Cigna Stem Cell Transplantation: Blood Cancers - (0533) Form

The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer’s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer’s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer’s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Each coverage request should be reviewed on its own merits. Medical directors are expected to exercise clinical judgment and have discretion in making individual coverage determinations. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Medical Coverage Policy: 0533 This Coverage Policy addresses hematopoietic stem cell transplantation (HSCT) for blood cancers such as leukemias, lymphomas and myeloma. Coverage Policy Coverage for hematopoietic stem cell transplantation (HSCT) varies across plans. Refer to the customer’s benefit plan document for coverage details. Indication Hematopoietic Stem Cell Transplantation (HSCT) Coverage Criteria All allogeneic transplantations must be from an appropriately matched human leukocyte antigen (HLA) donor. Acute Lymphoblastic Leukemia (ALL) Allogeneic hematopoietic stem-cell transplantation (HSCT) is considered medically necessary for the treatment of acute lymphoblastic leukemia (ALL) when ANY of the following criteria are met: • • B-cell lineage ALL with marrow relapse while on treatment or within six months of completing treatment failed induction therapy second or subsequent remission T-cell lineage ALL in first or subsequent remission • first remission with poor prognosis or high risk features* A second allogeneic HSCT is considered medically necessary for the treatment of ALL when relapsed disease occurs more than six months after first allogeneic HSCT. A tandem/sequential HSCT for the treatment of ALL is considered experimental, investigational or unproven. HSCT for the treatment of ALL is considered not medically necessary when ANY of the following conditions are present: active central nervous system (CNS) involvement • presence of any significant comorbid medical or psychiatric illness which would significantly compromise the clinical care and chances of survival advanced age in an adult See Appendix A Acute Myeloid Leukemia (AML) Allogeneic HSCT is considered medically necessary for the treatment of acute myeloid leukemia (AML) when ANY of the following criteria is met: • • • no induction treatment and any of the following:  antecedent hematological disease first remission for an adverse-risk or intermediate-risk* individual second or subsequent remission failed induction Medical Coverage Policy: 0533 Indication Hematopoietic Stem Cell Transplantation (HSCT) Coverage Criteria All allogeneic transplantations must be from an appropriately matched human leukocyte antigen (HLA) donor.  treatment-related secondary AML A second allogeneic HSCT is considered medically necessary for the treatment of AML when BOTH of the following criteria are met: relapse of disease occurring more than six months after first allogeneic HSCT second or subsequent remission Allogeneic HSCT is considered medically necessary for the treatment of blastic plasmacytoid dendritic cell neoplasm following complete remission. Autologous HSCT is considered medically necessary for the treatment of AML when allogeneic HSCT is not available or is not appropriate and EITHER of the following criteria is met: • first remission for a favorable/intermediate risk* individual second or subsequent remission Tandem HSCT is considered experimental, investigational or unproven for the treatment of AML See Appendix B Amyloidosis (systemic light- chain) Autologous HSCT is considered medically necessary for the treatment of amyloidosis (systemic light-chain) in the absence of severe or multiple comorbidities that would increase risk of poor result or death. A second autologous HSCT for the treatment of recurrent or refractory amyloidosis (systemic light-chain) is considered experimental, investigational or unproven. The following procedures for the treatment of amyloidosis (systemic light-chain) are considered experimental, investigational or unproven: • allogeneic HSCT tandem autologous HSCT Chronic Lymphocytic Leukemia (CLL) Allogeneic HSCT is considered medically necessary for the treatment of chronic lymphocytic leukemia (CLL) that is not responsive to standard therapy. Chronic Myeloid Leukemia (CML) Allogeneic HSCT is considered medically necessary for the treatment of chronic myeloid leukemia (CML) in ANY of the following: Medical Coverage Policy: 0533 Indication Hematopoietic Stem Cell Transplantation (HSCT) Coverage Criteria All allogeneic transplantations must be from an appropriately matched human leukocyte antigen (HLA) donor. hematologic remission not reached after three months of tyrosine kinase inhibitor (TKI) therapy no cytogenetic response or those in cytogenetic relapse at 6, 12, or 18 months after achieving initial hematologic remission after three months of TKI therapy molecular remission not reached by 12 months of TKI therapy • disease progression on TKI therapy to accelerated phase or blast crisis an individual who is not a candidate for TKI therapy Autologous HSCT for the treatment of CML is considered experimental, investigational or unproven. Chronic Myelomonocytic Leukemia (CMML) Allogeneic HSCT is considered medically necessary for the treatment of chronic myelomonocytic leukemia (CMML). Autologous HSCT for the treatment of CMML is considered experimental, investigational, or unproven. Hodgkin Lymphoma Autologous HSCT is considered medically necessary for the treatment of refractory, primary progressive or recurrent Hodgkin lymphoma. Allogeneic HSCT is considered medically necessary for the treatment of refractory, primary progressive, or recurrent Hodgkin lymphoma when the individual is not a candidate for autologous HSCT or in the setting of a failed autologous transplant. Juvenile Myelomonocytic Leukemia (JMML) Allogeneic HSCT is considered medically necessary for the treatment of juvenile myelomonocytic leukemia (JMML). Autologous HSCT for the treatment of JMML is considered experimental, investigational, or unproven. Multiple Myeloma (MM) Autologous HSCT for the treatment of active (i.e., symptomatic) multiple myeloma (MM) is considered medically necessary. A second autologous HSCT for the treatment of active (i.e., symptomatic) MM is considered medically necessary for EITHER of the following: as a tandem autologous HSCT following autologous HSCT • in an individual with progressive disease following a previous autologous HSCT Myelodysplastic Syndromes Allogeneic HSCT is considered medically necessary for the treatment of an individual with intermediate- or high-risk* myelodysplastic syndrome (MDS). Medical Coverage Policy: 0533 Indication Hematopoietic Stem Cell Transplantation (HSCT) Coverage Criteria All allogeneic transplantations must be from an appropriately matched human leukocyte antigen (HLA) donor. according to the Revised International Prognostic Scoring System (IPSS- R) for Myelodysplastic Syndromes Risk Assessment Myelofibrosis Allogeneic HSCT is considered medically necessary for the treatment of myelofibrosis for symptoms that persist, or worsen despite standard supportive care. Autologous HSCT is considered experimental, investigational or unproven for the treatment of myelofibrosis. Non-Hodgkin Lymphoma (NHL) Autologous HSCT is considered medically necessary for the treatment of an adult with stage II - IV or relapsed non-Hodgkin lymphoma (NHL). Allogeneic HSCT is considered medically necessary for the treatment of an adult with stage II - IV or relapsed non-Hodgkin lymphoma (NHL) who is not a candidate for autologous HSCT. Allogeneic or autologous HSCT as medically necessary for the treatment of a child with recurrent NHL with chemosensitive disease. The following procedures for the treatment of NHL are considered experimental, investigational or unproven: autologous OR allogeneic HSCT for stage I disease in an adult • tandem autologous OR allogeneic HSCT in an adult or a child POEMS Syndrome Autologous HSCT is considered medically necessary for the treatment of POEMS syndrome. Primary Central Nervous System (CNS) Lymphoma Systemic Mastocytosis Autologous HSCT is considered as medically necessary for the treatment of relapsed or refractory primary CNS lymphoma. Allogeneic hematopoietic stem-cell transplantation (HSCT) is considered medically necessary for the treatment of advanced / aggressive systemic mastocytosis. General Background Hematopoietic stem cell transplantation (HSCT), also called hematopoietic cell transplantation (HCT) or stem cell transplant, is a type of treatment for cancer (and a few other conditions as well). Bone marrow produces all of the different cells that make up the blood, such as red blood cells, white blood cells, and platelets. All of the cells of the immune system are also made in the Medical Coverage Policy: 0533 bone marrow. All of these cells develop from a type of precursor cell found in the bone marrow, called a "hematopoietic stem cell." Hematopoietic stem cells are found in the peripheral blood and the bone marrow; therefore, stem cells can be collected or harvested from either location. Some of the most effective treatments for cancer, such as chemotherapy and radiation, are toxic to the bone marrow. In general, the higher the dose, the more toxic the effects on the bone marrow. After the treatment, a healthy supply of stem cells is reintroduced, or transplanted. The transplanted cells then reestablish the blood cell production process in the bone marrow. HSCT is a method of replacing immature blood-forming cells in the bone marrow that have been destroyed by drugs, radiation, or disease. It may be autologous (i.e., using a person’s own stem cells) or allogeneic (i.e., using stem cells donated by someone else). Autologous transplant — In autologous transplantation, an individual’s own hematopoietic stem cells are removed before the high dose chemotherapy or radiation is given, and they are then frozen for storage and later use. After chemotherapy or radiation is complete, the harvested cells are thawed and returned to the individual, like a transfusion. Allogeneic transplant — In allogeneic transplantation, the hematopoietic stem cells come from a donor, ideally a brother or sister with a similar genetic makeup. If an individual does not have a suitably matched sibling, an unrelated person with a similar genetic makeup may be used. Under some circumstances, a parent or child who is only half- matched can also be used; this is termed a haploidentical transplant. In other circumstances, umbilical cord blood may be used in an umbilical cord blood transplant. Myeloablative transplant — A myeloablative transplantation uses very high doses of chemotherapy or radiation prior to transplantation with autologous or allogeneic hematopoietic stem cells. Non-myeloablative transplant — A non-myeloablative transplantation, sometimes referred to as reduced intensity transplant, allows an individual to have less intensive chemotherapy before transplantation with allogeneic hematopoietic stem cells. The idea is to minimize up front toxicity by using lower doses of intensive therapy, while retaining the immune graft versus tumor effect. This approach may be recommended for a variety of reasons including age, type of disease, other medical issues, or prior therapies. Racial disparities The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) have formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) to ensure equal access and outcomes for all patients in need. In addition to cellular therapy physicians, the initiative includes program administrators, health policy and health equity experts, health service researchers, participants from commercial payer organizations, and federal stakeholders. The ACCESS Initiative incorporates a comprehensive approach to reduce HCT/CT-related access barriers and resultant inferior outcomes. The inaugural ASTCT-NMDP ACCESS Workshop was held in Washington, DC on July 28 and 29, 2022, wherein committee members met to discuss and to define goals for 3 focus areas: awareness, poverty, and racial and ethnic inequity. The goals include:  Increasing awareness among community physicians of disease indications for HCT/CT and providing education for patients and caregivers on HCT/HCT availability, clinical trials, and support services available for them.  