Transplant Review Guidelines: Hematopoietic Stem Cell Transplantation Form

5

Indications If an indication is identified as “not standard of care”, the requested service may be covered if there is a state mandate, the member has a cancer clinical trial benefit, can be covered under the CRS program, if there is a life- threatening ill clause on the benefit plan, etc. and all provisions of the applicable benefit(s) have been met. Check for state mandates and the member’s benefit plan to determine eligibility. When reviewing the table on the following pages:  = Medically necessary

N = Not medically necessary

If nothing is indicated, this generally means that this is not considered an indication for stem cell transplant of the type requested and we do not expect to see requests for authorization for this type of stem cell transplant for this indication.

Disease/Indication

Auto

Allo

Comment

Leukemia Acute Lymphoblastic Leukemia (ALL) McNeer et al., 2019   Autologous SCT may be indicated in certain adults when there is no suitable allogeneic donor. Refer to the Medical Director. The following cytogenetic features are associated with pediatric high- risk disease and may influence the decision to transplant in CR1: • Hypodiploid ALL (< 44

chromosomes)

iAMP21

Acute Myeloid Leukemia (AML)

Dohner et al., 2017   Intermediate and high-risk AML including but not limited to: • First complete response (CR1) with poor-risk cytogenetics or molecular markers AML after relapse

CR2 and beyond See for the definition of risk markers and clinical risk factors. Autologous SCT may be indicated in certain adults when there is no suitable allogeneic donor. Refer to the Medical Director. © 2023 Optum, Inc. 6

Disease/Indication

Auto

Allo

Comment

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

N

N   There is a lack of data supporting auto for CLL; however, the availability of new agents such as idelalisib and ibrutinib, which are highly effective against this condition will likely change how stem cell transplantation is used in this disease. A history of prior treatment should be obtained with every transplant request. There are minimal to no data supporting auto in CML. Allo being used much less frequently in the era of tyrosine kinase inhibitors and primarily for the relatively rare very young patients and those exhibiting less than optimal responses to targeted therapy.

Prolymphocytic Leukemia  

Kalaycio et al., 2010; Krishnan et al., 2010

Myelodysplastic Syndromes & Mixed Myelodysplastic/Myeloproliferative Neoplasms Myelodysplastic Syndromes (MDS) 

N

Juvenile Myelomonocytic Leukemia (JMML/JCML)

N 

Chronic myelomonocytic leukemia (CMML)

Swerdlow et al., 2017

N 

The World Health Organization (WHO) classifies CMML as a myelodysplastic/myeloproliferative neoplasm.

Myeloproliferative Disorders Primary Myelofibrosis and related conditions (e.g., PRV)

Gagelman et al., 2019

Secondary Myelofibrosis

N

N   Allo approved with Intermediate-2 or High-Risk score using the Dynamic International Prognostic Scoring System Plus (DIPSS Plus). See for DIPSS Plus scoring system. The identification of adverse karyotypes is evolving. New clinical-molecular scoring systems may be useful in determining post-transplant prognosis. Allo transplant evaluation approved for patients with polycythemia vera or essential thrombocythemia.

Brain Tumors Anaplastic Astrocytoma

N

Not standard of care © 2023 Optum, Inc. 7

Disease/Indication

Auto

Allo

Comment

Brain stem glioma

N

Not standard of care

Ependymoma

N

Not standard of care

Germinoma

N

Not standard of care

Glioblastoma Multiforme (GBM) Medulloblastoma

Oligodendroglioma

Pineoblastoma Embryonal Tumors with Multi-layered Rosettes (ETMR). Formerly known as Primitive Neuroectodermal Tumor (PNET)

N     May be considered in infants

Germ Cell Tumors Testicular Germ Cell Tumor Extragonadal Germ Cell Tumor Seminoma

Choriocarcinoma

Embryonal Carcinoma

Mixed Germ Cell Tumors

Teratoma

Yolk-Sac Tumor (Endodermal Sinus Tumor) Germ Cell Tumor of the Ovary          Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved Tandem auto can be approved

Multiple Myeloma/ Plasma Cell Disorders Multiple Myeloma

Refer allograft request to Medical Director

a) Single auto

b) Tandem (auto   followed by auto)

c) Tandem (auto

See SPECIAL CONSIDERATIONS followed by allo)

d) Allogeneic

See SPECIAL CONSIDERATIONS

AL-Amyloidosis 

N Allogeneic SCT may be appropriate on clinical trial.

Waldenstrom Macroglobulinemia   © 2023 Optum, Inc. 8

Disease/Indication

Monoclonal gammopathy of renal significance (MGRS) Monoclonal gammopathy of uncertain significance (MGUS) POEMS (Polyneuropathy Organomegaly Endocrinopathy, Monoclonal Gammopathy Skin defects Syndrome) D'Souza et al., 2012; Ji et al., 2012; Li et al., 2013 Solitary Plasmacytoma

Hodgkin’s Lymphoma Hodgkin’s Lymphoma

Non-Hodgkin’s Lymphoma (NHL)

Small B-cell lymphocytic lymphoma

Follicular lymphoma Epperala et al., 2018; Oliansky et al., 2010; Sureda et al., 2018 Lymphoplasmacytoid lymphoma/immunocytoma Marginal zone lymphoma (mucosa-associated lymphoid tissue, splenic, nodal) Burkitt lymphoma

Diffuse, large cell lymphoma (mediastinal large cell, primary effusion) Oliansky et al. 2011 Mantle cell lymphoma

Precursor B-cell leukemia/lymphoma T-cell Lymphoma

Other Malignancies © 2023 Optum, Inc.

Auto

Allo

Comment

See SPECIAL CONSIDERATIONS.

N

N No transplant indicated 

N Autologous SCT may be appropriate. Refer to Medical Director.

N

N No transplant indicated  

N  For autologous transplants, tumors must be chemosensitive which is defined as a complete or partial response based on the Cheson criteria. See for Cheson criteria. Auto not standard of care. This is treated in the same manner as CLL. Refer to Medical Director.                 9

Disease/Indication

Atypical Teratoid Rhabdoid Tumors

Nikolaides et al., 2010 Blastic Plasmacytoid Dendritic Cell Neoplasm

Dietrich et al., 2014 Epithelial Ovarian Cancer

Ewing Tumor (Ewing Sarcoma) Neuroblastoma

Osteogenic sarcoma

Renal Cell Carcinoma

Retinoblastoma

Rhabdomyosarcoma/soft tissue sarcoma

Stiff et al., 2010 Supratentorial ependymoma

Venkatramani et al., 2013 Wilms Tumor

Brown et al.,2010; Campbell et al., 2004

Hematological Disorders Aplastic Anemia Blackfan-Diamond Syndrome Chronic Granulomatous Disease Congenital Agranulocytosis (Kostmann Syndrome) Congenital Amegakaryocytic Thrombocytopenia Dyskeratosis Congenita

Fanconi Anemia

Paroxysmal Nocturnal Hemoglobinuria (PNH) Shwachman-Diamond Syndrome © 2023 Optum, Inc. 

N N  

N N 

N  

Auto

N 

N

N

N

N

N

N

N

N         

Allo

Comment Tandem auto may be indicated. May be appropriate as part of a clinical trial.

