National Medical Policy

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1 National Medical Policy Subject: Policy Number: Stem Cell Transplantation in Adult Patients NMP263 Effective Date*: April 2006 Updated: June 2017 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Stem Cell Transplantation ( ): Erythropoiesis Stimulating Agents (ESAs) in Cancer and Related Neoplastic Conditions National Coverage Manual Citation X Local Coverage Determination (LCD)* Immune Globulin Intravenous: Erythropoiesis Stimulating Agents: Article (Local)* X Other Medicare Learning Matters Network. Number: MM7137. Updated on December 10, Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome (MDS): Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/MM7137.pdf MLN Matters Number: MM6416. March 13, April 2009 Update of the Hospital Outpatient Prospective Payment System (OPPS): Education/Medicare-Learning-Network- Stem Cell Transplantation in Adult Patients June

2 MLN/MLNMattersArticles/downloads/MM6416.pdf MLN Matters Number: MM6751. January 2010 Update of the Hospital Outpatient Prospective Payment System (OPPS): Education/Medicare-Learning-Network- MLN/MLNMattersArticles/downloads/MM6751.pdf CMS Manual System. Department of Health & Human Services (DHHS). Pub Medicare Claims Processing. Stem Cell Transplantation: Guidance/Guidance/Transmittals/downloads/R766CP. pdf None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under Reference/Website and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual. If there is no NCD, National Coverage Manual or region specific LCD/Article, follow the Health Net Hierarchy of Medical Resources for guidance. Current Policy Statement Specific disease descriptions can be accessed through the National Cancer Institute Web site under "Types of Cancer" at General Criteria for Stem Cell Transplants Health Net, Inc. considers high dose chemotherapy followed by bone marrow / stem cell / cord blood transplantation medically necessary for the treatment of certain disease processes if all of the following criteria are met: 1. Disease or condition where hematopoietic stem cell transplant provides improved outcomes over standard therapy; and 2. Good performance status based on the Karnofsky Performance Scale (see table below) or equivalent measurement scale; and 3. No serious, uncontrolled psychiatric illness that would hinder compliance with any stage of the transplant process; and 4. No neurologic illness independent of the disease process being treated; and 5. Full psychosocial evaluation including evaluation of support systems, etc.; and 6. No active hardcore drug abuse (e.g., cocaine, heroin, marijuana, narcotics obtained by prescription, etc. - not other substances like nicotine, caffeine, Stem Cell Transplantation in Adult Patients June

3 chocolate which would be considered minor substance abuse) or alcohol abuse (patient must have a documented six month abstinence from hardcore drug or alcohol use and ongoing participation in a formal treatment program, e.g., Alcoholics Anonymous); and 7. Documentation of the current status for the following: HIV, Hepatitis, Cytomegalovirus (CMV), Herpes Simplex Virus (HSV) profiling; and 8. No active infection (must be afebrile for greater than 48 hours and off antibiotics); and 9. Pulmonary function tests: FVC, FEV1, DLco must all be greater than or equal to 60% of predicted (Young children may be unable to comply and may be evaluated using age necessary testing); and 10. Left ventricular (LV) ejection fraction must be greater than or equal to 45%; and 11. Estimated creatinine clearance must be greater than or equal to 60 ml/min; and 12. Serum bilirubin and SGOT must be less than or equal to 1.5 times the institutional upper limit of normal; and 13. If hepatitis C RNA positive, individual is ineligible for transplant if liver function tests are elevated; and 14. Willingness and ability of the individual or legal guardian to give signed consent and to comply with regular follow-up requirements. Karnofsky Performance Scale GRADE DESCRIPTION KARNOFSKY RATING 0 Fully active, able to carry on all predisease activities without restriction Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work) 2 Ambulatory and capable of all self-care but unable to carry out any work activities; up and about more than 50% of waking hours 3 Capable of only limited self-care; confined to bed or chair 50% or more of waking hours 4 Completely disabled; cannot carry on any selfcare; totally confined to bed or chair (Niederhuber, 2000) or less Definitions 1. Chemoresponsiveness (chemosensitive) - a tumor demonstrates complete or partial remission (at least a 50% reduction in tumor burden). 2. Remission - a complete or partial disappearance of the signs and symptoms of disease in response to treatment. The period during which a disease is under control. A remission, however, is not necessarily a cure. 3. Primary refractory - a tumor that does not achieve a complete remission after initial standard dose chemotherapy. 4. Refractory disease - tumors that show < 50% reduction in tumor burden in response to chemotherapy. The refractoriness can be primary (failure to respond to initial therapy) or secondary (patient has initial response but fails to respond after disease relapse). Stem Cell Transplantation in Adult Patients June

4 5. Relapse - the return of symptoms and signs of a disease after a period of improvement, or the reappearance of disease in regions of prior disease (recurrence) and/or in new regions (extension) after initial therapy and attainment of complete response. 6. Salvage therapy - treatment that is given after the cancer has not responded to other treatments. Policy Statement (Please refer to Health Net NMP on Tandem Stem Cell Transplants in the Adult Patient) Health Net, Inc. considers certain diagnoses in patients who meet specific criteria medically necessary for high dose chemotherapy followed by bone marrow / stem cell / cord blood support because published studies have demonstrated improvement in health outcomes Autologous Stem Cell / Bone Marrow Transplant (in alphabetical order) Acute Leukemia Multiple Myeloma Amyloidosis, Primary Ewing s Sarcoma (Primitive Neuroectodermal Tumor [PNET]) Germ Cell Tumors (testicular, mediastinal, retroperitoneal, and ovarian germ cell tumors) Neuroblastoma (Adult) Non-Hodgkin s Lymphoma Investigational Diagnoses For Autologous Transplant Hodgkin s Disease (Lymphoma) Allogeneic Stem Cell / Bone Marrow Transplant (in alphabetical order) Acute Lymphocytic Leukemia Chronic Lymphocytic Lymphoma Acute Myelogenous (Myeloid) Leukemia Aplastic Anemia (includes Fanconi s anemia, Diamond- Blackfan syndrome, paroxysmal nocturnal hemoglobinuria and acquired diseases such as due to drug or toxin exposure) Chronic Myelogenous (Granulocytic) Leukemia Multiple Myeloma Myelodysplastic Syndrome Myeloproliferative Disorders (excludes CML includes Polycythemia Vera, Essential Thrombocythemia, Agnogenic Myeloid Metaplasia) Non-Hodgkin s Lymphoma Sickle Cell Anemia Stem Cell Transplantation in Adult Patients June

