Harvard Pilgrim HealthCare Medical Policy

Hematopoietic Stem-Cell Transplantation (HSCT)

Subject: Hematopoietic Stem-Cell Transplantation (HSCT)

Background: Hematopoietic stem cell transplantation (HSCT) has become a well-established life-saving treatment procedure for many patients with hematological malignancies, inborn errors, or bone marrow failure syndromes, including radiation injury. HSCT involves multiple steps, including stem cell mobilization and harvest, application of a conditioning regimen to partially or fully ablate the patient’s existing hematopoietic system, ex vivo graft manipulation and/or in vivo T cell depletion (in some protocols), infusion of the stem cell graft to repopulate the patient’s hematopoietic system with healthy cells, and post-transplant care and monitoring.

There are two main types of stem cell transplantation, autologous and allogeneic. An autologous transplant uses a patient's own stem cells. Stem cells are collected from the patient and frozen in liquid nitrogen before transplant conditioning. Following conditioning treatment, the patient's stem cells are returned to the body to help it produce healthy red and white blood cells and platelets. An allogeneic transplant uses stem cells from donor whose human leukocyte antigens (HLA) are acceptable matches to the patient's. The stem cell donor may be related to the patient or may be an unrelated volunteer found through a donor registry such as the National Marrow Donor Program. There are two main types of allogeneic transplants, myeloablative and non-myeloablative (or “reduced intensity”, or “mini” or “RIC”). A myeloablative transplant uses large doses of chemotherapy or a combination of chemotherapy and radiation to overcome resistance and eradicate a patient's malignancy. A reduced intensity or non-myeloablative allogeneic transplant uses a reduced amount of chemotherapy to suppress the patient's immune system enough so that the donor stem cells can take root. While the chemotherapy may kill some of the tumor cells, that is not the goal of the chemotherapy given prior to the transplant. With a reduction in the amount of cancerous tissue, the transplanted stem cells can produce high numbers of health white blood cells to attack the remaining cancer cells.

Poor graft function (PGF), a relevant complication following HSCT, is defined as frequent dependence on blood and/or platelet transfusions and/or growth factor support in the absence of other explanations, such as disease relapse, drugs, or infections, assuming that donor myeloid and lymphoid chimerism are within a desirable target level. The administration of donor CD34+ stem cell boost is a therapeutic option to improve PGF occurring after allogeneic stem cell transplant.

Authorization: Prior authorization is required for all hematopoietic stem cell transplantation (HSCT) requested for members enrolled in commercial (HMO, POS, and PPO) products.

Autologous HSCT

The Plan may authorize coverage of autologous hematopoietic stem cell transplantation for the following indications, when the specific criteria outlined below for each indication are met:

• Acute promyelocytic leukemia (APL)

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HPHC policies are based on medical science, and written to apply to the majority of people with a given condition. Individual members’ unique clinical circumstances, and capabilities of the local delivery system are considered when making individual UM determinations.

Coverage described in this policy is standard under most HPHC plans. Specific benefits may vary by product and/or employer group.

Please reference appropriate member materials (e.g., Benefit Handbook, Certificate of Coverage) for member-specific benefit information.

Amyloidosis

• Central nervous system tumors
• Hodgkin's Disease
• Multiple Myeloma and POEMS Syndrome
• Neuroblastoma
• Non-Hodgkin's lymphoma, adult
• Non-Hodgkin's lymphoma, pediatric
• Pediatric solid tumors
• Systemic Sclerosis
• Testicular cancer and malignant germ cell tumors

Allogeneic HSCT

The Plan may authorize coverage of allogeneic hematopoietic stem cell transplantation for the following indications, when the specific criteria outlined below for each indication are met:

• Acute promyelocytic leukemia (APL)
• Acute lymphocytic/lymphoblastic leukemia, adult (ALL)
• Acute lymphocytic/lymphoblastic leukemia, pediatric (ALL)
• Acute myelogenous leukemia (AML)
• Aplastic anemia
• Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)
• Chronic myelogenous leukemia (CML)
• Chronic myelomonocytic leukemia (CMML)/Juvenile myelomonocytic leukemia (JMML)
• Fanconi anemia
• Hodgkin's Disease
• Myelodysplastic syndrome
• Myelofibrosis
• Neuroblastoma
• Non-Hodgkin's lymphoma, adult
• Non-Hodgkin's lymphoma, pediatric
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Sickle cell disease
• Thalassemia
• Inherited immunodeficiency disorder
• Inherited metabolic disorders

Repeat allogeneic stem cell transplant is appropriate for primary and secondary failure to engraft and for disease relapse.