Not standard of care

Allogeneic not standard of care Tandem auto can be approved

Not standard of care

Not standard of care

Allogeneic not standard of care May be appropriate as part of a clinical trial. Refer to Medical Director May be appropriate in relapsed disease as part of a clinical trial. Refer to Medical Director 10

Disease/Indication

Sickle Cell Disease (SCD)

Thalassemia Major

Immunodeficiency Syndromes CD40 Ligand Deficiency Chediak-Higashi Syndrome Hemophagocytic Lymphohistiocytosis (HLH) (same as Familial Erythrophagocytic Lymphohistiocytosis - FEL) Leukocyte Adhesion Deficiency Omenn Syndrome

Severe Combined Immunodeficiency Disease (SCID)*

Wiskott-Aldrich Syndrome

X-linked Lymphoproliferative Syndrome Gaucher disease type I Pastores et al., 2004; Charrow et al.,2004; Peters & Steward, 2003; Jmoudiak & Futerman, 2005 © 2023 Optum, Inc.

Auto           

Allo

Comment American Society of Hematology (ASH) has published a guideline consisting of eight recommendations for HSCT for SCD (Kanter et al., 2021). Available at: American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation | Blood Advances | American Society of Hematology (ashpublications.org) In addition to classical SCID, there are a variety of severe mixed (B- and T- cell) immune deficiency syndromes, with or without defined genetic abnormalities, which can be treated with allogeneic stem cell transplant. As new genetic abnormalities are identified that can result in immunodeficiency syndromes, allogeneic transplantation may be appropriate treatment. Patients with the non-neuropathic type may benefit from a stem cell transplant following failed enzyme replacement therapy or if significant bone pain exists despite enzyme replacement therapy. 11

Disease/Indication

Niemann-Pick type B

Schuchman, 2009

Fucosidosis

Miano et al., 2001; Vellodi et al., 1995

Lysosomal storage diseases

Heese, 2008

Autoimmune Diseases Crohn’s Disease

Multiple Sclerosis Cohen et al., 2019; Hooper, 2011; Kurtzke, 1982; National Multiple Sclerosis Society, 2011 © 2023 Optum, Inc.

N

Y

Auto   

N

N

Allo

Comment In a non-cerebral form, transplantation may effectively diminish the impact of the accumulation of metabolic byproducts in lung and liver. These patients die from lung and liver disease and are candidates for stem cell transplantation. There is little experience with transplantation for fucosidosis, a very rare entity among rare entities, but reports indicate that stem cell transplantation performed early effectively ameliorates disease progression. Not standard of care. Must be performed under a clinical trial and would only be considered for approval if the member’s benefit plan supports participation in a clinical trial. • Patient must meet the definition of

relapsing-remitting (RR) or secondary progressive (SP) multiple sclerosis Expanded Disability Status Scale (EDSS) score between 2.0 and 6.0

Patient has failed treatment with one or more disease-modifying therapies (DMT)

Evidence of either of the following while being treated with DMT: − two or more clinical relapses at separate times but within the previous 12 months − one relapse and a magnetic resonance imaging (MRI) gadolinium- enhancing lesion(s) at a separate time than the relapse but within the previous 12 months See for definitions of Relapsing-Remitting MS (RRMS), Secondary-Progressive MS (SPMS), and relapse of MS. 12

Disease/Indication

Rheumatoid Arthritis

Systemic lupus erythematosus (SLE)

Systemic Sclerosis (Scleroderma)

Host et al., 2017; Sullivan et al., 2018

Inherited Metabolic Disorders Adrenoleukodystrophy

Epidermolysis Bullosa

Globoid Cell Leukodystrophy (Krabbe Disease) Hurler Syndrome (MPS I)

Hunter Syndrome (MPS II) © 2023 Optum, Inc.

N

N

Y

Auto

N

N

N     

Allo

Comment Not standard of care. Must be performed under a clinical trial and would only be considered for approval if the member’s benefit plan supports participation in a clinical trial. Not standard of care. Must be performed under a clinical trial and would only be considered for approval if the member’s benefit plan supports participation in a clinical trial. Adult patients at least 18 years of age with rapidly progressive systemic sclerosis (scleroderma) scleroderma (systemic sclerosis) at risk of organ failure with either: • Pulmonary involvement with active interstitial lung disease and both: − Consistent bronchoalveolar cell composition or ground-glass opacities on CT of the chest − Either a forced vital capacity (FVC) or a diffusing capacity of the lung carbon monoxide (DLco) of less than 70% of the predicted value. Renal involvement • Patient does not have ANY of the following: − a DLco of less than 40% of predicted value − an FVC of less than 45% of predicted value − a creatinine clearance of less than

40 ml per minute − pulmonary arterial hypertension, − a left ventricular ejection fraction of less than 50% • Patient is felt to be an

appropriate candidate for autologous transplant by the treating facility 13

Disease/Indication

Auto

Allo

Comment

Mannosidosis

Maroteaux-Lamy Syndrome (MPS VI) Metachromatic Leukodystrophy Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)    

Filosto et al., 2012 Halter et al., 2011; Osteopetrosis

Rett Syndrome  

Cardiac Conditions Heart Disease

N

N Not standard of care. It would only be considered for approval under a clinical trial if the member’s benefit plan supports participation in a clinical trial. Additional Condition/Disease Indications Refer to section titled: Hematopoietic Stem Cell Transplant Reference Sheet in the Error! Reference source not found.  The reference sheet includes a list of rare and unusual conditions where allogeneic transplant may be indicated. If there is a condition found within this reference that is not included above, refer to Medical Director.

Relative contraindications The following list contains potential contraindications for hematopoietic stem cell transplant. While the conditions listed below would not be absolute contraindications for treatment they need to be addressed prior to transplant. Infections − Systemic or uncontrolled infection including sepsis. Significant uncorrectable life-limiting medical conditions.

Severe end stage organ damage that would have an impact on patient survival.

Irreversible, severe brain damage. Social and Psychiatric Issues — It is expected that a patient has demonstrated adherence to all treatment plans and scheduled appointments and there is documentation of a support system and/or caregiver available to provide necessary care. A case should be referred for psychosocial evaluation and/or psychiatry consultation for guidance in any of the following circumstances: © 2023 Optum, Inc. 14 – Emotional instability, significant depression or other psychiatric illness that cannot be controlled that would impact ability to comply with a complex evaluation process, surgical procedure and post-transplant plan of care and/or ability to give informed consent (and does not have a representative/guardian/conservator). – Limited cognitive ability (memory loss, dementia, etc.) that would impact ability to comply with a complex evaluation process, surgical procedure and post-transplant plan of care and/or ability to give informed consent (and does not have a representative/guardian/conservator). – Lack of psychosocial support as indicated by either no identified caregiver or an uncommitted caregiver. This would include the lack of transportation to and from transplant related appointments, patient and/or caregiver is unable to adhere to the requirements of transplant related treatment plan. A care contract may be needed. – Lack of sufficient financial means to purchase post-transplant medications. – History of non-adherence that has not been successfully remediated. – Inability to give informed consent. If the patient has an authorized representative/guardian/conservator or parent in the case of a minor, that individual must understand and support the ongoing health care needs of the patient. Limited irreversible rehabilitative potential (Bunnapradist, 2007).