5 Immunodeficiency Disorders (includes Severe Combined Immunodeficiency [SCID], Wiskott-Aldrich Syndrome, Infantile Malignant Osteopetrosis, Chediak-Higashi Syndrome and Albers-Schonberg Disease [also known as marble bone disease]) Lipidoses (Lipid Storage Disorders) Mucolipidoses (Lysosomal Storage Diseases) Thalassemia Major Other Medically Necessary Conditions (includes severe infantile agranulocytosis [Kostmann s Syndrome]), Leukocyte Adhesion Deficiencies, X-linked Lymphoproliferation Syndrome, Amegakaryocytic Thrombocytopenia) Investigational Diagnoses for Allogeneic Transplant Mucopolysaccharidosis (includes Hurler s, Maroteaux-Lamy) Autologous Stem Cell Transplant Acute Leukemia Medically Necessary Transplant Indications 1. Acute leukemia in remission who have a high probability of relapse and who have no human leucocyte antigens HLA-matched. Cell types may include: Lymphoid Myeloid Monocytic Acute erythremia and erythroleukemia Amyloidosis, Primary Medically Necessary Autologous, peripheral stem cell is preferred. Prognosis depends greatly on extent of organ involvement. Transplant Indications 1. Patients with primary amyloid light chain (AL) amyloidosis in 2 or fewer organs Note: All transplants for amyloidosis remain best performed at centers experienced in performing this procedure on these patients. Investigational All forms of secondary amyloidosis (e.g., caused by chronic infection or inflammatory disease such as rheumatoid arthritis, familial Mediterranean fever, osteomyelitis, or granulomatous ileitis) Stem Cell Transplantation in Adult Patients June

6 Hodgkin s Disease (Lymphoma) Medically Necessary Transplant Indications Autologous transplantation is the treatment of choice for patients with advanced Hodgkin s Lymphoma, also known as Hodgkin s Disease (HD), relapsing after chemotherapy, when all of the following are met: 1. The patient is less than 60 years of age, and 2. Patient has Stage III or IV A or B disease or has Stage II or IIB disease that has relapsed (see Staging below) 3. Patient has chemoresponsive disease*; and 4. Patient meets any of the following: Patient fails to achieve a complete response with maximal primary chemotherapy and/or radiotherapy (i.e., partial remission); OR Patient is in a 1 st or 2 nd relapse** after a complete response to maximal chemotherapy and/or radiotherapy; OR The patient is in a 2 nd complete remission. *Chemoresponsiveness is defined as a tumor demonstrating either a complete or partial remission. Partial remission (response) is defined as at least a 50% decrease in tumor burden. ** Relapsed is defined as the return of symptoms and signs of a disease after a period of improvement, or the reappearance of disease in regions of prior disease (recurrence) and/or in new regions (extension) after initial therapy and attainment of complete response. Notes: 1. Patients in complete response after 2 nd line therapy have improved outcomes following high-dose therapy (HDT) /autologous stem cell rescue (ASCR). 2. In selected patients Brentuximab Vedotin can be used as 2 nd line therapy prior to HDT/ASCR to minimize the use of more intensive chemotherapy. 3. Autologous transplantation is the treatment of choice for patients relapsing after chemotherapy; allogeneic transplantation should only be used for patients for whom autologous transplant is not feasible (e.g., extensive involvement of bone marrow). 4. In rare cases, stem cell transplant may be medically necessary in a patient with Stage I disease with large primary tumor and failure to achieve a complete response to chemotherapy or relapse after chemotherapy. Stage I Stage II Stage III Stage IV Hodgkin s Lymphoma: Staging at time of Diagnosis One lymph node region involved, or a single organ site Two or more lymph node regions on the same side of the diaphragm involved, or involvement of a single organ or site along with associated lymph nodes Lymph node regions on both sides of the diaphragm involved, possibly plus local involvement of site or organ outside lymph nodes Widespread involvement of organs or tissues outside the lymphatic system Stem Cell Transplantation in Adult Patients June

7 Investigational As initial or upfront therapy (i.e., without a full course of standard-dose induction chemotherapy) For consolidation of patients in first complete remission Salvage high dose chemotherapy/allogeneic bone marrow or peripheral stem cell (HDC/AlloSCS) for relapse of HL/HD after high dose chemotherapy/autologous bone marrow or peripheral stem cell transplant Non-Hodgkin s Lymphoma Medically Necessary Stem Cell Transplantation in Adult Patients June