CD34(+) stem cell boost:

CD34(+) stem cell boost: The Plan may authorize CD34(+) selected stem cell boost when member has poor graft function following allogeneic HSCT.

Clinical Coverage Criteria by Indication

Acute Lymphocytic Leukemia (ALL), adult

The Plan may authorize coverage of an allogeneic HSCT from a human leukocyte antigen (HLA)-matched donor for the treatment of ALL in adults when one of the following criteria is met:

• Failed induction therapy

Any patient in first remission, even those not considered high risk.

• Second or subsequent remission

The Plan may authorize coverage of a second allogeneic HSCT from HLA-matched donor for the treatment of ALL in adults when relapsed disease occurs after first allogeneic HSCT.

Limitations:

The Plan does not cover HSCT for the treatment of ALL in adults with any of the following conditions because it is considered not medically necessary:

• Uncontrolled central nervous system (CNS) involvement

Acute Lymphocytic Leukemia (ALL), pediatric

The Plan may authorize coverage of an allogeneic HSCT from a related HLA-matched donor for the treatment of ALL in children when one of the following criteria is met:

• e Initial treatment of Philadelphia chromosome positive patients
• Second or subsequent remission
• Initial treatment of Philadelphia chromosome positive patients
• Failed induction therapy
• First remission for Members with high risk (as described above) of disease relapse

The Plan may authorize coverage of a second allogeneic HSCT from a related HLA-matched donor for the treatment of ALL in children when relapsed disease occurs more than six months after first allogeneic HSCT.

The Plan does not cover non-myeloablative allogeneic HSCT for this diagnosis.

Limitations:

The Plan does not cover HSCT for children with ALL when there is central nervous system (CNS) involvement, as it is considered not medically necessary.

Acute Promyelocytic Leukemia (APL)

Acute Promyelocytic Leukemia (APL) The Plan may authorize coverage of autologous HSCT for second remission only. The Plan may authorize coverage of an allogeneic HSCT from a human leukocyte antigen (HLA)-matched donor for the treatment of APL in adults when one of the following criteria is met:

• PCR positivity in patients who achieve remission

Acute Myelogenous Leukemia (AML)

The Plan may authorize coverage of an allogeneic HSCT from an HLA-matched or haploidentical cell donor for the treatment of adults and children with AML when one of the following criteria is met:

1. First remission
2. First relapse
3. Second remission

The Plan may authorize coverage of a second allogeneic HSCT from an HLA-matched donor for the treatment of adults and children with AML when all of the following criteria are met:

1. Relapsed disease after first allogeneic HSCT
2. No peripheral blood blasts
3. \<= 5% blasts in the bone marrow

The Plan may authorize coverage of a non-myeloablative (NMA) allogeneic HSCT for adults with AML based on guidelines for ablative transplantation subject to the following indications; age greater than 50, and/or ineligibility for fully ablative transplantation (based on either concomitant medical conditions or prior autologous transplantation/high dose chemo within one year).

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HPHC policies are based on medical science, and written to apply to the majority of people with a given condition. Individual members’ unique clinical circumstances, and capabilities of the local delivery system are considered when making individual UM determinations.

Coverage described in this policy is standard under most HPHC plans. Specific benefits may vary by product and/or employer group. Please reference appropriate member materials (e.g., Benefit Handbook, Certificate of Coverage) for member-specific benefit information.

Amyloidosis

Amyloidosis The Plan may authorize coverage of an autologous HSCT for the treatment of primary systemic amyloidosis (i.e., amyloid light-chain or AL) when all of the following criteria are met:

• Biopsy proven Amyloid
• Eastern Cooperative Oncology Group (ECOG) performance status 0-3 (refer to ECOG Performance Status)
• Single-organ involvement, or two-organ involvement with ECOG performance 0-1 (refer to ECOG Performance Status)
• Absence of Multiple Myeloma
• Cardiac interventricular septal thickness is less than or equal to 15 mm
• Serum creatinine is less than or equal to 2.0 mg/dl
• Adequate pulmonary function with normal oxygen saturation on room air
• Adequate liver function as defined as total bilirubin less than 2.0 mg/dl and transaminases less than two times normal

Aplastic Anemia

Aplastic Anemia The Plan may authorize coverage of allogeneic HSCT from an HLA-matched donor for Members who fail to respond to prior immunosuppressive therapy or who relapse following primary immunosuppressive therapy and who meet the following criteria:

• Bone marrow biopsy demonstrates one of the following:
• Less than 25% of normal cellularity
• Less than 50% of normal cellularity, with less than 30% of the cells hematopoietic

AND

• Testing must demonstrate two of the following:
• Absolute reticulocyte count less than 40,000/microL
• b.

