-HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, TRM, and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described above.

Metastatic RCC has an extremely poor prognosis, with a median survival of less than one year and five-year survival of less than 5%.^21, RCC is relatively resistant to chemotherapy but is susceptible to immune therapy, and interleukin-2 and/or interferon-α have induced responses and long-term PFS rates of in 4% to 15% of patients.^20,In addition, seven targeted therapies are approved by the U.S. Food and Drug Administration for the treatment of advanced RCC: sunitinib, sorafenib, pazopanib, axitinib, temsirolimus, everolimus, and bevacizumab.^5, Based on the susceptibility of RCC to immune therapies, the immune-based strategy of a graft-versus-tumor effect possible with an allogeneic transplant has led to an interest in its use in RCC. Childs et al (2000) published on the first series of patients with RCC treated with nonmyeloablative allo-HCT.^21, The investigators showed tumor regression in 10 (53%) of 19 patients with cytokine-refractory, metastatic RCC who received a human leukocyte antigen-identical sibling allo-HCT. Three patients had a CR and remained in remission 16, 25, and 27 months after transplant. Four of 7 patients with a partial response were alive without disease progression 9 to 19 months after transplantation. Other pilot trials have demonstrated the graft-versus-tumor effect of allo-HCT in metastatic RCC, but most have not shown as high a response rate as the Childs et al (2000) study. ORRs in these pilot trials have been approximately 25%, with CR rates of approximately 8%.^19, Prospective, randomized trials are needed to assess the net impact of this technique on the survival of patients with cytokine-refractory RCC.^19,

Bregni et al (2009) assessed the long-term benefit of allografting in 25 patients with cytokine-refractory metastatic RCC who received reduced-intensity conditioning (RIC) with allo-HCT from a sibling who was human leukocyte antigen-identical.^22, All patients received the same conditioning regimens. Response to allograft was available in 24 patients, with a CR in 1 patient and partial response in 4 patients. Twelve patients had a minor response or stable disease, and seven had progressive disease. The ORR (complete plus partial) was 20%. Six patients died because of transplant-related mortality. Median survival was 336 days (range, 12-2332+ days). The 1-year OS rate was 48% (95% CI, 28% to 68%) and the 5-year OS rate was 20% (95% CI, 4% to 36%). The authors concluded that allografting can induce long-term disease control in a small fraction of cytokine-resistant patients with RCC but that with the availability of novel targeted therapies for RCC, future treatment strategies should consider incorporating these therapies into the transplant regimen.

Section Summary: Allo-HCT in RCC

Evidence on the use of allo-HCT for RCC is based on a TEC Assessment and multiple case series. TEC Assessments found that HCTs did not meet the criteria for the treatment of RCC or other solid tumors. In the absence of RCTs, current evidence is insufficient to conclude whether allo-HCT results in improved OS among RCC patients.

Colorectal Cancer

Clinical Context and Therapy Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with CRC.

The question addressed in this policy is: Does allo-HCT improve the net health outcome for patients with CRC?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with CRC.

Interventions

The therapy being considered is allo-HCT. Allo-HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, TRM, and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described above.

Aglietta et al (2009) reported on their experience with 39 patients with metastatic CRC who underwent RIC allo-HCT between 1999 and 2004 at 9 European Group for Blood and Marrow Transplantation centers.^23, Patients were treated with one of five RIC regimens. Endpoints assessed were an achievement of mixed chimerism, the incidence of graft-versus-host disease, TRM, and toxicities, OS, and time to treatment failure (in patients who responded to the therapy). Patient population characteristics were heterogeneous; pretransplant disease status was a partial response in 2 patients, stable disease in 6 patients, and progressive disease in 31. Thirty-eight (97%) patients had previous treatment, some with only chemotherapy and others with surgery, chemotherapy, or both. After the transplant, tumor responses were complete and partial in 2% and 18% of patients, respectively, and 26% of patients had stable disease, for overall disease control in 46% of patients. Transplant-related mortality was 10%. Median overall follow-up was 202 days (range, 6-1020 days), after which time 33 patients had died and 6 were still alive. Tumor progression was the cause of death in 74% of patients. An assessment of the OS of patients was performed after stratifying by potential prognostic factors. Achievement of response after transplantation was associated with a difference in OS, with the 18 patients who had a response having a median OS of approximately 400 days vs approximately 120 days for those who had no response (p<0.001). The authors concluded the allo-HCT approach should be reserved for patients with a partial response or stable disease after second-line therapy for metastatic CRC and that second-generation clinical trials in these patients would be warranted.