8 Transplant Indications 1. Autologous transplantation is preferred over allogeneic. High-dose chemotherapy and autologous transplant should be reserved for patients age 70 or less in whom other treatments have failed and any of the following is met: Stage III or IV A or B, intermediate and high-grade NHL in second or subsequent clinical remission (see Staging below) Stage II or IIB disease that has relapsed Salvage therapy of relapsed*, chemosensitive** intermediate- or highgrade lymphoma. Relapsed, low-grade follicular NHL that has or has not undergone transformation. Primary therapy with evidence of low-grade histology Follicular Non-Hodgkin s Lymphoma for patients who have failed primary therapy. Lymphoblastic lymphoma and Burkitt s* lymphoma in first complete remission. Patients with chemosensitive, partial remission. Mantle cell lymphoma in first clinical remission 2. Non-Hodgkin s lymphomas presenting with any of the following poor prognostic features in first remission: Mantle cell lymphoma has a very poor prognosis Age > 60 years Presence of weight loss > 10lbs, fever, & night sweats Tumor mass > 7cm Mediastinal mass detectable on Chest X-ray Beta-2M fraction > 3.0mg/L Serum LDH level > 685 IU/L More than one extranodal site Relapsed is defined as the return of symptoms and signs of a disease after a period of improvement, or the reappearance of disease in regions of prior disease (recurrence) and/or in new regions (extension) after initial therapy and attainment of complete response. ** Chemosensitive indicates > 50% reduction in tumor burden and/or necessary indicators. Note: Additional, randomized studies comparing allogeneic and autologous approaches for relapsed non-hodgkin s lymphoma (NHL) are necessary to determine the most appropriate type of transplant. These studies would be specific for these individuals suffering from aggressive NHL, following high dose chemotherapy and radiation. Note: Upon medical review, autologous bone marrow transplant may be considered medically necessary for persons with chemoresistant disease where disease is relapsed and widely metastatic, and allogeneic transplantation cannot be offered. Note: For non-responders of non-hodgkin s lymphoma who receive a response after chemotherapy, consider allogeneic stem cell transplant; for relapsed Burkitt lymphoma, treatment options were clarified as 2 nd line chemotherapy followed by high dose therapy (HDT) or allogeneic SCT in selected patients, within a clinical trial. Stem Cell Transplantation in Adult Patients June

9 Investigational Small lymphocytic lymphoma (SLL) As initial therapy for all other subgroups of NHL Non-Hodgkin s Lymphoma: Staging Stage I One lymph node region involved, or a single organ site Stage II Two or more lymph node regions on the same side of the diaphragm involved, or involvement of a single organ or site along with associated lymph nodes Stage III Lymph node regions on both sides of the diaphragm involved, possibly plus local involvement of site or organ outside lymph nodes Stage IV Widespread involvement of organs or tissues outside the lymphatic system Stem Cell Transplantation in Adult Patients June

10 Multiple Myeloma Medically Necessary Transplant Indications Note: If the patient is over 50 years of age, autologous transplantation is preferred. If patient under 50 years of age, allogeneic transplantation may be considered, however lack of suitable donor has limited this approach. Donor lymphocyte infusions following allogeneic transplant have produced significant benefit. The majority of patients with Multiple Myeloma will relapse. Stem cell harvest adequate for 2 transplants should be done, if patient is candidate for transplant. Patients with stage II or III multiple myeloma (see Durie-Salmon Staging below) when any of the following is met: 1. Primary refractory multiple myeloma OR 2. In complete or partial remission from treatment of chemoresponsive disease* (defined as 50% decrease, either in measurable paraprotein [serum and/or urine] or in bone marrow infiltration, sustained for at least 1 month); OR AND 3. Patient in relapse that is responding to treatment; 4. All of the following are met: Adequate liver function bilirubin, SGOT less than 1.5x normal; and Patient must not have significant comorbid medical conditions, except for renal failure (see General Criteria for Stem Cell Transplant at beginning of policy); and No evidence of cardiac amyloid; and No evidence of indolent myeloma, smoldering myeloma, and/or monoclonal gammopathy of uncertain significance [MGUS]. Note: Patients should not have had extensive prior chemotherapy or radiation therapy (i.e. more than a year of alkylator-based chemotherapy and/or more than two prior alkylator-based chemotherapies; radiation therapy to no more than 10% of marrow producing bones). Must have chemoresponsive disease defined as: A > 25% reduction of measurable paraprotein, if abnormal pretreatment (No measurable paraprotein = CR); and/or 25% reduction in one of the following: plasma cells in bone marrow, quantitative immunoglobulins (IgG, IgA, IgM) or total protein; and/or Must not have new areas of lytic bone lesions. Investigational As initial therapy Patients in resistant, progressive relapse after a prior failed course of high dose chemotherapy and autologous stem cell support Transplant for invasive cancer or other significant condition, e.g., residual plasmacytoma Previous radiation therapy to bone marrow sites (pelvis, spine), unless the radiation therapist gives approval Evidence of heart disease possibly related to myeloma: Myocardial infarction within 6 months of treatment Cardiac arrhythmia Cardiomegaly Stem Cell Transplantation in Adult Patients June

11 ISS** Stage I Multiple Myeloma: The Durie-Salmon Staging System* All of the following bullets must be met for Stage I Hemoglobin value >10 g/dl Serum calcium value normal or 12 mg/dl Bone x-ray, normal bone structure or solitary bone plasmacytoma only Serum IgG less than 5 grams per deciliter; IgA les than 3 grams per deciliter Bence-jones proteinuria less than 4 grams per day ß2-M <3.5 and Albumin 3.5 Stage II Stage III Hemoglobin value <8.5 g/dl Serum calcium value >12 mg/dl More than two bone lesions Serum IgG between 5 and 7 per deciliter; IgA between 3 and 5 grams per deciliter Bence-jones proteinuria between 4 and 12 grams per day o Neither Stage I or Stage III One or more of the following bullets must be met for Stage III Significant anemia or hypercalcemia More than three bone lesions (Advanced lytic bone lesions) Serum IgG greater than 7 grams per deciliter; IgA greater than 5 grams per deciliter Bence-jones proteinuria greater than 12 grams per day Neither Stage I or Stage III ß2-M >5.5 *Note - Proper staging of myeloma helps in determining prognosis and developing a treatment plan. The Durie-Salmon system has been the most widely used myeloma staging system since 1975 (see table above). In this system, the clinical stage of disease (stage I, II, or III) is based on several measurements, including levels of M protein, the number of bone lesions, hemoglobin values, and serum calcium levels. There is somewhat of an overlap between the various myeloma categories and stages. For example, both patients with smoldering myeloma and patients with Stage I disease do not require immediate treatment, as it may take many months or years before the disease progresses, and patients with Stage II and III disease have active, symptomatic myeloma. Increasingly, physicians are relying less on the Durie- Salmon staging system and more on biologically relevant markers as prognostic indicators when making treatment choices. **Note - A new International Staging System (ISS) for myeloma has recently been proposed. This system appears to better discriminate between staging groups and can be widely used since it is based on easily measured serum levels of beta 2- microglobulin (ß2-M) and albumin. Stem Cell Transplantation in Adult Patients June