Identifying HCT/CT recipients at high risk of adverse outcomes due to socioeconomic adversity and developing patient-, center-, and policy-related initiatives to improve these patients’ access and survival.  Improving equity in access and outcomes for all HCT/CT recipients, regardless of race or ethnicity, by working with HCT/CT centers to address the gap in knowledge of these Medical Coverage Policy: 0533 patient populations and provide accurate data on the sociodemographic characteristics of patients in their regions. Ultimately, publications and policy changes based upon committee efforts would be laudable (Auletta, et al., 2022; National Marrow Donor Program). Landry (2021) conducted a systematic review of the literature which included 17 publications that evaluated racial disparities and access to SCT (11 retrospective cohort studies, one literature review, 3 cross-sectional studies, and 2 focus group samplings). In 2014, the Affordable Care Act (ACA) became fully implemented. This expansion of coverage for uninsured or underinsured has led to approximately 40% of SCT procedures performed in the United States now reimbursed by governmental payers. Eight of the included studies evaluating access to SCT were performed after 2014.  Three of these studies specifically evaluated utilization and found that ethnic minorities with multiple myeloma, ALL, AML, and AL amyloidosis are still underutilizing SCT, with significant differences in referral and time to referral for Blacks. Eight retrospective reviews found substantial variation in access to SCT by ethnic minorities (Black, Hispanic, or Asian) when compared to their Caucasian counterparts. Thirteen publications found racial disparities in either overall survival, progression free survival, treatment related mortality, relapse, or combinations of these outcomes. The author stated that “While variation in overall mortality between ethnic minorities and white patients has traditionally been attributed to decreased utilization of stem cell transplant, our review revealed that discouragement of potential donors, differences in treatment failure and/or transplant rejection, and overall stigmatization and mistrust of the medical profession likely play significant roles in continued, worse outcomes seen in minority patients.” Majhail et al. (2012) reviewed published literature and noted disparities by race exist in three areas related to HCT: donor availability, access to HCT and outcomes of HCT. About 70% of patients who need allogeneic HCT do not have a matched sibling and must rely on unrelated donors or umbilical cord blood (UCB). African-Americans/Blacks have a lower likelihood of finding an unrelated donor. The probability of finding a match within the National Marrow Donor Program’s (NMDP) Be The Match Registry is estimated to be 0.93 for Whites, 0.82 for Hispanics, 0.77 for Asian Americans and 0.58 for Blacks. Whites constitute nearly 74% donors in the registry, whereas the representation of Hispanics (10%), Blacks (7%) and Asians (7%) is less frequent. Contraindications Many factors affect the outcome of a tissue transplantation; the selection process is designed to obtain the best result for each individual. The presence of any significant comorbid conditions which would significantly compromise clinical care and chances of survival is a contraindication to transplant. Relative contraindications for HSCT include (but are not limited to): poor cardiac function (ejection fraction less than 35%) • poor liver function (bilirubin greater than 2.0 mg/dL and transaminases greater than two times normal), unless related to disease poor renal function (creatinine clearance less than 50 mL/min) (not applicable for most auto transplants) poor pulmonary function (diffusion capacity less than 50% of predicted) human immunodeficiency virus (HIV) if not controlled or active hepatitis B, hepatitis C or human T-cell lymphotrophic virus type 1(HTLV-1) Karnofsky rating less than 60% and/or Eastern Cooperative Oncology Group (ECOG) performance status greater than two Medical Coverage Policy: 0533 Blood Cancers Most blood cancers start in the bone marrow where blood is produced. Stem cells in bone marrow mature and develop into three types of blood cells: red blood cells, white blood cells, or platelets. In most blood cancers, the normal blood cell development process is interrupted by uncontrolled growth of an abnormal type of blood cell. There are three main types of blood cancers: Leukemia, a type of cancer found in blood and bone marrow, is caused by the rapid production of abnormal white blood cells. The high number of abnormal white blood cells are not able to fight infection, and they impair the ability of the bone marrow to produce red blood cells and platelets. Leukemia can be either acute or chronic. Chronic leukemia progresses more slowly than acute leukemia, which requires immediate treatment. Leukemia is also classified as lymphoblastic/lymphocytic or myeloid/myelogenous. Lymphocytic/Lymphoblastic leukemia refers to abnormal cell growth in the marrow cells that become lymphocytes, a type of white blood cell that plays a role in the immune system. In myeloid leukemia, abnormal cell growth occurs in the marrow cells that mature into red blood cells, white blood cells, and platelets. Lymphoma is a type of blood cancer that affects the lymphatic system, which removes excess fluids from the body and produces immune cells. Lymphocytes are a type of white blood cell that fight infection. Abnormal lymphocytes become lymphoma cells, which multiply and collect in lymph nodes and other tissues. Over time, these cancerous cells impair the immune system. Lymphomas are divided into two categories:  Non-Hodgkin lymphoma: Non-Hodgkin’s lymphomas are the most common. There are about 61 known types of non-Hodgkin lymphoma. About 85 percent of non- Hodgkin’s lymphomas diagnosed in the U.S. are B-cell lymphomas, which means they originated from this type of cell. B-cell lymphomas grow quickly (high-grade) or slowly (low-grade). There are over a dozen types of B-cell non-Hodgkin lymphomas. The rest are T cell lymphomas, named after a different cancerous white blood cell, or lymphocyte.  Hodgkin lymphoma: The Hodgkin’s lymphomas are the rarest types of the disease and are characterized by Reed-Sternberg cells. There are six different subtypes of Hodgkin’s lymphoma. Myeloma (multiple myeloma) is a cancer of the plasma cells. Because myeloma frequently occurs at many sites in the bone marrow, it is often referred to as ‘multiple myeloma’ (MM). Plasma cells are white blood cells that produce disease- and infection-fighting antibodies. The plasma cells make an abnormal protein (antibody) known by several different names, including monoclonal immunoglobulin, monoclonal protein (M-protein), M- spike, or paraprotein. There are other plasma cell disorders that also have abnormal plasma cells but do not meet the criteria to be called active multiple myeloma. These other plasma cell disorders include but are not limited to:  Smoldering multiple myeloma (SMM)  Light chain amyloidosis.  POEMS syndrome Myelodysplastic Syndromes (MDS) are conditions that can occur when the blood-forming cells in the bone marrow become abnormal (dysplastic). There are several different types of MDS, based on how many types of blood cells are affected and other factors. Medical Coverage Policy: 0533 Myelofibrosis is considered a myeloproliferative neoplasm. Three other disorders are commonly classified as MPNs: chronic myeloid leukemia, essential thrombocythemia and polycythemia vera. Also called primary myelofibrosis (PMF) or idiopathic myelofibrosis, it is characterized by replacement of the bone marrow by fibrous scar tissue, which reduces the ability of the marrow to produce red blood cells. POEMS (Polyneuropathy, organomegaly, endocrinopathy, M- protein, skin changes) syndrome is a rare plasma cell disorder characterized by demyelinating peripheral neuropathy and clonal plasma cell proliferation. It can be mistaken for chronic inflammatory demyelinating polyneuropathy. The clinical manifestations of POEMS syndrome can be debilitating; therefore, early diagnosis is essential (Khouri, et al., 2021). Primary Central Nervous System Lymphomas (PCNSL) accounts for approximately 3% of all neoplasms and 4% to 6% of all extranodal lymphomas. It is an aggressive form of non-Hodgkin lymphoma that develops within the brain, spinal cord, eye, or leptomeninges without evidence of systemic involvement. Pathologically, PCNSL is an angiocentric neoplasm composed of a dense monoclonal proliferation of lymphocytes, usually diffuse large B cells. More than 90% of these primary CNS diffuse large B-cell lymphoma cases are of the activated B-cell–like (ABC) subtype. The tumor is infiltrative and typically extends beyond the primary lesion, as shown by CT or MRI scans, into regions of the brain with an intact blood-brain barrier. The brain parenchyma is involved in more than 90% of all PCNSL patients, and the condition can be multifocal in more than 50% of cases (NCCN, 2023). Systemic Mastocytosis (SM) is no longer considered a subgroup of myeloproliferative neoplasms but is considered a distinct disease category. It results from a clonal, neoplastic proliferation of morphologically and immunophenotypically abnormal mast cells (MC) that accumulate in one or more organ systems. The clinical presentation of mastocytosis is heterogeneous, ranging from skin-limited disease (cutaneous mastocytosis, CM), particularly in pediatric cases where the majority have disease-onset within the first 2 years of life and commonly experience spontaneous regression of skin lesions at puberty, to a more aggressive variant with extra-cutaneous involvement (systemic mastocytosis, SM) that may be associated with multiorgan dysfunction/failure and shortened survival, that is generally seen in adult patients (Pardanani, et al., 2023). Professional Societies/Organizations The table below includes information and recommendations from the following sources: 1. The American Society for Transplantation and Cellular Therapy (ASTCT) (formerly known as the American Society for Blood and Marrow Transplantation [ASBMT]) Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy (Kanate, et al., 2020). 