• Absolute neutrophil count less than 500/microL
• Platelet count less than 20,000/microL

The Plan does not cover non-myeloablative allogeneic HSCT for aplastic anemia.

Central Nervous System Tumors

Central Nervous System Tumors The Plan may authorize coverage of autologous HSCT for the treatment of recurrent medulloblastoma or supratentorial primitive neuroectodermal tumors in children.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) The Plan may authorize coverage of allogeneic HSCT (myeloablative or non-myeloablative) from an HLA-matched donor for the treatment of CLL/SLL for any of the following indications:

• Members who have undergone transformation to a more aggressive histology
• Members with relapsed disease
• First remission for Members with del17/del11 CLL who have a complete/partial response to therapy

Chronic Myelogenous Leukemia

Chronic Myelogenous Leukemia The Plan may authorize coverage of an allogeneic HSCT from an HLA-matched donor for the treatment of chronic myelogenous leukemia (CML) that is resistant to tyrosine kinase inhibitors.

After allogeneic HSCT, The Plan may authorize coverage of donor leukocyte infusion for the treatment of cytogenetic or molecular relapsed CML.

The Plan may authorize coverage of a non-myeloablative allogeneic HSCT for the treatment of CML only in the context of a clinical trial. Please refer to Medical Necessity Guidelines: Clinical Trials - Routine Costs

Chronic Myelomonocytic Leukemia (CMML)/Juvenile Myelomonocytic Leukemia (JMML)

Chronic Myelomonocytic Leukemia (CMML)/Juvenile Myelomonocytic Leukemia (JMML) The Plan may authorize coverage of allogeneic HSCT (myeloablative or non-myeloablative) for the treatment of CMML or JMML from a suitable HLA matched donor.

Fanconi Anemia

Fanconi Anemia The Plan may authorize coverage of an allogeneic HSCT with an HLA-matched donor for the treatment of Fanconi anemia for Members who have failed conventional medical management.

Hodgkin's Disease

Hodgkin’s Disease The Plan may authorize coverage of an autologous HSCT following high-dose chemotherapy when either of the following criteria is met:

• Primary refractory Hodgkin’s disease
• Relapse after primary therapy

The Plan may authorize coverage of an allogeneic HSCT following high-dose chemotherapy when all of the following criteria are met:

1. A suitable human leukocyte antigen (HLA) matched donor has been identified and is available
2. The Member’s disease can be categorized as one of the following:

Primary refractory Hodgkin's disease

• Relapse after autologous HSCT

The Plan does not cover non-myeloablative allogeneic HSCT for the treatment of this diagnosis.

Inherited Immunodeficiency Disorder

Inherited Immunodeficiency Disorder The Plan may authorize coverage of allogeneic HSCT with a suitable human leukocyte antigen (HLA) matched donor for any of the following Inherited Immunodeficiency Disorders:

• Severe combined immunodeficiency (multiple types)
• Wiskott-Aldrich Syndrome
• X-linked hyper IgM syndrome (CD4 IgM deficiency)
• AID and UNG deficiencies (autosomal recessive hyper IgM syndromes)
• CD40 deficiency (autosomal recessive hyper IgM syndrome)
• X-linked lymphoproliferative disease
• Interferon gamma receptor defects
• NF kappa B essential modifier (NEMO) deficiency
• Chronic granulomatous disease
• Griscelli syndrome

The Plan may authorize coverage of non-myleoablative allogeneic HSCT with a matched sibling donor, a matched unrelated donor, or a mismatched related donor for any of the Inherited Immunodeficiency Disorders listed above.

Inherited Metabolic Disorders

Inherited Metabolic Disorders The Plan may authorize coverage of allogeneic HSCT (myeloablative or non-myeloablative) from an HLA-matched donor for any of the following inherited metabolic disorders:

• Hurler syndrome
• Maroteaux-Lamy syndrome

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Childhood-onset cerebral X-linked adrenoleukodystrophy

• Gaucher disease Type 3 which has failed enzyme replacement therapy
• Krabbe disease in asymptomatic newborns transplanted in the neonatal period
• Late onset Krabbe disease
• Late infantile and early juvenile metachromatic leukodystrophy (MLD) in asymptomatic Members
• Late juvenile and early adult MLD in patients with adequate neuropsychological function and independence in activities of daily living

Multiple Myeloma and POEMS Syndrome

Multiple Myeloma and POEMS Syndrome The Plan may authorize the coverage of a single or tandem autologous stem-cell transplantation following high dose chemotherapy for multiple myeloma and POEMS syndrome.