12 Neuroblastoma (Adult) Medically Necessary Transplant Indications 1. For initial treatment of high-risk neuroblastoma* (see definitions below) when both of the following are met: Patient does not have a concurrent condition/disease, which would seriously compromise the chance of attaining a durable complete remission with this therapy; and Patient has stem cell product that meets infusion criteria of viability and neuroblastoma stem cell contamination (less than 1 neuroblastoma cell per 100,000 peripheral blood progenitor cells or less than 10 % morphological evidence bone marrow involvement) prior to transplant AND any of the following is met: In partial or complete remission with chemotherapy As primary treatment for persons in Stage II to Stage III neuroblastoma (see Staging below) when associated with more than 10 copies of the n- myc oncogene; or As primary treatment for persons in Stage IV neuroblastoma; or As therapy for primary recurrent or primary refractory** neuroblastoma when further treatment with a conventional-dose therapy is unlikely to attain a durable remission. ** Primary refractory is defined as a tumor that does not achieve a complete remission after initial standard dose chemotherapy. Note: Low-risk and intermediate-risk neuroblastoma have a good chance of being cured. High-risk neuroblastoma may be difficult to cure. High-risk neuroblastoma in a patient > 1 year at diagnosis is defined as any one of the following: 1. Stage III disease with any of the following: Amplified n-myc status of > 10 copies of the n-mvc gene; or Elevated serum ferritin (> 142 ng/ml by radioimmunoassay or positive by counterimmunoelectrophoresis); or Unfavorable histology by the Shimada classification; or 4. Stage II disease, patients > 10 years AND > than 10 copies of the n-mvc gene 5. Stage IIA or IIB disease, in persons between ages 1 and 21 years, with amplified n-myc status of > 10 copies of the n-mvc gene and unfavorable histopathology by the Shimada classification 6. Stage I or II patients > 1 year at presentation with subsequent development of disseminated disease without interval chemotherapy or radiotherapy Note: We consider a salvage allogeneic or autologous stem cell transplant medically necessary for persons with chemosensitive disease who have relapsed after an allogeneic transplant or autologous bone marrow transplant. Investigational High-grade glial tumors of the brain in adults Neuroblastoma: Staging The tumor is in only one area and all of the tumor that can be seen is Stage I completely removed during surgery The tumor is in only one area and all of the tumor that can be seen cannot be Stage IIA completely removed during surgery Stem Cell Transplantation in Adult Patients June

13 The tumor is in only one area and all of the tumor that can be seen may be Stage IIB completely removed during surgery. Cancer cells are found in the lymph nodes near the tumor One of the following is true: Stage III The tumor cannot be completely removed during surgery and has spread from one side of the body to the other side and may also have spread to nearby lymph nodes; or The tumor is in only one area, on one side of the body, but has spread to lymph nodes on the other side of the body; or The tumor is in the middle of the body and has spread to tissues or lymph nodes on both sides of the body, and the tumor cannot be removed by surgery. The tumor has spread to distant lymph nodes, the skin, or other parts of the Stage IV body Ewing s Sarcoma (Primitive Neuroectodermal Tumor [PNET]) Medically Necessary Transplant Indications 1. Recurrent or refractory Ewing s sarcoma 2. Recurrent or refractory medulloblastoma and other PNETs, including: Neuroblastoma arising in the central nervous system Ependymoblastoma Pinealblastoma Investigational High-grade glial tumors of the brain in adults Treatment for ependymoma Germ Cell Tumors (testicular, mediastinal, retroperitoneal, and ovarian germ cell tumors) Medically Necessary Transplant Indications Health Net Inc. considers stem cell transplant medically necessary for any of the following: 1. Germ cell tumors of the ovary for any of the following: Relapsed germ cell tumors of the ovary that were responsive to standard chemotherapy As consolidation therapy for patients with germ cell tumors of the ovary that is in complete remission 2. Germ cell tumors arising in testicular, mediastinal, retroperitoneal areas that are refractory to (less than 50% reduction in tumor burden) or exhibit only a partial response (at least a 50% reduction in tumor burden) to standard dose platinum chemotherapy 3. As consolidation therapy for persons with testicular cancer who relapse after an initial course of standard dose chemotherapy 4. Patients with germ cell tumors in patients in second complete remission or second relapse following standard platinum-based chemotherapy Stem Cell Transplantation in Adult Patients June