Special considerations Additional consultation and/or evaluation may be indicated in these situations. Refer to Medical Director if questions remain. Multiple Myeloma Allogeneic stem cell transplant for multiple myeloma is controversial either as a single allogeneic transplant as initial therapy with curative intent or as the second stage of a planned tandem transplant proceeded by an autologous transplant. The following recommendations are consistent with the evolving practice and recognize the expertise of treating physicians within network programs. The recommendations may change as additional experience is gained with the newer disease modifying agents for the treatment of myeloma and as more experience is gained with reduced intensity allogeneic stem cell transplant for this disease. Note: Refer all requests for allogeneic stem cell transplant in multiple myeloma to Medical Director for review. − Allogeneic stem cell transplant may be appropriate therapy under the following circumstances:

o Initial therapy in newly diagnosed patients with high-risk disease and in otherwise good health High risk myeloma has been defined by the International Myeloma Working Group (IMWG) based on cytogenics [Presence of at least one of the following: del(17p), t(4;14) or t(14;16) determined by FISH] and the Mayo Clinic classification adds hypoploidy and t(14;20) to the IMWG definition. Regardless of the source of definition, the requestor should present evidence of sufficient factors that cause the case to be considered high risk. o Early relapse (less than 24 months) after primary therapy that included an autologous stem cell transplant or with high-risk features (i.e., cytogenetics, extramedullary disease, plasma cell leukemia, or high lactate dehydrogenase) if they respond favorably to salvage therapy. (Giralt, 2015) © 2023 Optum, Inc. 15 o Reduced intensity matched related donor (MRD) and matched unrelated donor (MUD) allogeneic SCT as the second transplant of a planned tandem transplant. (Bruno, 2009; Rotta, 2009) Monoclonal gammopathy of renal significance (MGRS) is a clonal proliferative disorder that produces a nephrotoxic monoclonal immunoglobulin and does not meet previously defined hematological criteria for treatment of a specific malignancy. Monoclonal immunoglobulin-related diseases show higher rates of recurrence after kidney transplantation (often > 80%) than their non-monoclonal counterparts They are poorly responsive to conventional immunosuppression (Leung et al., 2019). Targeting the underlying B-cell clone with chemotherapy, although it is not an evidently malignant clone per se, is the only available treatment option for MGRS. High-dose melphalan (HDM) supported by autologous SCT may be a therapeutic option in some patients (Fermand et al., 2013). Refer requests for SCT in patients with MGRS to Medical Director. − Autologous SCT may be appropriate in patients with MGRS who meet the following: o Have failed chemotherapy targeting the underlying B-cell clone

AND o Have sufficient renal function to tolerate high-dose chemotherapy Initial therapy in newly

diagnosed patients with high-risk disease and in otherwise good health HIV infection − Patients should have a formal infectious disease consult indicating adequate treatment and proper assessment of risks related to this transplant. − Patients with known HIV infection must be on a HAART regiment and there must be documented

evidence of viral load suppression. Refer to requesting program patient selection criteria for age-specific criteria − If outside program’s patient selection criteria, refer to Medical Director Serum creatinine < 2.5 mg/dL (≤ 1.5 mg/dL in children) or GFR > 50ml/min. − Serum creatinine may be higher in patients with multiple myeloma or other plasma cell dyscrasias. Patients with multiple myeloma with reduced renal function are not prohibited from undergoing autologous BMT when the decreased renal function is related to the multiple myeloma (myeloma kidney). This includes patients on hemodialysis with no other contraindications. Active untreated or untreatable malignancy in patients undergoing stem cell transplantation for non- malignant indications

− Refer to Medical Director Patients with post-transplant lymphoproliferative disease (PTLD), having failed other conventional therapies, must have no active disease as demonstrated by negative positron emission tomography (PET) scan and resolved adenopathy on computed tomography (CT) and/or magnetic resonance imaging (MRI) (Blaes, 2009; Khedmat, 2009, Panagiotidis, 2014). © 2023 Optum, Inc. 16

Hematopoietic Stem Cell Transplant — Timing for Stem Cell Transplant Consultation These 2022 guidelines were developed jointly by the National Marrow Donor Program® (NMDP®)/Be the Match® and the American Society for Transplant and Cellular Therapy (ASTCT), and are based on current clinical practice, medical literature, National Comprehensive Cancer Network® (NCCN®) Guidelines for the treatment of cancer and evidence-based reviews. The guidelines identify appropriate timing of consultation for autologous or allogeneic hematopoietic cell transplantation (HCT) based on disease characteristics. Evaluation and coordination of timing of HCT for eligible patients is determined in collaboration with the transplant center. Early referral is a critical factor for optimal transplant outcomes. In many situations, there may be a narrow window of opportunity to proceed to transplant and delays might preclude transplant or impair transplant outcomes. Research data comparing outcomes by disease status can be found at Referral Timing Guidelines Referral Timing Guidelines (bethematchclinical.org).

Adult leukemias and myelodysplasia

Acute Myeloid Leukemia (AML) High-resolution HLA typing is recommended at diagnosis for all patients • HCT consultation should take place early after initial diagnosis for all patient with AML, including: − Primary induction failure − Measurable (also known as minimal) residual disease after initial therapy − CR1- except favorable risk AML [defined as: t(8:2109q22;q22.1); RUNX1-RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11, mutated NPM1 without FLT3-ITD, biallelic mutated]. Early referral for allogeneic HCT should also be considered for any AML patients in CR1 who are 60 years or older; regardless of cytogenetic or genomic information. − Antecedent hematological disease (e.g., myelodysplastic syndrome [MDS]) − Treatment-related leukemia − First relapse − CR2 and beyond, if not previously evaluated Acute Lymphoblastic Leukemia (ALL) (adult defined as ≥ 40 years) High-resolution HLA typing is recommended at diagnosis for all patients • HCT consultation should take place early after initial diagnosis for all patients with ALL, including: − Primary induction failure − Measurable (also known as minimal) residual disease after initial therapy − CR1 − First relapse − CR2 and beyond, if not previously evaluated

Myelodysplastic Syndromes (MDS) High-resolution HLA typing is recommended at diagnosis for all patients • Any intermediate or high IPSS or IPSS-R score • Any MDS with poor prognostic features, including: − Treatment-related MDS − Refractory cytopenias − Adverse cytogenetics and molecular features © 2023 Optum, Inc. 17 − Transfusion dependence − Failure pf hypomethylating agents or chemotherapy − Moderate to severe marrow fibrosis

Chronic Myeloid Leukemia (CML) • Disease progression • • Accelerated phase • Blast crisis (myeloid or lymphoid) • T3151 mutation Inadequate hematologic or cytogenetic/molecular response to tyrosine kinase inhibitor (TKI) therapies

Intolerance to TKI therapies Myeloproliferative Neoplasms (MPN) (including BCR-ABL-negative myeloproliferative neoplasm and later stages of polycythemia vera and essential thrombocytosis) High-resolution HLA typing is recommended at diagnosis for all patients • Intermediate- or high-risk disease, including: − High-risk cytogenetics − Poor initial response or at progression

Myelofibrosis (MF) DIPSS Intermediate-2 (INT-2) and high risk disease • DIPSS Intermediate-1 (INT-1) with low platelet counts, refractory, red blood cell transfusion dependent, circulating blast cells > 2%, complex cytogenetics

High risk driver mutations (ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and TP53) or triple negative (lack of a driver mutation such as JAK2, MPL, or CALR) should be considered in decision making

Chronic Lymphocytic Leukemia (CLL) Resistance or intolerance to BTK inhibitors and/or BCL2 inhibitors

Pediatric Acute Leukemias and Myelodysplasia

Acute Myeloid Leukemia (AML) High-resolution HLA typing is recommended at diagnosis for all patients • Early after initial diagnosis, all patients with AML including: − Age < 2 years at diagnosis − Primary induction failure − Measurable (also known as minimal) residual disease after initial therapy − CR1 – except favorable risk AML [defined as: t(8;21)(q22;q22.1); RUNX1-RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q220); CBFB-MYH11, mutated NPM1 without FLT3-ITD or with FLT3-ITDlow, biallelic mutated CEBPA] − Monosomy 5 or 7 − Treatment-related leukemia − First relapse − CR2 and beyond, if not previously evaluated © 2023 Optum, Inc. 18