Section Summary: Allo-HCT in CRC

Evidence on the use of allo-HCT for CRC is based on a TEC Assessment and a case series. The TEC Assessment concluded that allo-HCT did not meet the criteria for the treatment of solid tumors. In the absence of RCTs, current evidence is insufficient to conclude whether allo-HCT improves OS among CRC patients.

Pancreatic Cancer

Clinical Context and Therapy Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with pancreatic cancer.

The question addressed in this policy is: Does allo-HCT improve the net health outcome for patients with pancreatic cancer?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with pancreatic cancer.

Interventions

The therapy being considered is allo-HCT. Allo-HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, TRM, and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described above.

Kanda et al (2008) reported on the efficacy of RIC allo-HCT for advanced pancreatic cancer in 22 patients from 3 transplantation centers in Japan.^24, RIC regimens differed across centers, and the patient population was fairly heterogeneous, with 15 patients having metastatic disease and 7 having locally advanced disease. All but one patient received chemotherapy of various combinations before a transplant, and ten patients received localized radiotherapy. After allo-HCT, 1 patient achieved CR, 2 had a partial response, 2 had a minor response, and 8 had stable disease, with an ORR of 23%. Median survival was 139 days, and the major cause of death was tumor progression (median duration of survival in advanced pancreatic cancer in the nontransplant setting is less than 6 months, even in patients treated with gemcitabine). Only one patient survived longer than one year after transplantation. The authors concluded that tumor response was observed in 25% of patients with advanced pancreatic cancer who underwent allo-HCT and that the response was not durable. However, based on their observation of a relationship between longer survival and the infusion of a higher number of CD34-positive cells or the development of chronic graft-versus-host disease, they recommended additional study to evaluate the immunologic effect on pancreatic cancer.

Abe et al (2009) reported on outcomes for 5 patients with chemotherapy-resistant, unresectable pancreatic adenocarcinoma who received nonmyeloablative conditioning with allo-HCT.^25, Median age was 54 years (range, 44-62 years). All patients had advanced disease, either with metastases or peritonitis, and had received at least one course of chemotherapy including gemcitabine. After allo-HCT, tumor response was only observed in 2 patients¾one had complete disappearance of the primary tumor and the other had a 20% reduction in tumor size; the remaining patients had progressive disease (n=2) or stable disease (n=1). Four patients died of progressive disease (median, 96 days; range, 28-209 days posttransplant). One patient died at day 57 secondary to rupture of the common bile duct from rapid tumor regression. The authors concluded that findings showed a graft-versus-tumor effect, but to obtain durable responses, an improved conditioning regimen and new strategies to control tumor growth after nonmyeloablative allo-HCT would be needed.

Omazic et al (2017) reported on outcomes for 2 patients who received allo-HCT from human leukocyte antigen-identical sibling donors following resection of pancreatic ductal adenocarcinoma.^26, These patients were compared with six controls who underwent radical surgery for pancreatic ductal adenocarcinoma but did not receive HCT. Both patients receiving HCT were tumor-free after nine years following diagnosis, whereas all the patients in the control group died within four years of diagnosis.

Section Summary: Allo-HCT in Pancreatic Cancer

Evidence on the use of allo-HCT for pancreatic cancer is based on a TEC Assessment, multiple case series, and a small comparative study. The TEC Assessment concluded that allo-HCT did not meet the criteria for the treatment of solid tumors. In the absence of RCTs, current evidence is insufficient to conclude whether allo-HCT improves OS among pancreatic cancer patients.

Nasopharyngeal Cancer

Clinical Context and Therapy Purpose

The purpose of allo-HCT is to provide a treatment option that is an alternative to or an improvement on existing therapies in patients with nasopharyngeal cancer.

The question addressed in this policy is: Does allo-HCT improve the net health outcome for patients with nasopharyngeal cancer?

The following PICOs were used to select literature to inform this review.

Patients

The relevant population of interest are individuals with nasopharyngeal cancer.

Interventions

The therapy being considered is allo-HCT. Allo-HCT is provided by oncologists and transplant specialists in a tertiary care setting.

Comparators

Comparators of interest include standard of care.

Outcomes

The general outcomes of interest are OS, DSS, TRM, and treatment-related morbidity.

Follow-up over months to years is of interest to monitor relevant outcomes.

Study Selection Criteria

Methodologically credible studies were selected using the principles described above.