14 Investigational As initial treatment (e.g., in lieu of an initial course of conventional platinumbased chemotherapy) of a poor risk germ cell tumor* As a treatment following first relapse (e.g., in lieu of a course of conventional chemotherapy) For treatment of epithelial and mixed epithelial/germ cell ovarian cancers Allogeneic bone marrow or peripheral stem cell transplant for the treatment of persons with germ cell tumors, including ovarian and testicular cancer A poor risk germ cell tumor are not chemotherapy sensitive tumors or have a high tumor burden All other indications for autologous transplant are considered investigational, including but not limited to the following: (Exceptions for medical necessaryness of other rare conditions are at the discretion of the medical director of the health plan) (in alphabetical order) Amyloidosis, secondary Myelodysplastic syndrome Aplastic anemia Nasopharyngeal cancer Arthritis, rheumatoid and juvenile idiopathic Neuroendocrine tumors arthritis Astrocytomas, malignant Non-Hodgkin s lymphomas, initial therapy of all types Autoimmune diseases (e.g., lupus) Oligodendroglioma Bile duct cancer Osteosarcoma Brain tumors (excluding PNET and Ovarian epithelial and mixed epithelial / germ neuroblastoma) cell cancers Breast cancer* Pancreatic cancer Cervical cancer Paranasal sinus cancer Chronic granulocytic leukemia Prostate cancer Chronic inflammatory demyelinating Rectal Cancer polyneuropathy Chronic lymphocytic leukemia (CLL) Renal Cell cancer (medically necessary if done within the context of a clinical trial) Chronic myelogenous leukemia (CML) Retinoblastoma Colon cancer Rhabdomyosarcoma Esophageal cancer Small cell lymphocytic lymphoma Ependymoma Smoldering myeloma Ewing sarcoma, initial treatment of low or Soft tissue sarcomas intermediate risk Fallopian tubes cancer Stomach cancer Gall bladder cancer Systemic lupus erythematosus (SLE) Germ cell tumors as initial treatment (e.g., in Systemic sclerosis (e.g., scleroderma) lieu of an initial course of conventional chemotherapy) Germ cell tumors as a treatment following first relapse (e.g., in lieu of a course of conventional chemotherapy) Glioblastoma multiforme Gliomas, malignant Hodgkin s Lymphomas Initial therapy Lung cancer, any histology Melanoma Multiple myeloma indolent, refractory, progressive, monoclonal gammopathy of uncertain significance (MGUS) Multiple sclerosis Thymic tumors Thyroid tumors Tumors of unknown primary origin Uterine cancer Waldenström s macroglobulinemia Wilms tumor Stem Cell Transplantation in Adult Patients June

15 Because evidence from several randomized studies reported negative outcomes and the exposure of one of the few trials with a positive outcome as seriously flawed All of the following are met: Allogeneic Stem Cell Transplant Acute Lymphocytic Leukemia (ALL) Medically Necessary Transplant Indications 1. Patient is 55 years of age or younger (In older individuals allogeneic HSCT may be considered based on performance status, co-morbidities, availability of appropriate transplant donor and transplant center expertise) 2. Patient has an HLA identical sibling donor or an HLA matched unrelated donor (HLA typing except for patients with a major contraindication to hematopoietic cell transplant (HCT) 3. Transplant is after the first (preferred) or second remission because better outcomes achieved if transplanted in remission where the lowest incidence of leukemic relapse results 4. Transplant is not performed during relapse 5. At a minimum, patient partially responds to chemotherapy but fails to achieve complete remission within 6 weeks of the start of induction 6. A patient has achieved a first complete response, but has high-risk disease as defined by any of the following: Philadelphia (Ph) chromosome is present Hypoploidy (presence of too few chromosomes Pseudodiploidy with translocation at 9; 22, 4; 11, or 8; 14. BCR-ABL gene mutations Complex karotype (> 5 chromosomal abnormalities) B-cell lineage with high leukocyte WBC (> 30,000/uL) Extramedullary disease (especially central nervous system) Note: Autologous transplantation is used only when an HLA-matched donor is not available. Investigational Initial therapy of ALL Adults not in complete remission, i.e., during relapse ALL relapsing after a prior course of HDC and stem cell support Stem Cell Transplantation in Adult Patients June

16 Chronic Lymphocytic Lymphoma Transplant Indications All of the following are met, as this is the only potentially curative therapy: 1. Patient is < 55 years of age; and 2. Patient has a good performance status, has been previously treated, has poor risk disease* at an advanced stage of their disease; and 3. No serious co-morbid conditions, and 4. Transplant is performed before the development of drug resistant disease * Adverse risk factors include (but are not limited to): Age Binet stage Unmutated (germline) immunoglobulin heavy chain gene Immunoglobulin Vh gene mutational status Lymphocyte count Rapid lymphocyte doubling time, defined as the doubling of peripheral blood absolute lymphocyte count (ALC) in less than 12 months. Serum beta-2 micro-globulin (B2M) CD38 positivity ZAP70 expression. Note: Older patients and patients with no identifiable molecular adverse prognostic features are less likely to ever require treatment. When treatment is indicated in these patients, goals of therapy should focus on minimizing the disease symptoms while avoiding excessive risk for treatment-related toxicity. Acute Myelogenous (Myeloid) Leukemia (AML) (sometimes called acute non-lymphocytic leukemia [ANLL]) Stem Cell Transplantation in Adult Patients June

17 Medically Necessary Transplant Indications Allogeneic transplant with an HLA-matched related or unrelated donor when all of the following are met: Age less than 60* Adequate end organ function No significant co-morbid illness AND Any one of the following indications: 1. Patients who are deemed as strong candidates for stem cell transplant and have an available donor should be transplanted in first remission 2. Patient with a short relapse free interval (i.e., typically less than 6 months) after attaining a first complete remission 3. Patient has high-risk disease defined by cytogenetic abnormalities achieved without translocation at 8;21, 15;17, or inverted chromosome Patient with intermediate risk in first remission 5. AML in early relapse (i.e., < 30% blasts in the blood & bone marrow) Notes: Autologous transplant should be reserved for patients who are not candidates for allogeneic transplant. Human leukocyte antigen (HLA) typing for patient with potential hematopoietic transplantation (HCT) in the future (except for patients with major contraindications to HCT). * For older patients >60 with AML, NCCN recommends using patient performance status, in addition to adverse features (e.g., unfavorable cytogenetics and therapy related AML or prior MDS) and comorbid conditions to select treatments rather than using their chronological age only Investigational AML relapsing after a prior course of HDC and stem cell support Stem Cell Transplantation in Adult Patients June