Myelodysplastic Syndrome

The Plan may authorize coverage of allogeneic hematopoietic HSCT for the treatment of Members with low-risk myelodysplastic syndrome, defined as having an International Prognostic Scoring System (IPSS- R) score of >1.5-3, who have an available HLA matched donor and have had failure/intolerance to hypomethylating agents.

The Plan may authorize coverage of allogeneic hematopoietic HSCT for the treatment of Members with intermediate or high-risk myelodysplastic syndrome, defined as having an IPSS-R score of >3-4.5 (intermediate) or >4.5 (high/very high) who have an available HLA matched donor.

The Plan may authorize coverage of non-myeloablative allogeneic HSCT for the treatment of low-risk myelodysplastic syndrome, defined as having an IPSS-R score of >1.5-3, when all of the following criteria are met:

1. The Member has had failure/intolerance to hypomethylating agents.
2. The member is not a candidate for high-dose chemotherapy followed by allogeneic transplantation.

A suitable HLA-matched donor has been identified and is available.

• The Plan may authorize coverage of non-myeloablative allogeneic HSCT for the treatment of intermediate or high-risk myelodysplastic syndrome, defined as having an IPSS-R score of >3-4.5 (intermediate) or >4.5 (high/very high), when both of the following criteria are met:
1. The Member is not a candidate for high-dose chemotherapy followed by allogeneic transplantation.
2. A suitable HLA-matched donor has been identified and is available.

Note: Risk stratification is according to the International Prognostic Scoring System (IPSS). This score is available at mds-foundation.org/ipss-r-calculator.

Myelofibrosis (Primary and Secondary)

Myelofibrosis (Primary and Secondary) The Plan may authorize the coverage of allogeneic HSCT (myeloablative or non-myeloablative) for the treatment of myelofibrosis for symptoms that persist or worsen despite standard supportive care.

Neuroblastoma

• The Plan may authorize coverage of a maximum of three tandem autologous HSCT for the treatment of high-risk neuroblastoma.

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HPHC policies are based on medical science, and written to apply to the majority of people with a given condition. Individual members’ unique clinical circumstances, and capabilities of the local delivery system are considered when making individual UM determinations.

Coverage described in this policy is standard under most HPHC plans. Specific benefits may vary by product and/or employer group. Please reference appropriate member materials (e.g., Benefit Handbook, Certificate of Coverage) for member-specific benefit information.

• The Plan may authorize coverage of an allogeneic HSCT from an HLA-matched donor (at least five of six HLA-match) for the treatment of high-risk neuroblastoma when the patient is not a candidate for autologous HSCT.
• The Plan does not cover non-myeloablative allogeneic HSCT for this diagnosis.

Non-Hodgkin's Lymphoma, Adult

Non-Hodgkin’s Lymphoma, Adult The Plan may authorize coverage of an autologous HSCT when the Member meets one of the following criteria:

• Recurrent, or refractory aggressive, or highly aggressive advanced stage disease (Stage III or IV) when Member responds to high dose chemotherapy. Purging is not covered.
• Refractory indolent disease.
• Recurrent indolent disease if relapse is within 12 months of initial remission.

The Plan may authorize coverage of allogeneic HSCT when the Member has a matched sibling or unrelated donor and one of the following criteria is met:

• Refractory indolent disease.
• Recurrent indolent disease if relapse is within 12 months of the initial remission.

The Plan will cover non-myeloablative allogeneic HSCT for Members with low grade lymphoma and who are unable to undergo fully ablative transplantation.

The Plan does not cover tandem autologous or allogeneic HSCT for this diagnosis.

Non-Hodgkin's Lymphoma, Pediatric

Non-Hodgkin’s Lymphoma, Pediatric The Plan may authorize coverage of an autologous or an allogeneic HSCT for the treatment of pediatric Members with non-Hodgkin’s lymphoma with chemo sensitive disease in second remission. The Plan may authorize coverage of a non-myeloablative allogeneic stem cell transplantation for relapsed disease following an autologous HSCT, and for high-risk Members who cannot receive an ablative allogeneic HSCT. The Plan does not cover tandem autologous or allogeneic HSCT for this diagnosis.