2. The National Comprehensive Cancer Network® (NCCN). NCCN GUIDELINES™ Clinical Practice Guidelines in Oncology. National Comprehensive Cancer Network. Note that all recommendations are category 2A unless otherwise stated. Cancer Acute Lymphoblastic/ Leukemia (ALL) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Medical Coverage Policy: 0533 Cancer Children (<18 years) Acute lymphoblastic leukemia CR1, standard risk Acute lymphoblastic leukemia CR1, high risk Acute lymphoblastic leukemia CR2 Acute lymphoblastic leukemia CR3+ Acute lymphoblastic leukemia Not in remission *Used in clinical practice but associated with high failure rates; hence, recommend clinical trial enrollment and nontransplant strategies when available. Allogeneic HCT N S S C C * Autologous HCT N N N N N Adults Acute lymphoblastic leukemia CR1, standard risk Acute lymphoblastic leukemia CR1, high risk Acute lymphoblastic leukemia CR2 Acute lymphoblastic leukemia CR3+ Acute lymphoblastic leukemia Not in remission *Used in clinical practice but associated with high failure rates; hence, recommend clinical trial enrollment and nontransplant strategies when available. Allogeneic HCT S S S S S* Autologous HCT N N N N N NCCN GUIDELINES™ Acute Lymphoblastic Leukemia (V.1.2022, April 4, 2022) Principles of Systemic Therapy Treatment of Adults ≥65 years or Adults with Substantial Comorbidities • For appropriate fit individuals achieving remission, consideration of autologous or reduced-intensity allogeneic stem cell transplant (SCT) may be appropriate (ALL-D, 9 of 10). of Treatment Phases in ALL Management Hematopoietic Stem Cell Transplantation As part of post-remission consolidative therapy, the decision to proceed with allogeneic/autologous HCT or prolonged maintenance are mutually exclusive approaches in ALL therapy. Each case will need to be individualized based on disease setting and features. Allogeneic HCT is more likely to be a primary part of post-consolidative therapy in AYA and adult patients with evidence of high-risk features (including Ph-positivity, Ph-like disease, or persistent MRD). Notably, while younger patients may experience lower transplant-related mortality, older age is by itself not a Medical Coverage Policy: 0533 Cancer contraindication. For this reason, HLA typing and bone marrow transplant referral should be considered for all newly diagnosed and relapsed transplant-naïve patients to facilitate timely donor identification, and ultimately allogeneic transplant if warranted. (MS-13) NCCN Recommendations for Ph-Positive ALL AYA and Adult Patients with Ph-Positive ALL The panel recommends that Ph-positive ALL AYA and adult patients less than 65 years of age and no substantial comorbidities be treated in a clinical trial, when possible. Many variables determine eligibility for allogeneic HCT including donor availability, depth of remission, comorbidities, and social support. The optimal time for a patient to receive allogeneic HCT is unclear; however, proceeding to allogenic HCT with MRD is not optimal and additional therapy is recommended to eliminate MRD before transplant. In cases of persistent or rising MRD, consolidation therapy options may include blinatumomab (B-ALL) with or without TKI, or continuation of multiagent chemotherapy or corticosteroid combined with a TKI. In younger AYA patients (aged ≤21 years), emerging data suggest that allogeneic HCT may not confer an advantage over chemotherapy combined with TKIs. Allogeneic HCT may be useful in appropriate candidates with MRD negativity, while considering post-HCT TKI following consolidation therapy. (MS-25, 26) Patients with Relapsed/Refractory Ph-Positive B-ALL For all patients with R/R Ph-positive B-ALL, participation in a clinical trial is preferred. If transplant-naïve patients experience a second CR prior to transplant, consolidative allogeneic HCT should be strongly considered. For patients with disease that relapses after an initial allogeneic HCT, other options may include a second allogeneic HCT and/or DLI. However, the role of allogeneic HCT following treatment with tisagenlecleucel or brexucabtagene autoleucel is unclear. (MS-26, 27) NCCN Recommendations for Ph-Negative ALL AYA Patients with Ph-Negative ALL The panel recommends that AYA patients with Ph-negative ALL (regardless of risk group) be treated in a clinical trial, where possible. (MS-43) For patients experiencing a CR following initial induction therapy, monitoring for MRD should be initiated (see NCCN Recommendations for MRD Assessment). If the resulting MRD status is negative, continuation of the multiagent chemotherapy protocol for consolidation and maintenance would be appropriate. Consolidation with allogeneic HCT may also be considered, especially if the patient has high-risk features. If the MRD status is positive, blinatumomab (for B-ALL) is recommended or allogeneic HCT may be considered. Although long-term remission after blinatumomab treatment Medical Coverage Policy: 0533 Cancer is possible, allogeneic HCT should be considered as consolidative therapy. If the MRD status is unknown, allogeneic HCT is recommended, especially if the patient has high-risk features, although MRD retesting should be considered at first available opportunity. A continuation of multiagent chemotherapy may also be considered, and MRD assessments should be performed at the earliest subsequent opportunity. In all cases, the optimal timing of HCT is unclear. Adult Patients with Ph-Negative ALL For adult patients with Ph-negative ALL, the panel recommends treatment in a clinical trial, where possible. For relatively fit patients (aged <65 years without substantial comorbidities), the recommended treatment approach is similar to that for AYA patients. For patients experiencing a CR after initial induction therapy, monitoring for MRD should be initiated (see NCCN Recommendations for MRD Assessment). If the resulting MRD status is negative, continuation of the multiagent chemotherapy protocol for consolidation and maintenance is recommended. Consolidation with allogeneic HCT may also be considered, especially if the patient has high-risk features. The effect of WBC counts on prognosis in adult patients with ALL is less firmly established than in pediatric populations. If the MRD status is positive, blinatumomab (for B-ALL) is recommended or allogeneic HCT may be considered. After blinatumomab treatment, consolidative therapy with allogeneic HCT should be considered. If the MRD status is unknown, allogeneic HCT is recommended, especially if the patient has high-risk features. A continuation of multiagent chemotherapy may also be considered. In all cases, the optimal timing of HCT is unclear. (MS-44) Patients with Relapsed/Refractory Ph-Negative B-ALL For patients with R/R Ph-negative B-ALL, the approach to second-line treatment may depend on the duration of the initial response. If transplant-naïve patients experience a second CR prior to transplant, consolidative allogeneic HCT should be strongly considered. For patients with disease that relapses after an initial allogeneic HCT, other options may include a second allogeneic HCT and/or DLI. However, the role of allogeneic HCT following treatment with tisagenlecleucel or brexucabtagene autoleucel is unclear. (MS-45) NCCN Recommendations for Evaluation and Treatment of Extramedullary Involvement Does not address HCT. NCCN GUIDELINES™ Pediatric Acute Lymphoblastic Leukemia (V.2.2023 — March 10, 2023) NCCN Principles of Hematopoietic stem cell transplant are listed on pages PEDALL-J, and provide detailed indications for: HCT (B-cell) in First Remission • HCT (B-cell) in Non-First Remission Settings • HCT (T-cell) Medical Coverage Policy: 0533 Cancer NCCN Recommendations for Ph-Negative or Ph-Like ALL Front-Line Management: The panel recommends that pediatric and AYA patients with Ph-negative or Ph-like ALL be treated in a clinical trial when possible. In all cases, HCT may be considered as part of consolidation or maintenance therapy. However, the role of allogeneic HCT following tisagenlecleucel is unclear. (MS-26, 27) R/R Management: For pediatric and AYA patients with Ph-negative or Ph- like ALL experiencing early or late first relapse, the panel recommends initial treatment with systemic therapy. (MS-27) NCCN Recommendations for Ph-Positive ALL Front-Line Management: The panel recommends that pediatric and AYA patients with Ph-positive ALL be treated in a clinical trial that incorporates TKIs when possible. In the absence of an appropriate clinical trial, patients are treated with chemotherapy and a TKI. As an alternative for maintenance, HCT may be considered. Of note, HCT is not required but may be considered for Ph-positive ALL in CR1. R/R Management: The NCCN Panel recommendations for pediatric and AYA patients with R/R Ph-positive ALL are similar to what has been summarized for R/R Ph-negative or Ph-like ALL.(MS-30) NCCN Recommendations for T-ALL Front-Line Management: The panel recommends that pediatric and AYA patients with T-ALL be treated in a clinical trial when possible. In the absence of an appropriate clinical trial, patients are treated with chemotherapy. Patients who have very-high-risk features may continue chemotherapy or pursue alternative therapy and consider HCT as part of consolidation therapy. However, it is recommended that additional therapy be given to achieve MRD negativity prior to HCT. (MS-32) R/R Management: For pediatric and AYA patients with T-ALL experiencing first relapse, the panel recommends initial treatment with clinical trial or chemotherapy. If patients experience CR2, consolidation therapy with chemotherapy should be continued with HCT. (MS-32) NCCN Recommendations for Infant ALL Front-Line Management: The panel recommends that infant patients with ALL be treated in a clinical trial when possible. In the absence of an appropriate clinical trial, patients are treated with Interfant-based chemotherapy. In all cases, HCT may be considered as part of consolidation or maintenance therapy. Medical Coverage Policy: 0533 Cancer R/R Management: The NCCN Panel recommendations for infant patients with R/R ALL are similar to what has been summarized for R/R Ph- negative or Ph-like ALL. (MS-34, 35) NCCN GUIDELINES™ Adolescent and Young Adult (AYA) Oncology (V.3.2023 — January 9, 2023) Hematopoietic Stem Cell Transplant HSCT is a potentially curative treatment option for an increasing number of AYA patients with leukemias and lymphomas. Graft-versus-host disease (GVHD), chronic immunosuppression, and gonadal dysfunction in males and females related to high-dose conditioning chemotherapy and RT are the major post-transplant complications associated with HSCT. Chronic GVHD has been identified as the leading cause of non-relapse mortality in HSCT survivors. AYA patients are at a higher risk of developing chronic GVHD than younger children. HSCT survivors are also at increased risk for late complications, which include recurrent infections, secondary cancers, cardiac dysfunction, growth failure, weight loss, neurocognitive delay, and other end-organ dysfunction. Allogeneic HSCT survivors irradiated at 30 years or younger are at higher risk of developing secondary solid cancers. Findings highlight the increasingly recognized need for long-term follow- up care that incorporates screening and surveillance of AYA survivors of HSCT. (MS-9) NCCN GUIDELINES™ Older Adult Oncology (V.1.2023 — February 14, 2023) A recommended assessment tool is the Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI). Acute Myeloid Leukemia (AML) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) (also referred to as acute myelogenous leukemia) Children (<18 years) Acute myeloid leukemia CR1, low risk Acute myeloid leukemia CR1, intermediate risk Acute myeloid leukemia CR1, high risk Acute myeloid leukemia CR2+ Acute myeloid leukemia Not in remission Acute promyelocytic leukemia Relapse Allogeneic HCT N C S S S R Autologous HCT N N N N N R Medical Coverage Policy: 0533 Cancer Adults Acute myeloid leukemia CR1, low risk Acute myeloid leukemia CR1, intermediate risk Acute myeloid leukemia CR1, high risk Acute myeloid leukemia CR2 Acute myeloid leukemia CR3+ Acute myeloid leukemia Not in remission Acute myeloid leukemia Therapy-related, CR1 Acute promyelocytic leukemia CR1 Acute promyelocytic leukemia CR2, molecular remission Acute promyelocytic leukemia CR2, not in molecular remission Acute promyelocytic leukemia CR3+ Acute promyelocytic leukemia Not in remission Acute promyelocytic leukemia Relapse after autologous transplant Blastic plasmacytoid dendritic cell neoplasm Allogeneic HCT N S S S S S S N C S C C C Autologous HCT C C N C N N N N S N N N N R R American Society of Transplantation and Cellular Therapy (Tarlock 2022) Hematopoietic Cell Transplantation in the Treatment of Pediatric Acute Myelogenous Leukemia and Myelodysplastic Syndromes: Guidelines from the American Society of Transplantation and Cellular Therapy Should children with favorable risk cytogenetic and molecular lesions (CBF, NPM1, CEBPA bZip) undergo HCT in first complete remission (CR1), even if measurable residual disease (MRD) positive (+) at first end of induction (EOI)? Recommendation = No Should children with FLT3-ITD undergo HCT in CR1? Recommendation = Yes Should children with high-risk cytomolecular abnormalities undergo HCT in CR1? Recommendation = Yes Should children who are MRD+ by flow cytometry at EOI and no other risk-stratifying lesion be considered for HCT in CR1? Recommendation = Yes Medical Coverage Policy: 0533 Cancer Should children with primary induction failure or refractory disease after 2-3 cycles of chemotherapy be considered for allogenic HCT, even if not in CR1? Recommendation = Yes Should children who relapse be offered HCT following attempts to obtain second complete remission (CR2)? Recommendation = Yes Should HCT be considered for Down syndrome (DS)-AML in certain situations of relapsed or highly refractory disease with careful consideration of its limitations and toxicity risk? Recommendation = Yes Should patients with