18 Aplastic Anemia (includes Fanconi s anemia, Diamond-Blackfan syndrome, paroxysmal nocturnal hemoglobinuria and acquired diseases such as due to drug or toxin exposure) Medically Necessary Transplant Indications When ALL of the following criteria are met: 1. For patient lacking an HLA-matched related donor 2. If they are 20 years of age, have failed 2 courses of immunosuppressive therapy (IST), and for patients < 20 years of age, after having failed one course of IST 3. Patient has severe aplastic anemia defined as having at least three (3) of the following corrected for hematocrit: Absolute neutrophil count < 500/mm 3 Platelets < 20,000/mm 3 Reticulocyte count < 1% Bone marrow cellularity < 20%; and 3. For patient failing antithymocyte globulin therapy, patient has 6 of 6 HLAmatched related or unrelated donor, OR 5 of 6 antigen matched family donor All of the following are met: Chronic Myelogenous (Granulocytic) Leukemia Medically Necessary Transplant Indications 1. Age less than 65 (Most centers limit to age less than 65 due to donor availability & high toxicity of the procedure) 2. Sibling matched transplants are preferred, however, transplants from unrelated matched donors can now be used for many patients with CML; and 3. Allogeneic transplantation using a suitable HLA-matched donor in the first or second chronic phase OR 1. Early transplant, typically within one year of diagnosis; or 2. First-line treatment option for the very rare individual presenting with blast phase at diagnosis; or 3. Individuals with T315I and other BCR-ABL1 mutations that are resistant to all TKI s*: or 4. Rare individuals intolerant to all TKI s; or 5. Advanced phase (AP)-CML or blast phase (BP)-CML. *The selection of TKI is based on prior therapy and/or mutational testing. There are some data regarding the efficacy of 2 nd generation TKI s against specific mutations. Investigational Stem Cell Transplantation in Adult Patients June

19 Immunodeficiency Disorders Medically Necessary Transplant Indications Patient has any one of the following diagnoses: Severe Combined Immunodeficiency Common variable immunodeficiency Combined Immunodeficiency Wiskott-Aldrich Syndrome DiGeorge syndrome Chediak-HIgAshi Syndrome Ataxia-Telangiectasia X-Linked Lymphoproliferative Disease Chronic Granulomatous Disease Hemophagocytic Lymphohistiocytosis Primary Granulocyte Dysfunction) Purine Nucleoside Phosphorylase Deficiency Job syndrome Leukocyte adhesion defects Panhypogammaglobulinemia Bruton disease Congenital agammaglobulinemia Selective deficiency of IgA Complement deficiencies X-linked hyper-igm Reticular dysgenesis Cartilage hair hypoplasia Pigmentary dilution (Griscelli) syndrome IL-2 deficiency Chronic mucocutaneous candidiasis Fas (CD95) deficiency Investigational Infants with complete DiGeorge syndrome, who have no HLA-identical donors and who therefore need a cultured allogeneic thymic transplantation Stem Cell Transplantation in Adult Patients June

20 1. When both of the following are met: Lipidoses (Lipid Storage Disorders) Medically Necessary Transplant Indications Patient has any one of the following diagnoses: Metachromatic leukodystrophy; or Gaucher s disease Type I, II, and III; or Krabbe disease (also known as globoid cell leukodystrophy and galactosylceramide lipidosis); and All of the following criteria are met: Patient is neurologically intact or minimal neurologic damage has occurred; and Patient has failed conventional therapy (such as diet modification or enzyme therapy); and Transplant to use a 5/6 or 6/6 antigen matched, HLA molecular typing negative family patient donor Investigational Fabry s disease Sandhoff disease Niemann-Pick disease of any type Wolman Disease (also known as acid lipase deficiency) Farber s disease GM1 gangliosidoses GM2 gangliosidoses (includes Tay-Sachs disease [also known as GM2 variant B] and Sandhoff disease) Mucolipidoses (Lysosomal Storage Diseases) Medically Necessary Transplant Indications 1. None of these diseases are medically necessary for any form of stem cell transplant. Investigational Mucolipidosis I (sialidosis) Mucolipidosis II (inclusion-cell, or I-cell, disease) Mucolipidosis III (pseudo-hurler polydystrophy) Mucolipidosis IV Mucopolysaccharidoses (Lysosomal Storage Diseases) Medically Necessary Transplant Indications 1. Hurler Syndrome (MPS-IH) - preferably before age 2 and in combination with intravenous enzyme replacement therapy (ERT) 2. Maroteaux-Lamy Syndrome (MPS-VI) based on the improvement of outcomes found in case reports, a single HSC transplantation from a matched related, matched unrelated, or haploidentical donor Stem Cell Transplantation in Adult Patients June