Acute Lymphoblastic Leukemia (ALL) (age < 15 years)

Infant at diagnosis − Unfavorable genetics − Age < 3 months with any WBC, or < 6 months with WBC > 300,000 at presentation Primary induction failure • Presence of measurable (also known as minimal) residual disease after initial therapy • High/very high-risk CR1, including: − Philadelphia chromosome positive slow-TKI responders or with IKZF1 deletions; Philadelphia-like − − 11q23 rearrangement

iAMP21 First relapse • CR2 and beyond, if not previously evaluated • Chimeric Antigen Receptor Therapy (CAR-T)

Acute Lymphoblastic Leukemia (ALL) (adolescent and young adults age 15-39 years) High-resolution HLA typing is recommended at diagnosis for all patients • Presence of measurable (also known as minimal) residual disease after initial therapy • High/very high-risk CR1, including: − Philadelphia chromosome positive or Philadelphia-like − − 11q23 rearrangement − B-cell with poor-risk cytogenetics

High-resolution HLA typing is recommended at diagnosis for all patients • Presence of measurable (also known as minimal) residual disease after initial therapy • High/very high-risk CR1, including: − Philadelphia chromosome positive or Philadelphia-like − − 11q23 rearrangement − B-cell with poor-risk cytogenetics

First relapse • CR2 and beyond, if not previously evaluated

Myelodysplastic Syndromes (MDS) At diagnosis for all subtypes

Juvenile Myelomonocytic Leukemia (JMML) At diagnosis

Plasma Cell Disorders

Multiple Myeloma At diagnosis • At progression and/or relapse

Light Chain Amyloidosis At diagnosis • At progression and/or relapse

POEMS Syndrome (Osteosclerotic Myeloma) At diagnosis © 2023 Optum, Inc. 19

Lymphomas

Non-Hodgkin Lymphoma

Follicular Poor response to initial treatment • • First relapse • Transformation to diffuse large B-cell lymphoma

Initial remission duration < 24 months

Diffuse Large B-cell Primary induction failure, including residual PET avid disease • First relapse • CR2 or subsequent remission • Double or triple hit (MYC and BCL-2 and/or BCL-6) at diagnosis • Primary CNS lymphoma at diagnosis PIF or first relapse High Grade B-cell

MYC and BCL-2 and/or BCL-6 rearrangements • Primary induction failure • CR1 • First relapse • CR2 or subsequent remission Mantle Cell

At diagnosis • First relapse • Bruton’s tyrosine kinase (BYK) intolerant or resistant disease

Mature T-cell CR1 • First relapse

Other High-risk Lymphomas At diagnosis

Other Malignant Diseases

Germ Cell Tumors Poor initial response • Short initial relapse © 2023 Optum, Inc. 20

Neuroblastoma

INSS stage 2 or 3 at diagnosis − MYCN amplification (> 4x above reference) INSS stage 4 at diagnosis − MYCN amplification (> 4x above reference) − Age > 18 months at diagnosis − Age 12-18 months with unfavorable characteristics Metastatic disease at diagnosis • Progressive disease while on therapy or relapsed disease Ewing family of Tumors Metastatic disease at diagnosis • First relapse or CR 2

Medulloblastoma First relapse or CR2

Non-Malignant Disorders Immune Deficiency Diseases (including severe combined immunodeficiency syndromes, Wiskott-Aldrich syndrome, Omenn syndrome, X-linked lymphoproliferative syndrome, severe congenital neutropenia and others) At diagnosis or if detected on newborn screening Inherited Metabolic Disorders (including Hurler syndrome, adrenoleukodystrophy, and others) At diagnosis or if detected on newborn screening

Hemoglobinopathies

Sickle Cell Disease Children with available matched sibling donor • All patients with aggressive course (stroke, end-organ complications, frequent pain crises) • All patients with an alternative donor option and any of the following: − Stroke or silent cerebral infarct or cognitive impairment > 24 hours − ≥ 2 episodes of acute chest syndrome/2-year period [or] recurrent acute chest syndrome − Regular red blood cell transfusion therapy (8 or more per year) − Tricuspid valve regurgitant jet (TRJ) velocity ≥ 2.7 m/sec − Chronic pain ≥ 6 months (leg ulcers, avascular necrosis) − Abnormal transcranial Doppler (TCD) velocity of ≥ 200 cm/sec or > 185 cm/sec with intracranial vasculopathy − Silent cerebral infarct − ≥ 3 severe vaso-occlusive pain crises per 2-year period © 2023 Optum, Inc. 21

Transfusion-dependent Thalassemias At diagnosis

Hemophagocytic Lymphohistiocytosis (HLH) At diagnosis Severe Aplastic Anemia and Other Marrow Failure Syndromes (including Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome and others) At diagnosis

Systemic Sclerosis At diagnosis or with diffuse disease, with increasing skin tightness score (modified Rodnan skin score, [mRSS]) and evidence of decrease (< 80%) in % predicted pulmonary function tests: forced vital capacity (FVC) and/or diffusion capacity (DLCO)

Multiple Sclerosis (MS) After MS relapse, with ≥ 2 relapse episodes in past 3 years, while on disease modifying therapy. Refer patient prior to progression of severe disability: patient must be able to walk 100 meters (with unilateral assistance: cane, crutch or brace) © 2023 Optum, Inc. 22