relapsed or refractory extramedullary disease (EMD) be considered for HCT with boost radiation to sites of persistent disease with conditioning? Recommendation = Yes • Should HCT in CR1 be offered for acute promyelocytic leukemia (PML)? Recommendation = No Should auto-HCT be offered in relapsed acute promyelocytic leukemia after induction of CR2 and PML-RARa PCR-negative? Recommendation = Yes American Society of Transplantation and Cellular Therapy (Dholaria 2021) Hematopoietic Cell Transplantation in the Treatment of Newly Diagnosed Adult Acute Myeloid Leukemia: An Evidence-Based Review from the American Society of Transplantation and Cellular Therapy. Should unfavorable-risk* patients undergo allo-HCT in CR1? Recommendation = Yes Should intermediate-risk* patients undergo allo-HCT in CR1? Recommendation = Yes Should favorable-risk* patients undergo allo-HCT in CR1? Recommendation = No (CBF-AML with KIT mutation may be considered for allo-HCT in CR1.) Is there any role of secondary mutational abnormalities in selecting a patient for allo-HCT? Recommendation = Unclear • Should the presence of MRD at the end of induction therapy be considered an indication to offer allo-HCT? Recommendation = Yes Should AML with induction failure undergo allo-HCT? Recommendation = Unclear Should secondary AML undergo allo-HCT in CR1? Recommendation = Yes Should therapy-related AML undergo allo-HCT in CR1? Recommendation = Yes (Except therapy-related AML with favorable karyotype [inv(16); t(8;21); t(15;17)]) • Should patients ≥60 years undergo allo-HCT in CR1? Recommendation = Yes Is auto-HCT a good alternative to chemotherapy consolidation in patients who are not eligible for allo-HCT? Recommendation = Yes (Favorable-risk or intermediate-risk with MRD─) * Risk stratification by European Leukemia Net 2017 guidelines. Medical Coverage Policy: 0533 Cancer NCCN GUIDELINES™ Acute Myeloid Leukemia (V.3.2023 — April 5, 2023) NCCN Recommendations The NCCN AML Panel strongly encourages enrollment in a clinical trial for treatment induction of younger patients (aged <60 years) with AML. (MS-34) HLA testing should be performed promptly in those who may be candidates for either fully ablative or reduced-intensity conditioning (RIC) allogeneic HCT from a matched sibling or an alternative donor, which constitutes the best option for long-term disease control. (MS-35) CBF Cytogenetic Translocations and MRD Negative There are insufficient data to evaluate the use of allogeneic HCT in first remission for patients with AML who are MRD negative and have favorable-risk cytogenetics outside of a clinical trial. (MS-40) Intermediate-Risk Cytogenetics and/or Molecular Abnormalities Including MRD Positive The panel members agree that transplant-based options (either matched sibling or alternate donor allogeneic HCT) or 3 to 4 cycles of HiDAC affords a lower risk of relapse and a somewhat higher DFS when given as consolidation for patients with intermediate-risk cytogenetics. The role of autologous HCT in the intermediate-risk group outside of clinical trials is diminishing due to improvements in allogeneic transplants, which are expanding the pool of potential donors outside the family setting. While autologous HCT is still incorporated into the clinical trial design in Europe, the consensus of the NCCN AML Panel was that autologous HCT should not be a recommended consolidation therapy outside the setting of a clinical trial. (MS-40) Treatment-Related Disease Other than CBF and/or Unfavorable Cytogenetics and/or Molecular Abnormalities The panel strongly recommends clinical trials as standard therapy for patients with poor prognostic features, which include FLT3-ITD abnormalities in the setting of otherwise NK-AML, high WBC (>50,000/mcL) at diagnosis, or adverse cytogenetics/molecular markers as well as secondary and therapy-related AML. If remission is observed, consolidation therapy is recommended, and strong consideration should be given to allogeneic HCT with matched sibling or alternative donor (including umbilical cord blood products) as part of consolidation strategy. (MS-41) NCCN Recommendations Similar to recommendations for adults younger than 60 years, the NCCN AML Panel encourages enrollment in a clinical trial for treatment induction of patients aged ≥60 years with AML. (MS-49) NCCN Recommendations Medical Coverage Policy: 0533 Cancer Previous Intensive Therapy For patients who had previously received intensive therapy, a marrow to document remission status upon hematologic recovery should be performed after 4 to 6 weeks. If a CR is observed, a clinical trial is recommended. Other post-remission or maintenance therapy recommendations include but are not limited to allogeneic HCT. (MS-52) For patients who experience induction failure, a clinical trial, low- intensity therapy (azacitidine, decitabine), allogeneic HCT (preferably in the context of a clinical trial), therapies for R/R disease (see Management of Relapsed/Refractory AML), or best supportive care are recommended treatment options. (MS-53) Previous Lower-Intensity Therapy For patients who previously received lower-intensity therapy, a marrow to document remission status upon hematologic recovery should be performed, with the timing dependent on the therapy used. If a response is observed, allogeneic HCT may be considered for select patients. (MS- 53) NCCN Recommendations The NCCN AML Panel recommends enrollment in a clinical trial for the management of Relapsed/Refractory AML as a strongly preferred option. Other options include targeted therapy or chemotherapy followed by allogeneic HCT. Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Due to the rarity of BPDCN, there have been limited established standardized therapeutic approaches. HCT seems to generate durable remissions, especially if given in first CR. (MS-68) NCCN Recommendations: With all treatment options, if CR is observed, allogeneic HCT or autologous HCT should be considered.(MS-69) Amyloidosis American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Adults Amyloid light chain amyloidosis Allogeneic HCT N Autologous HCT S NCCN GUIDELINES™ Systemic Light chain Amyloidosis (V.2.2023 — November 28, 2022) All patients with newly diagnosed systemic light chain amyloidosis (SLCA) should be assessed for autologous HCT eligibility. Those with low tumor burden can proceed to receive HCT immediately. Those who are not eligible for HCT due to high tumor burden may receive systemic therapy first, and their eligibility for transplant may be assessed after initiating systemic therapy based on improvements in functional status and/or organ response. The NCCN panel members recommend that Medical Coverage Policy: 0533 Cancer treatment of SLCA should be in the context of a clinical trial when possible, because data are insufficient to identify optimal treatment of the underlying plasma cell disorder. (MS-5) Chronic Lymphocytic Leukemia (CLL) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Adults Chronic lymphocytic leukemia High risk, 1st or greater remission Chronic lymphocytic leukemia T-cell prolymphocytic leukemia Chronic lymphocytic leukemia B-cell, prolymphocytic leukemia Chronic lymphocytic leukemia Transformation to high grade lymphoma Hairy cell leukemia First remission Hairy cell leukemia Second remission Hairy cell leukemia ≥ third remission or refractory disease Allogeneic HCT S S R C N N R Autologous HCT N R R S N N N NCCN GUIDELINES™ Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (V.2.2023 — January 25, 2023) Indications for Allogeneic HCT Allogeneic HCT can be considered for CLL/SLL refractory to small- molecule inhibitor therapy in patients without significant comorbidities. HCT-specific comorbidity index (HCT-CI) could be used for the assessment of comorbidities prior to HCT and to predict the risks of non- relapse mortality and the probabilities of survival after HCT. For patients with CLL/SLL with del(17p) or TP53 mutation, a discussion of allogeneic HCT could be considered for patients in remission with or after ibrutinib therapy, if CK (≥3 abnormalities) is present. However, available data suggest that CK (≥5 abnormalities) is associated with inferior OS and EFS following allogeneic HCT with reduced-intensity conditioning in patients with high-risk interphase cytogenetics. (MS-21, 22) NCCN GUIDELINES™ Hairy Cell Leukemia (V.1.2023 — August 30, 2022) Does not address Hematopoietic Stem Cell Transplantation Medical Coverage Policy: 0533 Cancer Chronic Myeloid Leukemia (CML) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Children (<18 years) Chronic myeloid leukemia Chronic phase Chronic myeloid leukemia Accelerated phase Chronic myeloid leukemia Blast phase Allogeneic HCT C C C Autologous HCT N N N Adults Chronic myeloid leukemia Chronic phase 1, TKI intolerant Chronic myeloid leukemia Chronic phase 1, TKI refractory Chronic myeloid leukemia Chronic phase 2+ Chronic myeloid leukemia Accelerated phase Chronic myeloid leukemia Blast phase Allogeneic HCT C C S S S Autologous HCT N N N N N NCCN GUIDELINES™ Chronic Myeloid Leukemia (V.2.2023 — April 13, 2023) Allogeneic Hematopoietic Cell Transplant Allogeneic HCT is a potentially curative treatment for patients with CML. Ongoing advances in alternative donor sources (such as unrelated donors and cord blood), more accurate HLA testing for a stringent selection of unrelated matched donors, and the use of reduced-intensity conditioning regimens have improved outcomes following allogeneic HCT. Allogeneic HCT is an appropriate treatment option for the very rare patients presenting with BP-CML at diagnosis, patients with disease that is resistant to TKIs, patients with progression to AP-CML or BP-CML while on TKI therapy, and patients with CML that is resistant and/or intolerant to all TKIs. The potential use of allogeneic HCT must be tied to faithful monitoring of disease since the major potential pitfall in delaying transplantation is “missing” the chronic phase interval. (MS-22) Chronic Myelomonocytic Leukemia (CMML) See Myelodysplastic Syndromes Medical Coverage Policy: 0533 Cancer Hodgkin Lymphoma American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Children (<18 years) Hodgkin lymphoma CR1 Hodgkin lymphoma Primary refractory, sensitive Hodgkin lymphoma Primary refractory, resistant Hodgkin lymphoma First relapse, sensitive Hodgkin lymphoma First relapse, resistant Hodgkin lymphoma Second or greater relapse Allogeneic HCT N N C N C C Autologous HCT N C N S N C Adults Hodgkin lymphoma CR1 (PET negative) Hodgkin lymphoma Primary refractory, sensitive Hodgkin lymphoma Primary refractory, resistant Hodgkin lymphoma First relapse, sensitive Hodgkin lymphoma First relapse, resistant Hodgkin lymphoma Second or greater relapse Hodgkin lymphoma Relapse after autologous transplant Allogeneic HCT N C C S C S S Autologous HCT N S N S N S N NCCN GUIDELINES™ Hodgkin Lymphoma (V.2.2023 — November 8, 2022) NCCN Recommendations for Refractory CHL Histologic confirmation with biopsy is recommended before initiating treatment for refractory disease. Although further cytoreduction and HDT/ASCR (with RT if not previously given) are often appropriate, occasional clinical circumstances may warrant the use of RT or systemic therapy with or without RT. Conventional-dose second-line systemic therapy may precede HDT/ASCR. RT should be strongly considered for selected sites of relapse that have not been previously irradiated. In radiation-naïve patients, TLI may be an appropriate component of HDT/ASCR. Medical Coverage Policy: 0533 Cancer Second-line systemic therapy followed by response assessment with FDG-PET is recommended for all patients. Patients with a Deauville score of 1 to 3 should proceed to HDT/ASCR with or without RT (category 1). Observation with or without RT can be considered, if HDT/ASCR is contraindicated. Maintenance therapy with BV can be considered for patients with high risk of relapse as defined by the AETHERA trial (defined as those having primary refractory disease, duration of first CR <1 year, or relapse with extranodal or advanced-stage disease). An alternative regimen with or without RT or RT alone is recommended for patients with a Deauville score of 4 or 5 after second-line systemic therapy. Autologous or