21 Investigational Scheie Syndrome (MPS-IS) as symptoms are mild and lifespan is normal, and the risks of HSC transplantation outweigh any benefit Hunter Syndrome (MPS-II) as there is no cure for this syndrome, ERT remains experimental and may not be able to prevent neurologic disease from progressing, and stem cell transplantation has not demonstrated amelioration of central nervous system disease Sanfilippo Syndrome (MPS-III) as there is no specific treatment for this syndrome, and studies demonstrate that patients subsequently suffered from declining mental function and have not been shown to benefit from stem cell transplantation. Patients with Type IIIA have been shown to have progression of CNS deterioration at the same or faster rate than before transplantation Morquio Syndrome (MPS-IV) as there is no specific treatment for this syndrome and ERT is still considered experimental. Morquio syndrome has not been shown to improve with stem cell transplantation and peer-reviewed, published literature does not supply any documentation of recent trials of transplantation for Morquio syndrome. Sly Syndrome based on the lack of demonstrated efficacy in humans, therefore, stem cell transplantation remains experimental / Investigational Multiple Myeloma Medically Necessary Multiple myeloma is characterized by the excessive growth and malfunction of plasma cells in the bone marrow. The growth of these extra plasma cells interferes with the production of red blood cells, white blood cells, and platelets. This causes anemia, susceptibility to infection, and increased tendencies toward bleeding. Note: Autologous transplant is preferred at the present time. Transplant Indications Myeloablative allogeneic SCT is an accepted option, only as part of a clinical trial in any of the following: Individuals whose disease responds to primary therapy: or Patients with Primary progressive disease (PD): or Patients with PD after initial autologous SCT Note: Allogeneic transplant for patients with MM is a NCCN category 3 when done off a clinical trial Investigational As initial therapy for multiple myeloma As salvage HDC/AlloSCS for relapse of incomplete remission after HDC/AuSCS A planned marrow ablative allogeneic transplantation following an autologous transplantation Multiple Myeloma: The Durie-Salmon Staging System No anemia or hypercalcemia Stage I Less than two bone lesions Serum IgG less than 5 grams per deciliter; IgA less than 3 grams per deciliter Bence-jones proteinuria less than 4 grams per day Mild anemia or hypercalcemia Stage II More than two bone lesions Serum IgG between 5 and 7 grams per deciliter; IgA between 3 and 5 grams per deciliter Stem Cell Transplantation in Adult Patients June

22 Stage III Bence-jones proteinuria between 4 and 12 grams per day Significant anemia or hypercalcemia More than three bone lesions Serum IgG greater than 7 grams per deciliter; IgA greater than 5 grams per deciliter Bence-jones proteinuria greater than 12 grams per day Stem Cell Transplantation in Adult Patients June

23 Myelodysplastic Syndrome Medically Necessary Success of bone marrow transplantation has been found to correlate with severity of Myelodysplastic Syndrome (MDS) as determined by the International Prognostic Scoring System (IPSS) score. Risk factors include the patient s age, performance status, major comorbid conditions, psychosocial status, the IPSS score and the availability of a suitable donor. Patients older than 55 or 60 years, especially with less than 10% marrow myeloblasts, would generally undergo hematopoietic stem cell transplant (HSCT) after reduced or low intensity conditioning (RIC). If myeloblasts count is elevated pre HSCT, debulking therapy is generally given. Transplant Indications 1. In patients with myelodysplasia (pre-leukemia) when all of the following are met: Has a HLA-matched donor; and Patient proceeds directly to transplant if has an International Prognostic Scoring System (IPSS) risk groups score of > 1.5 (patients with lower risk disease should be treated with other modalities first and followed closely, with transplant being deferred if possible) Indicators Value IPSS Score Myeloblasts 5% or less 0 5 to 10% to 20% to 30% 2.0 Cytogenetics Good 0 Intermediate 0.5 Poor 1.0 Blood cytopenias 0/1 0 2/3 0.5 Note: The first prognostic factor is the amount or percent of myeloblasts in the patient's bone marrow. Each increase of 10% over the reference range is equivalent to half a point. For cytogenetics (chromosomal abnormalities), good is no abnormality (46,XX or 46,XY), -Y, del(5q), del(20q); intermediate is other abnormalities, such as trisomy 8 (+8); and poor is complex (33 abnormalities or chromosome 7 abnormality, i.e., 7q- or -7). The number of cytopenias is scored by the presence of anemia (hemoglobin level below 10g/dl) plus thrombocytopenia (platelet count below 100 x 10 9 /l) or neutropenia (WBC < 500/mm 3 ) or pancytopenia, which is worth half a point. The presence of none or a single cytopenia indicates a good prognosis. The individual scores for bone marrow blast percentage, karyotype and cytopaenias are then added together to give the IPSS score. The scores for the risk groups are as follows: Low-0 INT INT High >2.5 Note: Consider 2 nd transplant or DLI immune based therapy for appropriate patients who had a prolonged remission after 1 st transplant. Stem Cell Transplantation in Adult Patients June

24 Myeloproliferative Disorders (excludes CML includes Polycythemia Vera, Chronic Myelogenous Leukemia, Essential Thrombocythemia, Agnogenic Myeloid Metaplasia) Medically Necessary Transplant Indications 1. Patients with essential thombocythemia with an associated thrombotic or hemorrhagic disorder. 2. When there is progression to myelofibrosis with myeloid metaplasia (a chronic myeloproliferative disorder characterized by bone marrow fibrosis and extramedullary hematopoiesis), or transformation into acute myelocytic leukemia Note: CML is a Myeloproliferative Disorder and criteria for transplant are discussed separately. Non-Hodgkin s Lymphoma Medically Necessary Stem Cell Transplantation in Adult Patients June