Pediatric Solid Tumors

Pediatric Solid Tumors The Plan may authorize coverage of high-dose chemotherapy followed by autologous HSCT for the treatment of the following:

• Relapsed Wilms’ tumor
• Metastatic retinoblastoma
• Relapsed Ewing’s sarcoma, not responsive to other therapies.
• Relapsed Peripheral Neuroectodermal Tumor (PNET): primary metastatic or bulky disease, not responsive to other therapies.
• Relapsed Rhabdomyosarcoma, not responsive to other therapies.
• Relapsed Desmoplastic small round cell tumor, not responsive to other therapies.
• Hepatoblastoma: Primary metastatic or recurrent.

Paroxysmal nocturnal hemoglobinuria (PNH)

The Plan may authorize allogeneic HSCT for treatment of PNH with co-existent severe bone marrow failure.

Sickle Cell Disease

Sickle Cell Disease The Plan may authorize coverage of an allogeneic HSCT in children, adolescents or young adults (under age 40) using bone marrow from a human leukocyte antigen (HLA)-matched related donor for the treatment of severe sickle cell disease characterized by one or more of the following:

• History of stroke or central nervous system event
• Recurrent acute chest syndrome, vaso-occlusive crises, or priapism
• Chronic transfusions (Member requires transfusions on a regular and ongoing basis, e.g., every 3-4 weeks)
• Abnormal transcranial Doppler study
• Sickle lung disease
• Sickle nephropathy
• Bilateral proliferative retinopathy and major visual impairment
• Osteonecrosis
• Red cell allo-immunization
• Impaired neuropsychological function combined with abnormal cerebral magnetic resonance imaging

The Plan does not cover non-myeloablative (NMA) allogeneic HSCT for this diagnosis.

Limitations:

The Plan does not cover HSCT for the treatment of sickle cell disease using stem cells derived from:

• Cord blood or peripheral blood
• Matched unrelated donors

Systemic Sclerosis/Scleroderma

Systemic Sclerosis/Scleroderma The Plan may authorize coverage of an autologous HSCT for the treatment of systemic sclerosis/scleroderma when ALL of the following are met:

• The Member is <65 years of age; AND
• Duration of condition of 5 years or less; AND
• Modified Rodnan skin score of 15 or higher; AND
• The Member has rapidly progressing disease with evidence of internal organ involvement, including but not limited to pulmonary complications (e.g. interstitial lung disease, pulmonary hypertension), cardiac complications (e.g. heart failure, arrhythmia, angina/atypical chest pain), and renal complications (e.g.

  impaired renal function, scleroderma renal crisis), AND

  • There is no known presence of neoplasm(s) in the Member; AND

  None of the organ involvement exclusion criteria below are met.

  Organ Involvement Exclusion Criteria

  Individuals with internal organ involvement indicated by the following measurements should not be considered for autologous HCT:

  • Cardiac: left ventricular ejection fraction <45%, mean pulmonary artery pressure >25 mm Hg, pulmonaryartery systolic pressure >40 mm Hg,
  • Pulmonary: DLCo (diffusing capacity) <40% of predicted value, forced vital capacity (FVC) <65% ofpredicted value
  • Renal: creatinine clearance <40 ml/minute

  Testicular Cancer and Metastatic Germ Cell Tumors

  The Plan may authorize coverage of a single or tandem high-dose chemotherapy followed by autologous HSCT for relapsed or refractory nonseminomatous testicular cancer, as well as relapsed or refractory germ cell cancer of the mediastinum or female genital tract.

  Thalassemia

  The Plan may authorize coverage of allogeneic HSCT for transfusion dependent thalassemia when donor is an HLA matched sibling. NOTE: HSCT offers no survival benefit over medical therapy

  Limitations:

  The Plan does not cover allogeneic HSCT if member has severe organ damage as a result of iron overload.

  Exclusions:

  The Plan considers hematopoietic stem cell transplantation (HSCT) contraindicated and thus not medically necessary when there is also the presence of any significant co-morbid conditions which would significantly compromise the Member’s clinical care and chances of survival.

  The Plan considers HSCT investigational and, therefore, not medically necessary for any indication other than those listed above in these guidelines.

  HPHC Medical Policy Page 8 of 11 Hematopoietic Stem-Cell Transplantation VAO1APR23PVA01APR23

  HPHC policies are based on medical science, and written to apply to the majority of people with a given condition. Individual members’ unique clinical circumstances, and capabilities of the local delivery system are considered when making individual UM determinations.

  Coverage described in this policy is standard under most HPHC plans. Specific benefits may vary by product and/or employer group. Please reference appropriate member materials (e.g., Benefit Handbook, Certificate of Coverage) for member-specific benefit information.