allogenic HCT following additional therapy may be considered in these patients. Another approach for patients with a Deauville score of 4 is to proceed with HDT/ASCR with or without RT, followed by maintenance therapy with BV for patients with a high risk of relapse. The panel has included allogeneic HCT with a category 3 recommendation for select patients with relapsed or refractory disease. Autologous or allogeneic HCT is an option for patients with FDG-PET– positive refractory HL (Deauville 5) that is responsive to RT alone or to subsequent systemic therapy, with or without RT. (MS-26, 27) NCCN Recommendations for Relapsed CHL Most patients require second-line systemic therapy followed by RT or HDT/ASCR with or without ISRT. (MS-27) Summary Second-line systemic therapy followed by HDT/ASCR with or without RT is recommended for patients with relapsed or refractory CHL. Maintenance therapy with BV (for 1 year) following HDT/ASCR can be considered for patients with high risk of relapse. (MS-28) NCCN GUIDELINES™ Pediatric Hodgkin Lymphoma (V.2.2023 — March 9, 2023) NCCN Recommendations for Low-Risk CHL For patients with stage IA, IIA, and IB CHL (with or without bulky disease; no E-lesions), the panel recommends enrollment in an ongoing clinical trial or treatment according to EuroNet-PHL-C1 (a category 1 recommendation) as the preferred strategies. (MS-8) NCCN Recommendations for Intermediate-Risk CHL For patients with stage IA/IIA CHL (with bulky disease; with or without E-lesions), IB CHL (with or without bulky disease or E-lesions), IIB CHL (no bulky disease; with or without E-lesions), and IIIA CHL, the panel recommends enrollment in an ongoing clinical trial or treatment according to AHOD0031 or EuroNet-PHL-C1 as the preferred strategies. (MS-10) NCCN Recommendations for High-Risk CHL For patients with stage IIB, IIIA, IIIB, and IV CHL, the panel recommends enrollment in an ongoing clinical trial or treatment with Bv- Medical Coverage Policy: 0533 Cancer AVE-PC according to AHOD1331 or treatment according to EuroNet-PHL- C1 as the preferred strategies. (MS-12) NCCN Recommendations for Relapsed or Refractory CHL Histologic confirmation with biopsy is recommended before initiating treatment for relapsed or refractory disease given the risk for transformation and high false-positive rate of FDG-PET/CT. If the biopsy is negative, the panel recommends either observation with short-interval follow-up or additional workup if there is a high index of suspicion. If the biopsy is positive, the panel recommends enrollment in a clinical trial if available, and referral to or consulting with a center of expertise, as several options exist for the treatment of R/R disease and there is a lack of data to support one regimen over another. Typically, patients are treated with re-induction therapies, and after an FDG-PET/CT or FDG-PET/MRI assessment, if metabolic CR is observed (Deauville score ≤3), treatment can be followed up with HDT/ASCR with or without ISRT and with or without maintenance therapy. In general, RT is performed as consolidation after transplant. If a metabolic CR is not achieved, RT may be used before transplant. (MS-15) NCCN Recommendations for Stage IA NLPHL with Complete Resection Confirmed by FDG-PET/CT For patients with stage IA NLPHL with complete resection confirmed by FDG-PET/CT, the panel recommends enrollment in an ongoing clinical trial or observation as the preferred strategies. (MS-16) NCCN Recommendations for Stage IA or IIA NLPHL with Incomplete Resection and Non-Bulky For patients with stage IA or IIA NLPHL with incomplete resection and non-bulky disease, the panel recommends enrollment in an ongoing clinical trial, AVPC x 3 cycles (category 1 recommendation), or CVbP with or without rituximab as preferred strategies. An FDA-approved biosimilar is an acceptable substitute for rituximab. (MS-17) NCCN GUIDELINES™ Cancer in People with HIV (V.1.2023 — December 20, 2022) Management of Hodgkin Lymphoma in ‘People with HIV’ (PWH) Autologous stem cell transplantation also appears to be safe and effective in PWH who have recurrent/relapsed Hodgkin lymphoma. (MS- 15) Allogeneic HCT also appears to be safe in this population (PWH with acute leukemia, myelodysplasia, or lymphoma) (MS-16) Juvenile Myelomonocytic Leukemia (JMML) Multiple Myeloma (MM) See Myelodysplastic Syndromes American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Medical Coverage Policy: 0533 Cancer Adults Myeloma, initial response Myeloma, sensitive relapse Myeloma, refractory Plasma cell disorders, Relapse after autologous transplant Plasma cell leukemia Allogeneic HCT D S C C S Autologous HCT S S C C C NCCN GUIDELINES™ Multiple Myeloma (V. 3.2023 — December 8, 2022) Transplant Eligibility All patients are assessed to determine eligibility for HCT. The NCCN Panel recommends that all patients eligible for HCT should be referred for evaluation by HCT center and hematopoietic stem cells (for at least two transplants, in younger patients) should be harvested. High-dose therapy with hematopoietic stem cell support is a critical component in the treatment plan of eligible patients newly diagnosed with MM. The types of HCT may be single autologous HCT, a tandem HCT (a planned second course of high-dose therapy and HCT within 6 months of the first course), or an allogeneic HCT. The NCCN Guidelines for Multiple Myeloma indicate that all types of HCT are appropriate in different clinical settings. In general, all candidates for high-dose chemotherapy must have sufficient hepatic, renal, pulmonary, and cardiac function. However, renal dysfunction is not an absolute contraindication to transplant. (MS-20, 21) Autologous Hematopoietic Cell Transplantation Autologous HCT results in high response rates and remains the standard of care after primary therapy for eligible patients. According to the NCCN Guidelines, for transplant-eligible patients autologous HCT is the preferred option after primary induction therapy while a delayed HCT after early stem cell collection and storage is appropriate as well. (Category 1) A repeat HCT can be considered for treatment of progressive/refractory disease after primary treatment in patients with prolonged response to initial HCT. (MS-21) Tandem Hematopoietic Cell Transplantation Tandem HCT refers to a planned second course of high-dose therapy and HCT within 6 months of the first course. The NCCN Multiple Myeloma Panel recommends collecting enough hematopoietic stem cells for at least one HCT in all eligible patients, and for 2 transplants in the younger patients if tandem transplant or salvage transplant would be considered. According to the NCCN Multiple Myeloma Panel, a tandem transplant with or without maintenance therapy can be considered for all patients who are candidates for HCT and is an option for patients who do not achieve at least a VGPR after the first autologous HCT and those with high-risk features. (MS-22, 23) Medical Coverage Policy: 0533 Cancer A second autologous HCT can be considered at the time of disease relapse. According to the NCCN Multiple Myeloma Panel, repeat autologous HCT for relapsed disease may be considered either on or off clinical trial depending on the time interval between the preceding HCT and documented progression. (MS-23) According to the NCCN Multiple Myeloma Panel, repeat autologous HCT for relapsed disease may be considered either on or off clinical trial depending on the time interval between the preceding HCT and documented progression. (MS-24) Allogeneic Hematopoietic Cell Transplantation Allogeneic HCT includes either myeloablative or nonmyeloablative (ie, “mini” transplant) transplants. Allogeneic HCT has been investigated as an alternative to autologous HCT to avoid the contamination of reinfused autologous tumor cells, but also to take advantage of the beneficial graft-versus-tumor effect associated with allogeneic transplants. However, lack of a suitable donor and increased morbidity has limited this approach, particularly for the typical older MM population. Non myeloablative transplants are designed to decrease the morbidity of the high-dose chemotherapy but preserve the beneficial graft-versus-tumor effect. Therefore, the principal difference between myeloablative and nonmyeloablative transplants relates to the chemotherapy regimen used. There is ongoing interest in myeloablative allogeneic HCT, particularly given the lack of a significant cure rate for single or tandem autologous HCT. (MS-24) American Society for Transplantation and Cellular Therapy (ASTCT) 2022 Clinical Practice Recommendations for Transplantation and Cellular Therapies in Multiple Myeloma (Dhakal, et al., 2022) The following are 2022 Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments in the First- Line Setting for MM: 1. The panel recommends early autologous transplantation as a consolidation therapy in eligible, newly diagnosed myeloma patients after 4-6 cycles of induction (Grade: A*) 2. The panel recommends mobilization and storage of peripheral blood stem cells in newly diagnosed myeloma patients not undergoing autologous transplantation after first line of therapy for future use as a treatment at first relapse (Grade: B) 3. The panel does not recommend using MRD testing to guide use of autologous transplantation after induction therapy in myeloma, outside the setting of a clinical trial (Grade: C) 4. The panel does not recommend age as the only selection factor when considering autologous transplantation in myeloma (Grade: B) 5. In the absence of clinical trial, the panel recommends early autologous transplantation in myeloma patients with high-risk Medical Coverage Policy: 0533 Cancer cytogenetics [t (4;14); t (14;16); t (14;20)], 1p deletion, 1q gain/amplification and 17p deletion (Grade: B) 6. The panel does not recommend tandem autologous transplantation in standard risk myeloma patients after induction, outside in the setting of a clinical trial (Grade: B) 7. The panel does not recommend routine multiagent consolidation therapy in patients in very good partial response or better after autologous transplantation outside the setting of clinical trial (Grade: B) 8. The panel does not recommend consolidation with CAR-T cell therapy in patients after first line therapy outside the setting of clinical trial (Grade: C) 9. The panel recommends lenalidomide maintenance after autologous transplantation in standard risk patients unless contraindicated (Grade: A) 10. The panel recommends bortezomib and lenalidomide maintenance or clinical trial after autologous transplantation in high-risk patients (Grade: B) 11. The panel does not recommend allogeneic transplantation except in the context of clinical trial (Grade: C) 12. The panel does not recommend tandem autologous-allogeneic transplantation except in the context of clinical trial (Grade: C) 13. The panel recommends dose adjusted melphalan in patients with renal impairment including on dialysis, >70 years and KPS<80 (Grade: B) 14. The panel recommends treating primary plasma cell leukemia similar to high-risk myeloma in the absence of clinical trial (Grade: B) The following are 2022 Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments for RR MM: 1. The panel recommends autologous transplantation in first relapse in patients who have not received transplant as a first-line therapy (Grade: A) 2. The panel recommends consideration of autologous transplantation in patients with primary refractory disease (Grade: C) 3. The panel recommends salvage second autologous transplantation in patients who were in remission for (at least) 36 months with maintenance and 18 months in the absence of maintenance (Grade: B) 4. The panel recommends CAR-T cell therapy after 4 or more prior lines of therapy (Grade: A) 5. The panel recommends clinical trial, if possible after CAR failures (Grade: B) 6. The panel encourages allogeneic transplantation in relapsed and/or refractory setting only in the context of clinical trial (Grade: B) A: There is good research-based evidence to support the recommendation. Medical Coverage Policy: 0533 Cancer B: There is fair research-based evidence to support the recommendation. C: The recommendation is based on expert opinion and panel consensus. X: There is evidence of harm