25 Autologous transplantation is preferred over allogeneic. However, high-dose chemotherapy and allogeneic transplant should be reserved for patients failing other forms of therapy. Note: Additional, randomized studies comparing allogeneic and autologous approaches for relapsed non-hodgkin s lymphoma (NHL) are necessary to determine the most appropriate type of transplant. These studies would be specific for these individuals suffering from aggressive NHL, following high dose chemotherapy and radiation. Allogeneic Transplant Indications 1. Non-Hodgkin s Lymphoma with HLA-matched donor and any of the following is met: Intermediate and high-grade NHL (Stage III or IV A or B) refractory to primary chemotherapy or in second or subsequent partial or complete clinical remission with chemosensitive disease Low grade follicular NHL that has relapsed after primary therapy, including persons who have relapsed after autologous BMT NHL Stage IV A or B, high-grade NHL with a lymphoma mass over 10 cm and with more than one involved extranodal site, in first clinical remission Relapsed low grade follicular NHL who have failed primary therapy Lymphoblastic lymphoma and Burkitt's in first complete remission Chemosensitive mantle cell lymphoma, as second-line consolidation (either myeloablative or nonmyeloablative allogeneic SCT). Chemosensitive mantle cell lymphoma with relapsed disease following complete response (CR) to induction therapy, those who obtain only a partial response (PR) to induction therapy or those with progressive disease are appropriate candidates for clinical trials with high dose therapy with autologous or allogeneic stem cell rescue Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) refractory to chemoimmunotherapy or who develop recurrence within the 12 months after purine analog treatment. As second line therapy in individuals with CLL without del (p17) or del (11q) in a select population of patients (without significant comorbidities) with short responses to chemoimmunotherapy regime, but would generally be considered after re-induction of remission. CLL with del (17p) who have achieved complete response (CR) or partial response (PR) to first line therapy. CLL with del (11q) with PR to first line therapy or participation in clinical trial Individuals with Richter s transformation (histologic transformation to Diffuse Large B-Cell Lymphoma (DLBCL) or Hodgkin s lymphoma following response to initial therapy Investigational As initial therapy (i.e., without a full course of standard-dose induction chemotherapy) Sickle Cell Anemia Stem Cell Transplantation in Adult Patients June

26 Medically Necessary Transplant Indications 1. When all of the following criteria are met: Documented homozygous sickle cell anemia Children and young adults ( 25 years of age) who have an HLAmatched, related donor who is unaffected by the disease Who have one or more of the following features associated with increased risk of stroke or end-organ damage: prior stroke (CVA) or at increased risk of stroke (e.g., stopping regular blood transfusions End-organ damage acute, recurrent chest syndrome characterized by a rapid clinical course of chest pain, cough, progressive anemia, hypoxemia, and the presence of new pulmonary infiltrates on chest radiographs, with or without fever recurrent vaso-occlusive ("pain") crises red blood cell alloimmunization on chronic transfusion therapy Investigational Sickle cell trait Thalassemia Major Medically Necessary Transplant Indications 1. Thalassemia Major (Homozygous beta-thalassemia, Hemoglobin E-Thalassemia) in children and young adults 30 years of age when all of the following criteria are met: Patient shows deterioration with conventional treatments including transfusions, splenectomy, and deferoxamine; and Patient has minimal hepatomegaly, portal fibrosis, and active hepatitis; and Has a 5/6 or 6/6 HLA-matched donor Other Medically Necessary Conditions Medically Necessary Kostmann s Syndrome (severe infantile agranulocytosis) Amegakaryocytic Thrombocytopenia Infantile Malignant Osteopetrosis (Albers-Schoenberg Syndrome, Marble Bone Disease) Kostmann neutropenia Familial erythrophagocytic lymphohistiocytosis Duncan syndrome Neutrophil actin deficiencies All other indications for allogeneic transplant are considered investigational, including but not limited to the following: (Exceptions for the medical necessity of other rare conditions are at the discretion of the medical director of the health plan) Astrocytomas and Gliomas, malignant Beta-thalassemia major (in alphabetical order) Polycythemia vera Polymyositis Breast Cancer Chronic inflammatory demyelinating polyneuropathy Ovarian germ cell tumors Primitive Neuroectodermal Tumors (PNET), including medulloblastoma and ependymoma Stem Cell Transplantation in Adult Patients June

27 Dermatomyositis Ewing sarcoma Germ Cell Tumors (testicular, mediastinal, retroperitoneal, ovarian) Idiopathic thrombocytopenic purpura Juvenile rheumatoid arthritis Lupus erythematosus Medulloblastoma Melanoma Multiple sclerosis Osteosarcoma Ovarian epithelial and mixed epithelial / germ cell cancers Renal cell carcinoma Retinoblastoma Rhabdomyosarcoma Rheumatoid arthritis, Adult and Juvenile Severe systemic juvenile rheumatoid arthritis Sarcoma Systemic lupus erythematosus Systemic sclerosis (Scleroderma) Testicular cancer Wilms' tumor Codes Related To This Policy NOTE: The codes listed in this policy are for reference purposes only. Listing of a code in this policy does not imply that the service described by this code is a covered or noncovered health service. Coverage is determined by the benefit documents and medical necessity criteria. This list of codes may not be all inclusive. On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and inpatient procedures have been replaced by ICD-10 code sets. ICD-9 Codes Malignant neoplasm of retroperitoneum Malignant neoplasm of mediastinum code range Neuroblastoma Non-Hodgkin s disease Hodgkin s lymphoma, unspecified site Mycosis fungoides, unspecified site Multiple myeloma in relapse Chronic lymphocytic leukemia of B-cell type not having achieved remission High grade myelodysplastic syndrome lesions Amyloidosis Mucopolysaccharidosis (Hurler's and Maroteaux-Lamy syndromes) Other specified disorders of metabolism (histiocytosis) Wiskott-Aldrich syndrome Combined immunity deficiency (severe combined immunodeficiency) Thalassemia Sickle cell anemia Hemoglobinuria due to hemolysis from external causes (paroxysmal nocturnal hemoglobinuria) Other Agranulocytosis Functional disorders of polymorphonuclear neutrophils (chronic granulomatous disease) Genetic anomalies of leukocytes (Chediak-Higashi) Leukodystrophy (globoid cell, metachromatic, adrenoleukodystrophy) Osteopetrosis ICD-10 Codes C38-C38.8 Malignant neoplasm of heart, mediastinum and pleura Stem Cell Transplantation in Adult Patients June