Toh et al (2011) reported on outcomes of a phase 2 trial of 21 patients with pretreated metastatic nasopharyngeal cancer.^27, Median patient age was 48 years (range, 34-57 years), and patients had received a median of 2 previous chemotherapy regimens (range, 1-8 regimens). All patients had extensive metastases. Patients underwent a nonmyeloablative allo-HCT with sibling allografts. Seven (33%) patients showed a partial response and 3 (14%) achieved stable disease. Four patients were alive at 2 years, and 3 showed prolonged disease control of 344, 525, and 550 days. After a median follow-up of 209 days (range, 4-1147 days), the median PFS was 100 days (95% CI, 66 to 128 days) and the median OS was 209 days (95% CI, 128 to 236 days). One- and 2-year OS rates were 29% and 19%, respectively, comparable to the median 7- to 14-month OS rates reported in the literature for metastatic nasopharyngeal patients treated with salvage chemotherapy without HCT.

Section Summary: Allo-HCT in Nasopharyngeal Cancer

Evidence on the use of allo-HCT for nasopharyngeal cancer is based on a TEC Assessment and a phase 2 trial. The TEC Assessment concluded that allo-HCT did not meet the criteria for the treatment of solid tumors. In the absence of RCTs, current evidence is insufficient to conclude whether allo-HCT improves OS among nasopharyngeal cancer patients.

Mixed Tumor Types

Omazic et al (2016) reported on long-term follow-up for 61 patients with a variety of solid tumor types considered incurable with conventional therapies who were treated with allo-HCT from 1999 to 2012.^28, Tumors included metastatic renal carcinoma (n=22), cholangiocarcinoma (n=17), colon cancer (n=15), prostate cancer (n=3), pancreatic adenocarcinoma (n=3), and breast cancer (n=1). Most patients (n=59) had undergone surgical debulking of the primary tumor, and 31 patients had previously undergone additional therapy with cytotoxic chemotherapy, radiotherapy, or immunotherapy. Conditioning was myeloablative in 23 patients, reduced-intensity in 36 patients, and nonmyeloablative in 2 patients. Over a median follow-up of 8 years, OS rates at 5 and 10 years were 15% and 9%, respectively.

Summary of Evidence

Autologous HCT

For individuals who have adult soft tissue sarcomas who receive autologous HCT, the evidence includes two TEC Assessments, a randomized controlled trial, and a number of phase 2 single-arm studies, some of which have been summarized in a systematic review. The relevant outcomes are overall survival (OS), disease-specific survival, and treatment-related mortality and morbidity. The 1995 and 1999 TEC Assessments, focusing on autologous HCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of HCT on patient survival. Although a small phase 2 randomized controlled trial reported longer survival for patients treated with autologous HCT than with standard chemotherapy, this trial did not show a survival benefit with HCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have small cell lung cancer who receive autologous HCT, the evidence includes two TEC Assessments, several randomized controlled trials, and systematic reviews of these studies. The relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. The 1995 and 1999 TEC Assessments, focusing on autologous HCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of HCT on patient survival. Studies published since the TEC Assessments have not reported increased OS for patients with small cell lung cancer treated with autologous HCT. The evidence is insufficient to determine the effects of the technology on health outcomes.

Allo-HCT

For individuals who have renal cell carcinoma, colorectal cancer, pancreatic cancer, or nasopharyngeal cancer who receive allo-HCT, the evidence includes a TEC Assessment and small single-arm series. The relevant outcomes are OS, disease-specific survival, and treatment-related mortality and morbidity. The 1995 and 1999 TEC Assessments, focusing on allo-HCT as primary and salvage therapy for a variety of solid tumors, found that the available evidence did not permit conclusions about the effect of allo-HCT on patient survival. Since the publication of the TEC Assessments, the evidence for allo-HCT to treat renal cell carcinoma, colorectal cancer, pancreatic cancer, and nasopharyngeal cancer has been limited to small case series. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines (2019) on the tumors addressed in this policy do not discuss hematopoietic cell transplantation (HCT) as a treatment option.^29,

American Society for Blood and Marrow Transplantation

The American Society for Blood and Marrow Transplantation (2015) issued guidelines related to indications for autologous and allogeneic HCT.^30, The tumors addressed herein for which the Society has provided recommendations are listed in Table 1.

Table 1. Recommendations for Use of Autologous and Allogeneic HCT

Condition	Treatment Option	Recommendation
Ewing sarcoma, high-risk	Allogeneic HCT	Not generally recommended
	Autologous HCT	Standard of care, clinical evidence available
Renal cancer, metastatic	Allogeneic HCT	Developmental
	Autologous HCT	Not generally recommended

HCT: hematopoietic cell transplantation.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 2.