Bashey A, Pérez WAS, Zhang M-J, et al. Comparison of twin and autologous transplants for multiple myeloma. Biol Blood Marrow Transplant. 2008;14(10):1118-24. Bensinger WI. (2) Reduced intensity allogeneic stem cell transplantation in multiple myeloma. Front Biosci. 2007 May;12:4384-4392. Blade J , Rosin, L, Cibeira MT, et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. Blood. 2010;115(18):3655-3663. Blaes AH et al. Positron emission tomography scanning in the setting of post-transplant lymphoproliferative disorders. Clin Transplant. 2009 Nov-Dec;23(6):794-9. Brown E, Hebra A, Jenrette J, Hudspeth MP. Successful treatment of late, recurrent Wilms' tumor with high dose chemotherapy and autologous stem cell rescue in third complete response. J Pediatr Hematol Oncol. 2010;32(6):e241-e243. doi:10.1097/MPH.0b013e3181e5e25b. Bruno B et al (1). A comparison of allografting with autografting for newly diagnosed myeloma. N Engl J Med. 2007;356(11):1110-1120. Bruno B, et al (2). Unrelated donor hematopoietic cell transplantation after non-cytoreductive conditioning for patients with high-risk myeloma. Eur J Haematol. 2007 Apr;78(4):330-337. Bruno, B et al (3). Nonmyeloablative allografting for newly diagnosed multiple myeloma: the experience of the Gruppo Italiano Trapianti di Midollo. Blood. 2009;113:3375-3382. Bruno B, Giaconne L. Sorasio R, Boccadero M (4). Role of allogeneic stem cell transplant in multiple myeloma. Semin Hematol. 2009 Apr;46(2):158-165. Brunstein CG, Barker JN, Weisdorf DJ, et al. (1) Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007 Oct;110(8):3064-3070. Brunstein CG, Cantero S, Coa Q, et al. (2) Promising progression-free survival for patients low and intermediate grade lymphoid malignancies after nonmyeloablative umbilical cord blood transplantation. Biol Blood Marrow Transplant. 2009;15:214-222. Bunnapradist S, Danovitch G. Evaluation of Adult Kidney Transplant Candidates. Am J Kidney Dis. 2007 Nov; 50(5):890-898. Campbell AD, Cohn SL, Reynolds M, et al. Treatment of relapsed Wilms’ tumor with high-dose therapy and autologous hematopoietic stem-cell rescue: the experience at Children’s Memorial Hospital. J Clin Oncol. 2004;22(14):2885-2890. Castagna L, Sarina B, Bramanti S, et al. Donor lymphocyte infusion after allogeneic stem cell transplantation. Transfus Apher Sci. 2016 Jun;54(3):345-55. doi: 10.1016/j.transci.2016.05.011. Epub 2016 May 13. PMID: 27216544. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895- 2901. Charrow J, Andersson HC, Kaplan P, et al. Enzyme replacement therapy and monitoring for children with type 1 Gaucher disease: Consensus recommendations. J Pediatr. 2004;144:112-120. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579-86. Cohen JA, Baldassari LE, Atkins HL, et al. Autologous Hematopoietic Cell Transplantation for Treatment-Refractory Relapsing Multiple Sclerosis: Position Statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2019;25(5):845-854. doi:10.1016/j.bbmt.2019.02.014 D'Souza A, Lacy M, Gertz M, et al. Long-term outcomes after autologous stem cell transplantation for patients with POEMS syndrome (osteosclerotic myeloma): a single-center experience. Blood. 2012 Jul;120(1):56-62. de Lima M, Shpall E. Strategies for widening the use of cord blood in hematopoietic stem cell transplantation. Haematologica. 2006;91(5):584-7. © 2023 Optum, Inc. 23 Devine, SM, Flomenberg, N, Vesole, et al. (1) Rapid mobilization of CD34+ cells following administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and Non-Hodgkin’s Lymphoma. J Clin Oncol. 2004;22:1095-1102. Devine SM, Vij R, Rettig M, et al. (2) Rapid mobilization of functional donor hematopoietic cells without G- CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112(4):990-998. Dietrich S, Weidle J, Rieger J, et al. Rituximab Maintenance Therapy After Autologous Stem Cell Transplantation Prolongs Progression-Free Survival in Patients with Mantle Cell Lymphoma. Leukemia. 2014;28:708-709. doi:10.1038/leu.2013.332 DiPersio J, Stadtmauer EA, Nademanee AP, et al. (1) A phase III, multicenter, randomized, double-blind, placebo-controlled, comparative trial of AMD3100 (Plerixafor)+G-CSF vs. G-CSF+placebo for mobilization in multiple myeloma (MM) patients for autologous hematopoietic stem cell (aHSC) transplantation. Blood (ASH Annual Meeting Abstracts). 2007;110: Abstract 445. © 2007 American Society of Hematology. DiPersio J, Micallef I, Stiff PJ, et al. (2) A phase III, multicenter, randomized, double-blind, placebo controlled, comparative trial of AMD3100 (Plerixafor)+G-CSF vs. placebo+G-CSF in Non-Hodgkin’s lymphoma (NHL) patients for autologous hematopoietic stem cell (aHSC) transplantation. Blood (ASH Annual Meeting Abstracts). 2007;110: Abstract 601. © 2007 American Society of Hematology. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. doi:10.1182/blood-2016- 08-733196 Epperala N. et al. Fludarabine and Busulfan versus Fludarabine, Cyclophosphamide, and Rituximab as Reduced-Intensity Conditioning for Allogeneic Transplantation in Follicular Lymphoma. Biol Blood Marrow Transplant 2018; 24:78–85. Fermand JP, Bridoux F, Kyle RA, et al., International Kidney and Monoclonal Gammopathy Research Group. How I treat monoclonal gammopathy of renal significance (MGRS). Blood. 2013 Nov 21;122(22):3583-90. doi: 10.1182/blood-2013-05-495929. Epub 2013 Oct 9. PMID: 24108460. Filosto M, Scarpelli M, Tonin P, et al. Course and management of allogeneic stem cell transplantation in patients with mitochondrial neurogastrointestinal encephalomyopathy. J Neurol. 2012;259(12):2699-706. Flomenberg N, Devine SM, Dipersio JF, et al. The use of AMD3100 plus G-CSF for autologous hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood. 2005;106(5):1867-1874. Freed J, Talano J, Small T, Ricci A, Cairo MS. Allogeneic cellular and autologous stem cell therapy for sickle cell disease. Bone Marrow Transplant. 2012 Dec;47(12):1489-98. doi: 10.1038/bmt.2011.245. Epub 2011 Dec 19. Gagelmann N, Ditschkowski M, Bogdanov R, et al. Comprehensive clinical-molecular transplant scoring system for myelofibrosis undergoing stem cell transplantation. Blood. 2019 May 16;133(20):2233-2242. doi: 10.1182/blood-2018- 12-890889. Epub 2019 Feb 13. PMID: 30760453. Giralt S, Garderet L, Durie B, et al. American Society of Blood and Marrow Transplantation, European Society of Blood and Marrow Transplantation, Blood and Marrow Transplant Clinical Trials Network, and International Myeloma Working Group Consensus Conference on Salvage Hematopoietic Cell Transplantation in Patients with Relapsed Multiple Myeloma. Biol Blood Marrow Transplant. 2015 Dec;21(12):2039-51. doi:10.1016/j.bbmt. Halter J, Schüpbach WM, Casali C, et al. Allogeneic hematopoietic SCT as treatment option for patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a consensus conference proposal for a standardized approach. Bone Marrow Transplant. 2011 Mar;46(3):330-7. Harousseau JL, Moreau P. Autologous hematopoietic stem-cell transplantation for multiple myeloma. N Engl J Med. 2009;360(25):2645-2654. Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008;15:119-126. Horwitz ME, Stiff PJ, Cutler C, et al. Omidubicel vs standard myeloablative umbilical cord blood transplantation: results of a phase 3 randomized study. Blood. 2021 Oct 21;138(16):1429-1440. doi: 10.1182/blood.2021011719. PMID: 34157093; PMCID: PMC9710469. Host L, Nikpour M, Calderone A, et al. Autologous stem cell transplantation in systemic sclerosis: a systematic review. Clin Exp Rheumatol. 2017;35 Suppl 106(4):198-207. © 2023 Optum, Inc. 24 Ji ZF, Zhang DY, Weng SQ, et al. POEMS Syndrome: A report of 14 cases and review of the literature. ISRN Gastroenterol. 