from this intervention. (ASTCT/ Dhakal, et al., 2022) Myelodysplastic Syndromes American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Children (<18 years) Myelodysplastic syndromes (MDS) Low risk Myelodysplastic syndromes High risk Juvenile myelomonocytic leukemia Myelodysplastic syndromes Therapy related Allogeneic HCT C S S S Autologous HCT N N N N Adults Myelodysplastic syndromes Low/intermediate – 1 risk Myelodysplastic syndromes Intermediate-2/high risk Myelodysplastic syndromes Therapy-related, CR1 Allogeneic HCT C S S Autologous HCT N N N American Society for Transplantation and Cellular Therapy (DeFilipp, 2023) Hematopoietic Cell Transplantation in the Management of Myelodysplastic Syndrome: An Evidence-Based Review from the American Society for Transplantation and Cellular Therapy Committee on Practice Guidelines Should allogeneic HCT routinely be offered early for advanced (IPSS intermediate-2 [int-2] and high risk) (int-2/high) de novo MDS? Recommendation = Yes Should allogeneic HCT routinely be offered early for lower risk (intermediate-1) (low/int-1) de novo MDS? Recommendation = No Should eligibility for HCT in MDS be limited by age? Recommendation = No Should eligibility for HCT in MDS be limited by comorbidity? Recommendation = Unclear Should HCT be offered for patients with therapy-related MDS? Recommendation = Yes Medical Coverage Policy: 0533 Cancer Should patients be assessed for chromosomal anomalies and somatic mutations prior to HCT? Recommendation = Yes Should HCT be offered for patients with high-risk cytogenetic or molecular disease? Recommendation = Yes Should patients with MDS receive disease-directed therapy prior to HCT? Recommendation = Unclear NCCN GUIDELINES™ Myelodysplastic Syndromes (V.1.2023 — September 12, 2022) Myelodysplastic/Myeloproliferative Neoplasms The category of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) was added to the 2008 update of the WHO classification of myeloid neoplasms. This category includes chronic myelomonocytic leukemia (CMML); atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative; and juvenile myelomonocytic leukemia (JMML) as disorders having overlapping dysplastic and proliferative features. The management of CMML depends on the characteristics of the patient’s disease and is typically focused on supportive care and cytoreductive therapy.38 Patients who are asymptomatic with low-risk disease may be observed until disease progression. In patients with CMML-1 and CMML- 2, hypomethylating agents (HMAs), decitabine and azacitidine (AzaC) have demonstrated efficacy, and emerging data suggest utility of ruxolitinib in this context. Patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for hematopoietic stem cell transplantation (HCT). (MS-5) Allogeneic HCT is the only treatment modality that can induce long-term remissions in aCML. HMAs and/or ruxolitinib and/or allogeneic HCT may be considered for patients with BCR-ABL negative aCML. Allogeneic HCT is the main treatment option for JMML. (MS-6) High-Intensity Therapy High-intensity therapy includes intensive induction chemotherapy or HCT. (MS-33) Therapy for Higher-Risk Disease (IPSS Intermediate-2, High; IPSS-R Intermediate, High, Very High; or WPSS High, Very High) Treatment for higher-risk patients is dependent on whether they are possible candidates for intensive therapy (eg, allogeneic HCT, intensive chemotherapy). For patients who are transplant candidates, an HLA-matched sibling or HLA-matched unrelated donor can be considered. Results with HLA- matched unrelated donors have improved to levels comparable to those obtained with HLA-matched siblings. With the increasing use of cord blood or HLA-haploidentical related donors, HCT has become a viable option for many patients. High-dose conditioning is typically used for younger patients, whereas RIC for HCT is generally the strategy in older individuals. (MS-38) Medical Coverage Policy: 0533 Cancer NCCN GUIDELINES™ Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes (V. 1.2023 — May 19, 2023 1.2022, April 14, 2022) Myeloid/Lymphoid Neoplasms with Eosinophilia and PDGFRA or PDGFRB Rearrangement Durable remissions are only rarely achieved with induction chemotherapy or allogeneic hematopoietic cell transplant (HCT). (MS-12) Myeloid/Lymphoid Neoplasms with Eosinophilia and FGFR1 or JAK2 or ABL1 or FLT3 Rearrangement MLN-Eo with the above-mentioned TK fusion gene rearrangements are generally associated with an aggressive clinical course, relapse, or disease progression to blast phase and allogeneic HCT is the only potentially curative option. (MS-13) Myelofibrosis American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Adults (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Myelofibrosis and myeloproliferative diseases, Primary, low risk Myelofibrosis and myeloproliferative diseases, Primary, intermediate/high risk Myelofibrosis and myeloproliferative diseases, Secondary Myelofibrosis and myeloproliferative diseases, Hypereosinophilic syndromes, refractory Allogeneic HCT C C C R Autologous HCT N N N N NCCN GUIDELINES™Myeloproliferative Neoplasms (V.1.2023 — May 19, 2023) Allogeneic HCT is the only potentially curative treatment option resulting in long-term remissions for patients with MF. (MS-19) Lower-Risk MF Patients with asymptomatic lower-risk MF should be observed and monitored for signs and symptoms of disease progression with MPN-SAF TSS (MPN-10). Enrollment in a clinical trial is also an option. (MS-22) Higher-Risk MF Evaluation for allogeneic HCT is recommended for all patients with higher-risk MF and allogeneic HCT is recommended for patients who meet transplant eligibility criteria. (MS-23) Medical Coverage Policy: 0533 Cancer Disease Progression to Advanced Phase or Transformation to Acute Myeloid Leukemia Allogeneic HCT remains the only curative option resulting in long-term disease control in selected transplant-eligible patients who achieve a CR to induction chemotherapy. (MS-30) Non-Hodgkin Lymphoma (NHL) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Children (<18 years) Anaplastic large cell lymphoma CR1 Anaplastic large cell lymphoma Primary refractory, sensitive Anaplastic large cell lymphoma Primary refractory, resistant Anaplastic large cell lymphoma First relapse, sensitive Anaplastic large cell lymphoma First relapse, resistant Anaplastic large cell lymphoma Second or greater relapse Burkitt lymphoma (BL) First remission Burkitt lymphoma First or greater relapse, sensitive Burkitt lymphoma First or greater relapse, resistant Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt), CR1, standard risk Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt), CR1, high risk Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt), CR2 Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt), CR3+ Lymphoblastic B-cell non-Hodgkin lymphoma (non-Burkitt), Not in remission T cell non-Hodgkin lymphoma CR1, standard risk T cell non-Hodgkin lymphoma CR1, high risk T cell non-Hodgkin lymphoma Allogeneic HCT N C C C C C N C C N S S C C N Autologous HCT N C N C N C N C N N N N N N R R R S C Medical Coverage Policy: 0533 Cancer Medical Coverage Policy: 0533 CR2 T cell non-Hodgkin lymphoma CR3+ T cell non-Hodgkin lymphoma Not in remission Adults Burkitt lymphoma (BL) CR1 Burkitt lymphoma First or greater relapse, sensitive Burkitt lymphoma First or greater relapse, resistant Burkitt lymphoma Relapse after autologous transplant Cutaneous T cell lymphoma (CTCL) Relapse Diffuse large B cell lymphoma CR 1 (PET negative) Diffuse large B cell lymphoma Primary refractory, sensitive Diffuse large B cell lymphoma Primary refractory, resistant Diffuse large B cell lymphoma First relapse, sensitive Diffuse large B cell lymphoma First relapse, resistant Diffuse large B cell lymphoma Second or greater relapse Diffuse large B cell lymphoma Relapse after autologous transplant Diffuse large B cell lymphoma Plasmablastic lymphoma CR1 Diffuse large B cell lymphoma Plasmablastic lymphoma Relapse Follicular lymphoma CR 1 Follicular lymphoma Primary refractory, sensitive Follicular lymphoma Primary refractory, resistant Follicular lymphoma First relapse, sensitive (including POD24) Follicular lymphoma First relapse, resistant Follicular lymphoma Second or greater relapse C C Allogeneic HCT N C C C S N S S S S S S R R N N S N S S C N Autologous HCT N C N N C N S N S N S N R C N S N S N S Cancer Medical Coverage Policy: 0533 Follicular lymphoma Transformation to high grade lymphoma Follicular lymphoma Relapse after autologous transplant High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements CR 1 (PET negative) High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements Primary refractory, sensitive High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements Primary refractory, resistant High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements First relapse, sensitive High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements First relapse, resistant High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements Second or greater relapse High-grade B cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements Relapse after autologous transplant Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia CR 1 Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia Primary refractory, sensitive Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia Primary refractory, resistant Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia First or greater relapse, sensitive Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia First or greater relapse, resistant Lymphoplasmacytic lymphoma/ Waldenstrom macroglobulinemia Relapse after autologous transplant Mantle cell lymphoma C S N R R R R R R N N R C R C C S N C C N C N C N N C N S N N S Cancer CR 1/first partial remission Mantle cell lymphoma Primary refractory, sensitive Mantle cell lymphoma Primary refractory, resistant Mantle cell lymphoma First relapse, sensitive Mantle cell lymphoma First relapse, resistant Mantle cell lymphoma Second or greater relapse Mantle cell lymphoma Relapse after autologous transplant T cell lymphoma CR 1/first partial remission T cell lymphoma Primary refractory, sensitive T cell lymphoma Primary refractory, resistant T cell lymphoma First relapse, sensitive T cell lymphoma First relapse, resistant T cell lymphoma Second or greater relapse T cell lymphoma Relapse after autologous transplant S C S C S S S S C S C S S N S N S N S S N S N C S N NCCN GUIDELINES™ B-cell Lymphoma (V.3.2023 — May 11, 2023 4.2022, June 9, 2022) Burkitt Lymphoma NCCN Recommendations It is preferred that patients with BL receive treatment at centers with expertise in the management of this highly aggressive disease. Participation in clinical trials is recommended for all patients. CHOP or CHOP-like therapy is not adequate for the treatment of BL The management of patients with B-cell lymphomas with features intermediate between BL and DLBCL (now included in the new category, HGBL, NOS) as well as those patients with double-hit or triple-hit lymphomas (HGBL with translocations of MYC and BCL2 and/or BCL6) has not been well studied. Therefore, these patients are best managed in the context of clinical trials evaluating novel targeted agents. (MS-144) Patients with relapsed or refractory disease should be treated in the context of a clinical trial. Consolidation with high-dose therapy and autologous stem cell rescue (HDT/ASCR) or allogeneic HCT (if donor available) may be considered for selected patients achieving a CR or PR to second-line therapy. (MS-145) HIV-Related B-Cell Lymphomas NCCN Recommendations Medical Coverage Policy: 0533 Cancer The NCCN Guidelines recommend the use of ART and growth factor support along with full-dose chemotherapy with or without rituximab. (MS-153) Post-Transplant Lymphoproliferative Disorders NCCN Recommendations Treatment options for PTLD depend on the histological subtype and should be individualized. RI, if possible, should be a part of the initial treatment approach for all patients with PTLD. Initial management strategies include reduction of calcineurin inhibition (cyclosporin or tacrolimus) by 50% and discontinuation of antimetabolic agents (azathioprine or mycophenolate mofetil). (MS-167) Follicular