Table 2. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT03236883	Phase I Study of Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Pancreatic Cancer	30	Apr 2019 (Last update posted 08/02/17)

NCT: national clinical trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Hematopoietic Cell Transplantation for Miscellaneous Solid Tumors in Adults
Hematopoietic Stem Cell Transplantation for Miscellaneous Solid Tumors in Adults
High Dose Chemotherapy with Hematopoietic Stem Cell Support for Miscellaneous Solid Tumors in Adults
Allogeneic Bone Marrow Transplant, Miscellaneous Solid Tumors in Adults
Autologous Bone Marrow Transplant, Miscellaneous Solid Tumors in Adults
Bile Duct Cancer, High Dose Chemotherapy
Bone Marrow Transplant, Miscellaneous Solid Tumors in Adults
Cervical Cancer, High Dose Chemotherapy
Colon Cancer, High Dose Chemotherapy
Esophageal Cancer, High Dose Chemotherapy
Fallopian Tube Cancer, High Dose Chemotherapy
Gallbladder Cancer, High Dose Chemotherapy
Head and Neck Tumors, High Dose Chemotherapy
Lung Cancer, High Dose Chemotherapy
Malignant Melanoma, High Dose Chemotherapy
Nasopharyngeal Cancer, High Dose Chemotherapy
Neuroendocrine Tumors, High Dose Chemotherapy
Pancreatic Cancer, High Dose Chemotherapy
Paranasal Sinus Cancer, High Dose Chemotherapy
Prostate Cancer, High Dose Chemotherapy
Rectal Cancer, High Dose Chemotherapy
Renal Cell Cancer, High Dose Chemotherapy
Small Cell Lung Cancer, High Dose Chemotherapy
Soft Tissue Sarcomas, High Dose Chemotherapy
Stem Cell Transplant, Miscellaneous Solid Tumors in Adults
Stomach Cancer, High Dose Chemotherapy
Thymus Tumors, High Dose Chemotherapy
Thyroid Tumors, High Dose Chemotherapy
Transplantation, Bone Marrow/Stem Cell for Miscellaneous Solid Tumors in Adults
Tumors of Unknown Primary Origin, High Dose Chemotherapy
Uterine Cancer, High Dose Chemotherapy

References:
1. Carnevale-Schianca F, Ricchiardi A, Capaldi A, et al. Allogeneic hemopoietic stem cell transplantation in solid tumors. Transplant Proc. Jul-Aug 2005;37(6):2664-2666. PMID 16182778

2. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). High-Dose Chemotherapy with Autologous Stem-Cell Support for Miscellaneous Solid Tumors In Adults. TEC Assessments. 1995;10:Tab 4.

3. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Salvage High-Dose Chemotherapy with Allogeneic Stem Cell Support for Relapse Following High-Dose Chemotherapy with Autologous Stem Cell Support for Non-lymphoid Solid Tumors. TEC Assessments. 1999;14:Tab 11.

4. Pedrazzoli P, Ledermann JA, Lotz JP, et al. High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults. Ann Oncol. Oct 2006;17(10):1479-1488. PMID 16547069

5. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: kidney cancer. Version 2.2018. http://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed November 11, 2019.

6. Kasper B, Dietrich S, Mechtersheimer G, et al. Large institutional experience with dose-intensive chemotherapy and stem cell support in the management of sarcoma patients. Oncology. Mar 2007;73(1-2):58-64. PMID 18334832

7. Schlemmer M, Wendtner CM, Falk M, et al. Efficacy of consolidation high-dose chemotherapy with ifosfamide, carboplatin and etoposide (HD-ICE) followed by autologous peripheral blood stem cell rescue in chemosensitive patients with metastatic soft tissue sarcomas. Oncology. Mar 2006;71(1-2):32-39. PMID 17344669

8. Peinemann F, Enk H, Smith LA. Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for nonrhabdomyosarcoma soft tissue sarcomas. Cochrane Database Syst Rev. Apr 13 2017;4:CD008216. PMID 28407197

9. Peinemann F, Labeit AM. Autologous haematopoietic stem cell transplantation following high-dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas: a Cochrane systematic review. BMJ Open. Jul 29 2014;4(7):e005033. PMID 25079925

10. Kasper B, Scharrenbroich I, Schmitt T, et al. Consolidation with high-dose chemotherapy and stem cell support for responding patients with metastatic soft tissue sarcomas: prospective, single-institutional phase II study. Bone Marrow Transplant. Jul 2010;45(7):1234-1238. PMID 19935728

11. Hartmann JT, Horger M, Kluba T, et al. A non-comparative phase II study of dose-intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult-type soft tissue sarcomas. Invest New Drugs. Dec 2013;31(6):1592-1601. PMID 24091981