2012;2012:584287. Jmoudiak M, Futerman AH. Gaucher disease: Pathological mechanisms and modern management. Br J Haematol. 2005;129:178-188. Kalaycio ME, Kukreja M, Woolfrey AE, et al. Allogeneic hematopoietic cell transplant for prolymphocytic leukemia. Biol Blood Marrow Transplant. 2010;16:543. Kanter J, Liem RI, Bernaudin F, et al. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021 Sep 28;5(18):3668-3689. doi: 10.1182/bloodadvances.2021004394C. PMID: 34581773; PMCID: PMC8945587. Khedmat H. Early onset post transplantation lymphoproliferative disorders: analysis of international data from 5 studies. Ann Transplant. 2009;14(3):74-7. Klingebiel T, Cornish J, Labopin M, et al. on behalf of the Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT). Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood. 2010;115(17):3437- 3446. Krishnan B, Else M, Tjonnfjord GE, et al. Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study. Br J Haematol. 2010;149:907. Kumar A, Kharfan-Dabaja MA, Glasmacher A, et al. Tandem versus single autologous hematopoietic cell transplantation for the treatment of multiple myeloma: a systematic review and meta-analysis. J Natl Cancer Inst. 2009;101:100-106. LeMaistre CF et al. Standardization for terminology of episodes of hematopoietic stem cell patient transplant care. Biol Blood Marrow Transplant 2013; 19(6):851-57. Leung N, Bridoux F, Batuman V, et al. Publisher Correction: The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019 Feb;15(2):121. doi: 10.1038/s41581-018-0102-7. Erratum for: Nat Rev Nephrol. 2019 Jan;15(1):45-59. PMID: 30568288; PMCID: PMC7608309. Li J, Zhang W, Duan MH, et al. PBSC mobilization in newly diagnosed patients with POEMS syndrome: outcomes and prognostic factors. Bone Marrow Transplant. 2013 Feb;48(2):233-7. Lin C, Horwitz ME. Corrigendum to 'Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials'. Transplant Cell Ther. 2023 Jul 5:S2666-6367(23)01356-8. doi: 10.1016/j.jtct.2023.06.009. Epub ahead of print. Erratum for: Transplant Cell Ther. 2023 May;29(5):338.e1-338.e6. PMID: 37421972. Lin C, Schwarzbach A, Sanz J, et al. Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials. Transplant Cell Ther. 2023 May;29(5):338.e1-338.e6. doi: 10.1016/j.jtct.2023.01.031. Epub 2023 Feb 10. Erratum in: Transplant Cell Ther. 2023 Jul 5;: PMID: 36775201; PMCID: PMC10149622. McNeer JL, Devidas M, Dai Y, et al. Hematopoietic Stem-Cell Transplantation Does Not Improve the Poor Outcome of Children with Hypodiploid Acute Lymphoblastic Leukemia: A Report From Children's Oncology Group. J Clin Oncol. 2019;37(10):780-789. doi:10.1200/JCO.18.00884 Miano M, Lanino E, Gatti R, et al. Four-year follow-up of a case of fucosidosis treated with unrelated donor bone marrow transplantation. Bone Marrow Transplant. 2001;27:747-751. National Marrow Donor Program®/Be The Match® and the American Society for Blood and Marrow Transplantation 2022 Referral Guidelines: Recommended Timing for Transplant Consultation. March 2022. Navarro WH, Loberiza, Jr. FR, Bajorunaite R, et al. Effect of body mass index on mortality of patients with lymphoma undergoing autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2006;12:541-551. © 2023 Optum, Inc. 25 Navarro WH, Agovi M-A, Logan BR, et al. Obesity does not preclude safe and effective myeloablative hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in adults. Biol Blood Marrow Transplant. 2010;16:1-9. Nicolaides T, Tihan T, et al. High-dose chemotherapy and autologous stem cell rescue for atypical teratoid/rhabdoid tumor of the central nervous system. J Neurooncol. 2010 May; 98(1): 117-123. doi: 10.1007/s11060-009-007. Oliansky DM, Rizzo JD, Aplan PD, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myeloid leukemia in children: an evidence-based review. Biol Blood Marrow Transplant. 2007;13:1-25. Oliansky DM, Appelbaum F, Cassileth PA, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biol Blood Marrow Transplant. 2008;14:137-180. Oliansky DM, Antin JH, Bennett JM, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of myelodysplastic syndromes: an evidence-based review. Biol Blood Marrow Transplant. 2009;15:137-172. Oliansky DM, Gordon LI, King J, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of follicular lymphoma: an evidence-based review. Biol Blood Marrow Transplant. 2010;16:443-468. Oliansky DM, Czuczman M, Fisher RI, et al. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of diffuse large B cell lymphoma: update of the 2001 evidence-based review. Biol Blood Marrow Transplant. 2011;17:20-47. Optum Stem Cell Transplant Expert Panel Meeting. June 17, 2015. Panagiotidis E, Quigley AM, Pencharz D, et al. (18)F-fluorodeoxyglucose positron emission tomography/computed tomography in diagnosis of post-transplant lymphoproliferative disorder. Leuk Lymphoma. 2014;55(3):515-519. doi:10.3109/10428194.2013.813501 Passamonti F, Cervantes F, Vannucchi AM, et al A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703-1708. Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher disease. Semin Hematol. 2004;41:4-14. Patel JP, Levine RL. How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia? Hematology Am Soc Hematol Educ Program. 2012;2012:28-34. Peters C, Steward CG. Hematopoietic cell transplantation for inherited metabolic diseases: An overview of outcomes and practice guidelines. Bone Marrow Transplant. 2003;31:229-239. Popat U, Mehta RS, Rezvani K, et al. Enforced fucosylation of cord blood hematopoietic cells accelerates neutrophil and platelet engraftment after transplantation. Blood. 2015 May 7;125(19):2885-92. doi: 10.1182/blood-2015-01-607366. Epub 2015 Mar 16. PMID: 25778529; PMCID: PMC4424412. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538-48. Rotta et al. Long-term outcome of patients with multiple myeloma after autologous hematopoietic cell transplantation and nonmyeloablative conditioning. Blood. 2009;113:3383-3391. Schiller GJ. High-risk acute myelogenous leukemia: treatment today…and tomorrow. Hematology Am Soc Hematol Educ Program. 2013;2013:201-8. Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. Int J Clin Pharmacol Ther. 2009;47 Suppl 1:S48-57. Short NJ, Jabbour E. Minimal Residual Disease in Acute Lymphoblastic Leukemia: How to Recognize and Treat It. Curr Oncol Rep. 2017;19(1):6. doi:10.1007/s11912-017-0565-x Stiff PJ, Agovi M-A, Antman KH, et al. High-dose chemotherapy with blood or bone marrow transplants for rhabdomyosarcoma. Biol Blood Marrow Transplant. 2010;16:525-532. © 2023 Optum, Inc. 26 Sullivan KM, Majhail NS, Bredeson C. et al. Systemic sclerosis as an indication for autologous hematopoietic cell transplantation: position statement from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2018;24:1961-64. Sureda A. et al. Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed Follicular Lymphoma: A Combined Analysis on Behalf of the Lymphoma Working Party of the EBMT and the Lymphoma Committee of the CIBMTR. Cancer 2018;124:1733-42. Swerdlow SH, Campo E, Harris, NL (Eds.). WHO classification of tumours of haematopoietic and lymphoid tissues. World Health Organization Classification of Tumours. Revised 4th edition. Volume 2. 2017. Vellodi A, Cragg H, Winchester B, et al. Allogeneic bone marrow transplantation for fucosidosis. Bone Marrow Transplant. 1995;15:153-158. Venkatramani R. et al. Outcome of infants and young children with newly diagnosed ependymoma treated on the ‘‘Head Start’’ III prospective clinical trial. J Neurooncol. 2013;11392):285-91. © 2023 Optum, Inc. 27