Second-line Consolidation or Extended Dosing HDT/ASCR is an appropriate consolidative therapy for patients with second or third remission. (MS-24) Nodal Marginal Zone Lymphoma Second-line Consolidation or Extended Dosing HDT/ASCR is included as an option for consolidative therapy for patients with disease responding to second-line therapy. Allogeneic hematopoietic cell transplant (HCT) may also be considered for highly selected patients. (MS-64) Histologically Transformed Marginal Zone Lymphoma HDT/ASCR and allogeneic HCT may be reasonable treatment options for selected patients with histologically transformed MZL. (MS-70) Mantle Cell Lymphoma Consolidation After Aggressive Induction Therapy The panel recommends consolidation with HDT/ASCR for eligible patients in CR following induction therapy with aggressive regimens, although no studies have compared maintenance rituximab with HDT/ASCR for patients in first CR. Rituximab maintenance following HDT/ASCR is included with a category 1 recommendation. (MS-86) Allogeneic HCT using reduced-intensity conditioning (RIC) has been evaluated as a consolidation strategy for patients in remission following treatment for relapsed/refractory MCL (MS-92) Diffuse Large B-Cell Lymphoma HDT/ASCR is therefore not routinely recommended. (MS-108) Relapsed or Refractory Disease: Consolidation therapy with HDT/ASCR (category 1 for patients with CR) with or without RT is recommended for patients with CR or PR to second-line therapy, if they are candidates for transplant. (MS-113) Burkitt Lymphoma Relapsed or Refractory Disease Consolidation with high-dose therapy and autologous stem cell rescue (HDT/ASCR) or allogeneic HCT (if donor available) may be considered for selected patients achieving a CR or PR to second-line therapy. (MS-145) Medical Coverage Policy: 0533 Cancer NCCN GUIDELINES™ Pediatric Aggressive Mature B-Cell Lymphomas (V.1.2023 — April 4, 2023) Burkitt Lymphoma and Diffuse Large B-Cell Lymphoma Treatment for Relapsed or Refractory Disease Second-line therapy followed by consolidation with autologous or allogeneic HCT (based on response to second-line therapy) is recommended for most patients if they are not enrolled in a clinical trial. Most patients with relapsed/refractory disease achieving a CR to second- line therapy should receive an autologous or allogeneic HCT. Patients with a PR to second-line therapy can also receive an autologous or allogeneic HCT. (MS-11) Primary Mediastinal Large B-Cell Lymphoma Treatment for Relapsed/Refractory Disease The management of relapsed/refractory PMBL in both pediatric and adult patients is similar to the management of relapsed/refractory DLBCL - second-line therapy with cross-resistant chemoimmunotherapy regimens followed by autologous HCT. Patients with a CR to second-line therapy should receive an autologous HCT. Allogeneic HCT is not considered an optimal approach. (MS-14) NCCN GUIDELINES™ Primary Cutaneous Lymphomas (V.1.2023 — January 5, 2023) Mycosis Fungoides/Sézary Syndrome (MFSS) Allogeneic HCT has a role in a subset of patients with advanced-stage MF and SS who have received multiple lines of therapy. (MS-29) Allogeneic HCT may be considered for appropriate patients with stage IIB–IV disease that is refractory to multiple primary treatment options. Allogeneic HCT is generally reserved for patients with systemic disease and/or extensive skin involvement that is refractory to or progressive after multiple lines of systemic therapy options. (MS-30) NCCN GUIDELINES™ T-cell Lymphomas (V.1.2023 — January 5, 2023) Peripheral T-Cell Lymphomas Treatment for Relapsed or Refractory Disease Further data from prospective studies are needed to determine the role of HDT/ASCR and allogeneic HCT in patients with relapsed/refractory PTCL. (MS-17) Second-line systemic therapy followed by consolidation with HDT/ASCR or allogeneic HCT for those with a CR or PR is recommended for patients who are candidates for transplant. (MS-18) Breast Implant-Associated ALCL High-dose therapy followed by autologous HCT could be considered for patients achieving complete response to systemic therapy. (MS-36) T-Cell Large Granular Lymphocytic Leukemia Medical Coverage Policy: 0533 Cancer NCCN Recommendations Low-dose methotrexate or cyclophosphamide (with or without corticosteroids) or cyclosporine are included as options for first-line therapy. (MS-44) T-Cell Prolymphocytic Leukemia Data from retrospective studies suggest that allogeneic HCT may offer the best chance for long-term disease control in a subgroup of patients with T-PLL. (MS-53) NCCN Recommendations Given the poor prognosis associated with T-PLL, the NCCN Guidelines Panel recommends that patients be managed in a clinical trial. In patients who achieve a CR or PR following initial therapy, consolidation with allogeneic HCT should be considered. Autologous HCT may be considered, if a donor is not available and if the patient is not physically fit enough to undergo allogeneic HCT. (MS-53, 54) Adult T-Cell Leukemia/Lymphoma Available evidence mostly from retrospective studies suggest that allogeneic HCT may be associated with long term survival in some patients with ATLL, suggesting a contribution of graft-versus- leukemia/lymphoma (GVL) effect. (MS-66) NCCN Recommendations In the NCCN Guidelines, patients with ATLL are classified into four subtypes (chronic, smoldering, acute, and lymphoma) according to the Shimoyama criteria. There are no optimal standard treatment regimens for the management of ATLL. Thus, the NCCN Guidelines Panel recommends enrollment in clinical trials as one of the options for all patients with ATLL. (MS-67) Hepatosplenic T-Cell Lymphoma NCCN Recommendations The optimal treatment approach remains undefined given the absence of data from prospective randomized clinical studies. (MS-78) Consolidation therapy with allogeneic HCT is recommended for eligible patients with complete response or partial response after initial induction therapy or second-line therapy. Consolidation therapy with autologous HCT can be considered if a suitable donor is not available or for patients who are ineligible for allogeneic HCT. (MS-79) Extranodal Natural Killer/T-Cell Lymphomas, Nasal Type Data confirm that hematopoietic stem cell transplant (HSCT) should be considered for consolidation in selected patients with relapsed ENKL (MS- 91) NCCN Recommendations Participation in a clinical trial is the preferred option for all patients with ENKL with any stage of disease. (MS-91) There are no clear data to suggest whether allogeneic or autologous HCT is preferred and treatment should be individualized. (MS-93) Relapsed/Refractory Disease HCT is an option for eligible patients. Several small case reports have reported favorable long-term outcomes after allogeneic HCT in patients Medical Coverage Policy: 0533 Cancer with relapsed/refractory disease. Allogeneic HCT is preferred if a donor is available. (MS-93) Aggressive NK-Cell Leukemia Allogeneic HCT may be helpful to improve the outcome of patients with ANKL and the panel favors consolidation with allogeneic HCT (over autologous HCT) for patients in first remission. (MS-94) NCCN GUIDELINES™ Waldenstrom Macroglobulinemia/ Lymphoplasmacytic Lymphoma (V. 1.2023 — July 6, 2022) Therapy for Previously Treated WM HCT is also an option for relapsed WM in selected patients. HCT options listed in the NCCN Guidelines for WM/LPL are for high-dose therapy with autologous stem cell rescue. According to the NCCN Panel, myeloablative or non-myeloablative allogeneic HCT may be considered, but in the context of a clinical trial. (MS-13) American Society of Transplantation and Cellular Therapy (ASTCT) Clinical Practice Recommendations for Transplantation and Cellular Therapies in Mantle Cell Lymphoma (Munshi, et al., 2021) The following are 2021 Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments in the First- Line Setting for MCL: 1. The panel recommends autologous HCT as consolidation therapy in eligible, newly diagnosed MCL patients (without TP53 mutation or biallelic deletion) in complete remission or partial remission after first-line therapies.(Grade: A*) 2. The panel does not recommend autologous transplantation as consolidation therapy in MCL patients with disease not responsive to most recent antilymphoma therapy. (Grade: B) 3. The panel does not recommend using measurable residual disease (MRD) testing to guide use of autologous transplantation consolidation after first-line therapies in MCL outside the setting of a clinical trial. (Grade: C) 4. The panel does not recommend using MIPI or MIPI-c prognostic score as a criterion determining use of autologous transplantation as consolidation therapy in eligible newly diagnosed MCL patients in first complete remission or partial remission after first-line therapies. (Grade: C) 5. The panel does not recommend allogeneic transplantation consolidation in MCL patients (without TP53 mutation or biallelic deletion), achieving a complete or partial remission after first-line therapies. (Grade: B) 6. The panel does not recommend consolidation with CAR T cell therapy in MCL patients achieving a complete or partial remission after first-line therapies outside the setting of a clinical trial. (Grade: C) Medical Coverage Policy: 0533 Cancer 7. If a TP53 mutation (or biallelic deletion) is present, the panel recognizes that outcomes are poor for MCL patients in complete or partial remission after first-line therapies who then undergo autologous transplantation. However, no specific alternative strategy has yet been shown to improve outcomes in such patients. Therefore, the panel recommends considering autologous transplantation consolidation as well as alternative consolidation strategies (eg, CAR T cell therapy or allogeneic transplantation), ideally in the context of a clinical trial, for such patients. (Grade: C) The following are 2021 Final Clinical Practice Guidelines Consensus Statements for Transplantation and CAR T Cell Treatments for R/R MCL: 1. If a TP53 mutation (or biallelic deletion) is present, the panel does not recommend autologous transplantation in relapsed MCL patients achieving a complete or partial remission after second or subsequent lines of therapy.(Grade: B) 2. The panel recommends both CAR T cell therapy or allogeneic transplant consolidation as acceptable options, in relapsed MCL patients with TP53 mutation (or biallelic deletion) in a complete or partial remission after second or subsequent lines of therapy. (Grade: C) 3. If a TP53 mutation (or biallelic deletion) is present, the panel recommends treatment with CAR T cells in relapsed MCL patients, with disease unresponsive to last antilymphoma therapy. (Grade: B) 4. In relapsed MCL patients, the panel recommends offering CAR T cell therapy before proceeding with allogeneic transplantation. (Grade: C) 5. Regarding timing of CAR T cell application in relapsed MCL patients (without TP53 mutation or biallelic deletion), the panel recommends offering CAR T cell therapy to patients relapsing after (or who are intolerant to) at least one BTK inhibitor. (Grade: B) 6. The panel does not recommend allogeneic transplantation in relapsed MCL patients with disease refractory to most recent antilymphoma treatment. (Grade:B) 7. The panel recommends allogeneic transplantation for eligible relapsed MCL patients who have achieved only a partial remission with a BTK inhibitor in second or subsequent treatment line, particularly in regions without access to CAR T cell therapy or in subjects where such therapy is not feasible. (Grade: B) 8. The panel recommends allogeneic transplantation in eligible MCL patients relapsing/progressing after CAR T cell therapy, if they achieve a complete or partial remission or if they have stable disease with subsequent antilymphoma therapies. (Grade: C) 9. Among eligible MCL patients lacking a TP53 mutation (or biallelic deletion) not undergoing autologous transplant consolidation following first-line therapies, the panel recommends considering autologous transplantation consolidation therapy in patients who Medical Coverage Policy: 0533 Cancer have achieved a complete remission after second-line chemoimmunotherapies. (Grade: B) 10. The panel recommends considering allogeneic