12. Tsujimura H, Miyaki T, Yamada S, et al. Successful treatment of histiocytic sarcoma with induction chemotherapy consisting of dose-escalated CHOP plus etoposide and upfront consolidation auto-transplantation. Int J Hematol. Nov 2014;100(5):507-510. PMID 25062797

13. Lorigan P, Woll PJ, O'Brien ME, et al. Randomized phase III trial of dose-dense chemotherapy supported by whole-blood hematopoietic progenitors in better-prognosis small-cell lung cancer. J Natl Cancer Inst. May 4 2005;97(9):666-674. PMID 15870437

14. Crivellari G, Monfardini S, Stragliotto S, et al. Increasing chemotherapy in small-cell lung cancer: from dose intensity and density to megadoses. Oncologist. Jan 2007;12(1):79-89. PMID 17227903

15. Jiang J, Shi HZ, Deng JM, et al. Efficacy of intensified chemotherapy with hematopoietic progenitors in small-cell lung cancer: A meta-analysis of the published literature. Lung Cancer. Aug 2009;65(2):214-218. PMID 19118919

16. Nishimura M, Nasu K, Ohta H, et al. High dose chemotherapy for refractory urothelial carcinoma supported by peripheral blood stem cell transplantation. Cancer. Nov 1 1999;86(9):1827-1831. PMID 10547557

17. Airoldi M, De Crescenzo A, Pedani F, et al. Feasibility and long-term results of autologous PBSC transplantation in recurrent undifferentiated nasopharyngeal carcinoma. Head Neck. Sep 2001;23(9):799-803. PMID 11505492

18. Lee JA, Choi SY, Kang HJ, et al. Treatment outcome of osteosarcoma after bilateral retinoblastoma: a retrospective study of eight cases. Br J Ophthalmol. Oct 2014;98(10):1355-1359. PMID 24795337

19. Imanguli MM, Childs RW. Hematopoietic stem cell transplantation for solid tumors. Update Cancer Ther. 2006;1(3):343-352.

20. Demirer T, Barkholt L, Blaise D, et al. Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors. Nat Clin Pract Oncol. May 2008;5(5):256-267. PMID 18398414

21. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. Sep 14 2000;343(11):750-758. PMID 10984562

22. Bregni M, Bernardi M, Servida P, et al. Long-term follow-up of metastatic renal cancer patients undergoing reduced-intensity allografting. Bone Marrow Transplant. Aug 2009;44(4):237-242. PMID 19234510

23. Aglietta M, Barkholt L, Schianca FC, et al. Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adoptive cell therapy approach. The European Group for Blood and Marrow Transplantation Experience. Biol Blood Marrow Transplant. Mar 2009;15(3):326-335. PMID 19203723

24. Kanda Y, Omuro Y, Baba E, et al. Allo-SCT using reduced-intensity conditioning against advanced pancreatic cancer: a Japanese survey. Bone Marrow Transplant. Jul 2008;42(2):99-103. PMID 18391987

25. Abe Y, Ito T, Baba E, et al. Nonmyeloablative allogeneic hematopoietic stem cell transplantation as immunotherapy for pancreatic cancer. Pancreas. Oct 2009;38(7):815-819. PMID 19696692

26. Omazic B, Ayoglu B, Lohr M, et al. A preliminary report: radical surgery and stem cell transplantation for the treatment of patients with pancreatic cancer. J Immunother. Mar 23 2017. PMID 28338506

27. Toh HC, Chia WK, Sun L, et al. Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation. Bone Marrow Transplant. Apr 2011;46(4):573-579. PMID 20661236

28. Omazic B, Remberger M, Barkholt L, et al. Long-term follow-up of allogeneic hematopoietic stem cell transplantation for solid cancer. Biol Blood Marrow Transplant. Apr 2016;22(4):676-681. PMID 26740375

29. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 27, 2019.

30. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015;21(11):1863-1869. PMID 26256941

31. Centers for Medicare & Medicaid Services. National Coverage Determination (NCD) for STEM CELL Transplantation (110.8.1). 2010; https://www.cms.gov/medicare-coverage-database/details/ncd- details.aspx?ncdid=45&ncdver=5&coverageselection=both&articletype=all&policytype=final&s=pennsylvania&ke yword=stem+cell&keywordlookup=title&keywordsearchtype=and&bc=gaaaabaaaaaa&. Accessed December 12, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

38204
38205
38206
38208
38209
38210
38211
38212
38213
38214
38215
38220
38221
38240
38241

S2150