A

Multiple Sclerosis Definitions Relapsing-Remitting MS (RRMS) A pattern of symptoms of multiple sclerosis in which symptomatic attacks occur that last 24 hours or more., followed by complete or almost complete improvement. This is the most common form of multiple sclerosis. About 85% of people with MS are initially diagnosed with RRMS. People with RRMS have temporary periods called relapses, flare-up or exacerbations, when new symptoms appear. (Hooper, 2011)

Secondary-Progressive MS (SPMS) A pattern of symptoms of multiple sclerosis in which there are relapses and remissions, followed by more steady progression of symptoms. In SPMS, symptoms worsen more steadily over time, with or without the occurrence of relapses and remissions. Most people who are diagnosed with RRMS will transition to SPMS at some point. (National Multiple Sclerosis Society, 2011) Relapse A relapse of MS (also known as also known as an exacerbation attack or flare-up) is the occurrence new symptoms or the worsening of old symptoms. It can be very mild, or severe enough to interfere with a person’s ability to function. No two exacerbations are alike. Symptoms vary from person to person and from one exacerbation to another. For example, the exacerbation might be an episode of optic neuritis (caused by inflammation of the optic nerve that impairs vision), or problems with balance or severe fatigue. Some relapses produce only one symptom (related to inflammation in a single area of the central nervous system). Other relapses cause two or more symptoms at the same time (related to inflammation in more than one area of the central nervous system). To be a true exacerbation, the attack must last at least 24 hours and be separated from the previous attack by at least 30 days. It must also occur in the absence of infection, or other cause. Most exacerbations last from a few days to several weeks or even months. (National Multiple Sclerosis Society, 2011) Hooper K. Managing Progressive MS. New York, NY: National Multiple Sclerosis Society; 2011. Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33(11):1444-1452. Multiple Sclerosis: Just the Facts New York, NY; National Multiple Sclerosis Society;2011 Gale Encyclopedia of Medicine. Copyright 2008 The Gale Group, Inc. https://www.nationalmssociety.org/Treating-MS/Managing-Relapses © 2023 Optum, Inc. 28

B

Clinical, Cytogenetic and Mutational Risk Stratification for AML

Favorable risk: Cytogenetics – t(8;21) – inv(16) or t(16;16) Mutations

– Kit

Intermediate risk (one or more of the following) Cytogenetics

– Normal – +8 Mutations

– Flt3 ITD-positive

– Mutant TET2, MLL-PTD, DNMT3A, ASXL1, PHF6 Unfavorable (high) risk (one or more of the following): Cytogenetics – -5/-7 – 11q23, 20q

– 3 or more Clinical features:

– CR2 and beyond – Age > 70 – Refractory to induction chemotherapy – Persistence of minimal residual disease following induction Patel JP, Levine RL. How do novel molecular genetic markers influence treatment decisions in acute myeloid leukemia? Hematology Am Soc Hematol Educ Program. 2012; 2012:28-34. © 2023 Optum, Inc. 29

C The Dynamic International Prognostic Scoring System (DIPSS) and Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) for Primary Myelofibrosis (PMF)

DIPSS Factors Age > 65

Point Value 1 Hemoglobin level < 10 g/dl 2 White blood cell count (WBC) > 25 x 109/L 1 Peripheral blood blasts > 1% 1

Presence of constitutional symptoms 1 DIPSS Risk Categories: Low (0 points), Intermediate 1 (1 point), Intermediate 2 (2-3 points), High (≥ 4 points).

DIPSS-Plus Factors

Point Value Adverse karyotypes* 1 Platelets < 100 x 109/L 1

RBC transfusion need 1 Adverse karyotypes include +8, -5/del5q, -7/del7qi(17q), inv(3), 11q23 rearrangements. DIPSS-Plus Risk Categories: Low (0 points), Intermediate 1 (1 point), Intermediate 2 (2-3 points, High (4-6 points). Gangat N, Caramazza D, Vaidya R. et al. DIPSS Plus: A refined dynamic international prognostic scoring system for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29(4):392-97. Salit, RB & Deeg HJ. Transplant decisions in patients with myelofibrosis: should mutations be the judge? Biol Blood Marrow Transplant. 2018; 24: 649-58. © 2023 Optum, Inc. 30

D Complete Remission and Partial Remission Highlights from Revised Response Criteria for Malignant Lymphoma

Complete Remission (CR): Disappearance of all evidence of disease.

Nodal masses FDG-avid or PET positive prior to therapy: mass of any size permitted if PET negative • Variably FDG-avid or PET negative: regression to normal size on CT

Spleen, Liver Not palpable, nodules disappeared

Bone marrow

Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative

Partial Remission (PR): Regression of measurable disease and no new sites.

Nodal masses Greater than 50% decrease in sum of the products of diameters (SPD) of up to 6 largest dominant masses, no increase in size of other nodes – FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site – Variably FDG-avid or PET negative; regression on CT NOTE: In the absence of adequate size measurements one can use a greater than 50% decrease in the Standardized Uptake Value (SUV) to document PR.

Spleen, Liver Greater than 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen.

Bone marrow

Irrelevant if positive prior to therapy; cell type should be specified. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579–86. Available at: http://jco.ascopubs.org/content/25/5/579.full.pdf+html. © 2023 Optum, Inc. 31

E

Hematopoietic Stem Cell Transplant Reference Sheet The following is a list of rare and unusual conditions where allogeneic transplant may be indicated. The list was reviewed and accepted by the 2018 Optum Hematopoietic Stem Cell Transplant Expert Panel. If there is a condition found on this list that is not included in the “Indications” section above, refer to Medical Director.

1. Lymphocyte Immunodeficiencies (many fall under ‘severe combined immunodeficiency’ classification)

   Adenosine deaminase deficiency

   Artemis deficiency

   Calcium channel deficiency

   Cernunnos-XLF immunodeficiency

   CHARGE syndrome with immune deficiency Common gamma chain deficiency

   Deficiencies in CD 45, CD3, CD8

   DiGeorge syndrome

   DNA ligase IV

   DOCK8 immunodeficiency syndrome

   GATA2 deficiency

   Interleukin-7 receptor alpha deficiency

   Janus-associated kinase 3 (JAK3) deficiency

   Major histocompatibility class II deficiency

   Purine nucleoside phosphorylase deficiency

   Recombinase-activating gene (RAG) 1/2 deficiency

   Reticular dysgenesis Winged helix deficiency

   Zeta-chain-associated protein-70 (ZAP-70) deficiency

2. Phagocytic Deficiencies

   Chediak-Higashi syndrome

   Griscelli syndrome, type 2

   Interferon-gamma receptor deficiencies

   Leukocyte adhesion deficiency

   Shwachman-Diamond syndrome* may be considered as marrow failure syndrome rather than immunodeficiency

3. Other Immunodeficiencies

   Autoimmune lymphoproliferative syndrome

   Cartilage hair hypoplasia

   CD25 deficiency © 2023 Optum, Inc. 32

   Familial hemophagocytic lymphohistiocytosis

   Hyper IgD and IgE syndromes

   ICF syndrome IPEX syndrome NEMO deficiency

   NF-κB inhibitor, alpha (IκB-alpha) Antoine C, Muller S, Cant A, et al. Long term survival and transplantation of hematopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003 Feb;361(9357):553-60. PMID: 12598139254. Burroughs L, Woolfrey A, Shimamura A. Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am. 2009 Apr;23(2):233-48. PMID: 19327581. Coppa GV, Gabrielli O, Zampini L, et al. Bone marrow transplantation in Hunter syndrome (mucopolysaccharidosis type II): two-year follow-up of the first Italian patient and review of the literature. Pediatr Med Chir. 1995 May-Jun;17(3):227-35. PMID:7567644. Ehlert K, Roth J, Frosch M, et al. Farber's disease without central nervous system involvement: bone-marrow transplantation provides a promising new approach. Ann Rheum Dis. 2006;65(12):1665-6. Filipovich A. Hematopoietic cell transplantation for correction of primary immunodeficiencies. Bone Marrow Transplant. 2008 Aug;42 Suppl 1:S49-S52. PMID: 18724301. Guffon N, Bertrand Y, Forest I, et al. Bone marrow transplantation in children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr. 2009 May;154(5):733-7. Heese BA. Current strategies in the management of lysosomal storage diseases. Semin Pediatr Neurol. 2008 Sep;15(3):119-26. PMID: 18708002. Myers KC, Davies SM. Hematopoietic stem cell transplantation for bone marrow failure syndromes in children. Biol Blood Marrow Transplant. 2009 Mar;15(3):279-92. PMID:19203719. Orange JS, Hossny EM, Weiler CR, et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. 2006 Apr;117(4 Suppl):S525-53. PMID: 16580469. Tolar J, Blazar BR, Wagner JE. Concise review: Transplantation of human hematopoietic cells for extracellular matrix protein deficiency in epidermolysis bullosa. Stem Cells. 2011 Jun;29(6):900-6. doi: 10.1002/stem.647. Review. PubMed PMID: 21557391. Vellodi A, Young E, Cooper A, et al. Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis. 1999 Jun;22(5):638-48. Vormoor J, Ehlert K, Groll AH, et al. Successful hematopoietic stem cell transplantation in Farber disease. J Pediatr. 2004 Jan;144(1):132-4. © 2023 Optum, Inc. 33

   F

   Updated Criteria for Diagnosis of Multiple Myeloma

   Multiple myeloma DIAGNOSTIC CRITERIA: ALL 3 REQUIRED Monoclonal plasma cells in the bone marrow > 10% and/or presence of a biopsy-proven plasmacytoma • Monoclonal protein present in the serum and/or urine • Myeloma-related organ dysfunction (1 or more) *

   Traditional CRAB Criteria: [C] Calcium elevation in the blood S. Calcium >10.5 mg/l or upper limit of normal

   [R] Renal insufficiency S. Creatinine > 2 mg/dl [A] Anemia Hemoglobin < 10 g/dl or 2 g < normal

   [B] Lytic bone lesions or osteoporosis NOTE: These criteria identify stage IB and stages II and IIIA/B myeloma by Durie Salmon stage. Stage IA becomes smoldering or indolent myeloma. If no monoclonal protein is detected (non-secretory disease), then > 30 % monoclonal bone marrow plasma cells and/or a biopsy-proven plasmacytoma required. * The revised International Myeloma Working Group (IMWG) criteria will allow, in addition to the classic CRAB features, the following three markers as “myeloma defining events” (MDEs): Sixty percent or greater clonal plasma cells on bone marrow examination

   Serum involved/uninvolved free light chain ratio of 100 or greater, provided the absolute level of the involved free light chain is at least 100 mg/l (a patient’s “involved” free light chain – either kappa or lambda – is the one that is above the normal reference range; the uninvolved light chain is the one that typically is in, or below, the normal range)

   More than one focal lesion on MRI that is at least 5 mm or greater in size The presence of at least one of these markers will be considered sufficient for a diagnosis of multiple myeloma, regardless of the presence or absence of symptoms or CRAB features. Each of these markers has been shown in two or more independent studies to be associated with an approximately 80 % or higher risk of developing myeloma-related organ damage within two years. In addition, the IMWG criteria allow the use of CT and PET-CT for detecting osteolytic bone lesions in order to make the diagnosis of myeloma. In patients with equivocal findings on MRI, CT, and/or PET-CT, the IMWG recommends follow-up imaging. The use of modern imaging methods at diagnosis and follow-up will enable the diagnosis of myeloma to be made before serious bone damage, such as pathologic fractures, can develop.

   Monoclonal Gammopathy of Undetermined Significance (MGUS) DIAGNOSTIC CRITERIA: ALL 3 REQUIRED Serum monoclonal protein and/or urine monoclonal protein level low*

   Monoclonal bone marrow plasma cells < 10 % © 2023 Optum, Inc. 34 Normal serum calcium, hemoglobin level and serum creatinine

   Low is defined as:

   Serum IgG < 3.5 g/dl

   Serum IgA < 2.0 g/dl No bone lesions on full skeletal x-ray survey and/or other imaging if performed.

   No clinical or laboratory features of amyloidosis or light chain deposition disease. Urine monoclonal kappa or lambda < 1.0 g/24 hours. The definition of MGUS has not changed. However, a new entity termed light chain MGUS has been defined.

   Smoldering or indolent myeloma DIAGNOSTIC CRITERIA: ALL 3 REQUIRED Monoclonal protein present in the serum and/or urine

   Monoclonal plasma cells present in the bone marrow and/or a tissue biopsy

   Not meeting criteria for MGUS, multiple myeloma, or solitary plasmacytoma of bone NOTE: These criteria identify stage IA myeloma by Durie Salmon stage. The diagnosis of smoldering myeloma will now have an upper limit of 60% for the percentage of clonal plasma cells in the marrow. Patients considered to have smoldering myeloma should not have any myeloma defining events or amyloidosis. A new kind of smoldering multiple myeloma, termed light chain smoldering multiple myeloma, has been recently described in a study conducted at the Mayo Clinic, and the specific monoclonal protein level required for this diagnosis has also been added. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15: e538-48. © 2023 Optum, Inc. 35

   Version

   Date of annual review 1.0 07/19/2012: New guideline. Approved by Medical Technology Assessment Committee 1.0

   08/14/2012: Approved by National Medical Care Management Committee 2.0 10/10/13: Revised and updated. Approved by Medical Technology Assessment Committee 2.0

   10/16/2013: Approved by Complex Medical Conditions Policy Committee 2.0

   11/12/13: Approved by the National Medical Care Management Committee 3.0

   08/07/2014: Approved by Medical Technology Assessment Committee 3.0

   09/09/2014: Approved by National Medical Care Management Committee 4.0 8/25/2015: Annual review; revised and updated 4.0

   09/03/2015: Approved by Medical Technology Assessment Committee 4.0

   10/13/2015: Approved by National Medical Care Management Committee 5.0 08/15/2016: Annual review. Revised and updated. Transplant Review Guidelines separated into two documents: Hematopoietic Stem Cell Transplantation and Solid Organ Transplantation. 5.0

   09/01/2016: Approved by Medical Technology Assessment Committee 5.0

   09/13/2016: Approved by National Medical Care Management Committee 6.0

   6/22/2017: Approved by Optum Policy and Guideline Committee 6.0

   07/06/2017: Approved by Medical Technology Assessment Committee 6.0

   07/11/2017: Approved by National Medical Care Management Committee 7.0 09/07/2017: New content relevant to CAR-T Therapy approved by Medical Technology Assessment Committee. 7.0 09/12/2017: New content relevant to CAR-T Therapy approved by National Medical Care Management Committee. 7.0 11/1/2017: Updated to reflect FDA-approval of new CAR-T Therapy agent axicabtagene ciloleucel (Yescarta™, Kite Pharma). 7.0 11/13/2017: Corrected CAR-T prior authorization statement on page 7. 8.0

   08/02/2018: Approved by Medical Technology Assessment Committee 8.0

   09/11/2018: Approved by National Medical Care Management Committee 9.0 4/17/2019: Annual review with Optum Stem Cell Expert Panel. Minor revisions including addition of CMML to approved indications for allogeneic stem cell transplant; revised the preferred scoring system for primary myelofibrosis; revised systemic sclerosis indication to approve autologous transplant; added allogeneic transplant evaluation for secondary myelofibrosis in patients with polycythemia vera and essential thrombocytopenia; and added DIPSS-Plus factors table and scoring directions. Updated references. © 2023 Optum, Inc. 36 9.0

   06/06/2019: Approved by Medical Technology Assessment Committee 9.0

   06/11/2019: Approved by National Medical Care Management Committee 9.0 12/2/2019: Corrected follicular lymphoma indication on page 10. Updated supporting references. 10.0 6/10/2020: Annual review with Optum Stem Cell Expert Panel. Revisions to the MRD statement, Relative Contraindications and Special Considerations sections, and NMDP recommendations for timing of transplant consultation.