transplant consolidation in eligible MCL patients who still have detectable disease at 3 or more months following CAR T cell therapy. (Grade: C) A: There is good research-based evidence to support the recommendation. B: There is fair research-based evidence to support the recommendation. C: The recommendation is based on expert opinion and panel consensus. X: There is evidence of harm from this intervention. (ASTCT/Munshi, et al., 2021) POEMS Syndrome American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Adults POEMS syndrome Allogeneic HCT N Autologous HCT C National Organization for Rare Disorders (NORD): On a patient information webpage on POEMS Syndrome, NORD states that “There is no standard treatment for POEMS syndrome. Treatment options for patients diagnosed with POEMS syndrome include radiation therapy, chemotherapy, and/or hematopoietic cell transplantation.” Primary Central Nervous System (CNS) Lymphoma (PCNSL) American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Children (<18 years) Allogeneic HCT Autologous HCT Adults Primary central nervous system Lymphoma, CR1/first partial remission (consolidation) Primary central nervous system Lymphoma, Relapse, sensitive Allogeneic HCT N N Autologous HCT C C NCCN GUIDELINES™ Central Nervous System (CNS) Cancers (V. 1.2023 — March 24, 2023) Primary CNS Lymphomas (PCNSLs) Medical Coverage Policy: 0533 Cancer NCCN Recommendations Newly diagnoses disease - Treatment following induction high-dose methotrexate-based therapy depends on disease response. Given the rarity of this disease, there are few high-quality studies to inform treatment decision-making. For patients who have a complete or unconfirmed complete response, consolidation therapy options that may be considered include high-dose chemotherapy (cytarabine/thiotepa followed by carmustine/thiotepa; or thiotepa/busulfan/cyclophosphamide [TBC]) with stem cell rescue or low-dose WBRT. (MS-31) Relapsed or Refractory Disease – High-dose chemotherapy with stem cell rescue may also be considered as treatment for relapsed/refractory disease in patients who did not previously receive this treatment (ie, patients who were treated with high-dose methotrexate-based therapy or with WBRT) (category 2B). Regardless of primary treatment received, stem cell rescue should only be used for relapsed/refractory disease if there is a complete or partial response to reinduction high-dose chemotherapy. For patients previously treated with high-dose chemotherapy with stem cell rescue, retreatment may be considered if there was a previous disease response and if time to relapse was at least one year. For patients who did not have a response to high-dose chemotherapy with stem cell rescue, and the time to relapse was less than one year, treatment options include RT to the whole brain or to the involved field. Regardless of time to relapse, using a different systemic therapy regimen (without stem cell rescue) and best supportive care are also options. (MS-32) Systemic Mastocytosis American Society for Transplantation and Cellular Therapy (2020) (CR: complete response; N: Not generally recommended; C: standard of care, clinical evidence available; S: standard of care; R: standard of care, rare indication; D: developmental) Adults Systemic mastocytosis Allogeneic HCT R Autologous HCT N NCCN GUIDELINES™ Systemic Mastocytosis (V.1.2023 — May 24, 2023) Allogeneic HCT Allogeneic HCT has been evaluated in patients with advanced SM and the outcomes are significantly affected by the subtype of SM and the type of conditioning regimen used. Reduced-intensity conditioning regimens were associated with lower survival than myeloablative conditioning regimens. (MS-18) Evaluation for allogeneic HCT should be considered for patients with ASM and MCL if there is adequate response to initial treatment with cytoreductive therapy. Among patients with SM-AHN, allogeneic HCT should be considered as part of initial treatment when the AHN Medical Coverage Policy: 0533 Cancer component requires HCT. It should also be considered if the SM component presents as advanced SM (and there is adequate response to initial treatment with cytoreductive therapy) or progresses to advanced SM during treatment. Prophylactic anti-mediator drug therapy (corticosteroids, antihistamines, and epinephrine) should be used with the conditioning regimen in all patients. (MS-18) American Society for Transplantation and Cellular Therapy (ASTCT 2023) Evaluation of Children with Malignancies for Blood and Marrow Transplantation: A Report from the ASTCT Committee on Practice Guidelines (Fraint, et al., 2023) states: The underlying disease indication for HCT is the main driver of HCT planning and its tempo, donor selection, and preparative evaluation checklists. Allogeneic HCT indications in pediatric malignant disease typically include high-risk acute myeloid leukemia (AML), relapsed or refractory acute lymphoid leukemia (ALL), relapsed or refractory chronic myeloid leukemia, juvenile myelomonocytic leukemia, myelodysplastic syndrome, and some high-risk lymphomas, whereas autologous HCT is indicated for lymphomas and a variety of high-risk solid tumors, with the most common procedure being tandem autologous HCT for high-risk neuroblastoma. These indications have been described in more detail by (Kanate, et al., 2020) an ASTCT Committee on Practice Guidelines Task Force. Literature Review ALL: Several randomized controlled trials (RCTs) and case studies have demonstrated improved outcomes with the use of myeloablative conditioning and allogeneic HSCT in subsets of adults with five-year overall survival (OS) rates of 28%–69% (Cornelissen, 2009; Tomblyn, 2009; Goldstone, 2008; Fielding, 2007; Vey, 2007; Oyekunle, 2006). Although variables exist, several studies have demonstrated improved outcomes with the use of myeloablative allogeneic HSCT compared with autologous HSCT or chemotherapy in selected infants and children with ALL (Eckert, 2013; Schrauder, 2006; Balduzzi, 2005; Dalle, 2005; Sanders, 2005; Klingebiel, 2005). Data are not robust regarding improved overall survival rates for the use of autologous HSCT compared with allogeneic HSCT. However, this therapy may result in improved disease-free survival (DFS) and may be an acceptable treatment option for selected individuals who are ineligible for allogeneic HSCT (Thomas, 2004). AML: Several randomized controlled trials, meta-analyses and retrospective reviews have demonstrated relapse (RFS)-, disease-free (DFS), and overall (OS) survival benefit with the use of myeloablative allogeneic HSCT in first complete remission for individuals with poor- and intermediate risk AML. No improvement was noted for individuals with good-risk disease (Schetelig, 2015; Li, et al., 2015; Stelljes, 2011; Koreth, 2009; Fagioli, 2008; Gassas, 2008). Although clinical trial data are limited, non-myeloablative or reduced-intensity conditioning permits the use of allogeneic HSCT for a subset of individuals who may be unable to tolerate the toxic effects of myeloablative chemotherapy prior to allogeneic HSCT (Scott, 2017; Abdul Wahid, 2014; Lioure, 2012; Baron, 2007; Grigg, 2007; Martino, 2007). Two meta-analyses evaluated the outcomes of autologous HSCT versus chemotherapy in six studies of adult patients with AML in first CR. Patients receiving autologous HSCT had better EFS Medical Coverage Policy: 0533 in both studies; however, there was no difference in OS. The studies did not address the effect in the high-risk population (Levi, 2004; Nathan, 2004). Amyloidosis (systemic light-chain): Several prospective case series and retrospective studies have demonstrated higher complete response rates in addition to improved outcomes after high- dose chemotherapy and autologous HSCT, in selected subgroups with AL amyloidosis (Chee, 2010; Cibeira, 2011; Sanchorawala, 2007). CLL: There are scarce randomized controlled trials evaluating the role of allogeneic hematopoietic stem-cell transplantation (HSCT) in chronic lymphocytic leukemia (CLL); however, the evidence demonstrated by several nonrandomized trials suggests that high-dose allogeneic HSCT may be potentially curative for a select population of patients with CLL based on the long-term survival of some patients who have achieved a complete remission (Moreno, 2005; Oscier, 2004). Several case series and retrospective studies involving non-myeloablative conditioning and allogeneic HSCT have demonstrated improved remission rates, improved progression-free and overall survival rates at variable time intervals (Khouri, 2007; Brown, 2006). Several prospective comparisons have investigated the safety and effectiveness of autologous HSCT for CLL (Reljic, 2015; Magni, 2014; Brion, 2012; Dreger, 2012; Michalett, 2011) CML: The published, peer-reviewed scientific literature supports the safety and effectiveness of allogeneic HSCT for the treatment of CML in selected individuals. Although it remains a research interest, improved outcomes have not been demonstrated for autologous HSCT compared with conventional chemotherapy in individuals with CML and the role of autologous HSCT has not been established for this indication (Hehlman, 2008; Kebriaei, 2007) CMML/JMML: Data from randomized controlled clinical trials are lacking; however, several prospective and retrospective studies have demonstrated improved overall survival (OS) with myeloablative allogeneic HSCT (Symeonidis, 2015; Yabe, 2014; Park, 2013). Hodgkin Lymphoma: Rancea et al. (2013) published a Cochrane review regarding the effectiveness of high-dose chemotherapy followed by autologous stem cell transplantation for patients with relapsed/refractory Hodgkin lymphoma. The authors included three randomized controlled open-label trials with 14 publications, assessing 398 patients. Data from this systematic review suggest a survival benefit for patients with relapsed or refractory HL after first-line therapy in those treated with HDCT followed by ASCT compared to patients treated with conventional chemotherapy. A systematic review and meta-analysis published by Rashidi et al. (2016) reported autologous HSCT outcomes of 38 studies (42 reports) involving 1850 patients. The primary endpoints were six-month, one-year, two-year and three-year relapse-free survival (RFS) and overall survival (OS). The pooled estimates for RFS were 77%, 50%, 37% and 31% at six months and one, two and three years, respectively. The corresponding outcomes for OS were 83%, 68%, 58% and 50%, respectively. Data suggests that non-durable remissions are a major shortcoming of allogeneic HSCT in Hodgkin lymphoma. Multiple Myeloma: Allogeneic HSCT may include the use of a myeloablative or nonmyeloablative conditioning regimen (Kuruvilla, 2007; Kennedy, 2006; Rotta, 2008). Although autologous HSCT is not curative, studies demonstrate an improvement in complete response rates and prolongation of median overall survival (OS) by approximately 12 months (Giralt, 2009; Barlogie, 2006 [a-c]). Several randomized controlled trials have demonstrated improved response rates and overall Medical Coverage Policy: 0533 survival (OS) rates with the use of tandem compared with single autologous transplantation (Kumar, 2009; Bruno, 2007). Myelodysplastic Syndromes: Allogeneic HSCT offers the potential for long-term disease-free survival (DFS) and is a component of the standard of care for individuals with good performance status and no significant comorbidity for individuals with de novo and secondary myelodysplastic syndromes (Alessandrino, 2008; Kebriaei, 2005). Autologous HSCT may be appropriate in a carefully selected subset of individuals who achieve complete remission following induction chemotherapy and in whom suitable autologous stem-cells can be collected (Alessandrino, 2002; Kroger, 2006 de Witte, 2007). Myelofibrosis: Allo-HSCT remains an important curative option for patients with PMF. When assessing a PMF patient for transplantation, focus should be placed on: (1) pre-transplant symptom burden and quality of life, (2) age, (3) comorbidities, (4) disease-specific factors, (5) functional status, and (6) availability of related donors. Unfortunately, despite the dramatic improvements in transplantation over the years, many patients with PMF who undergo transplant evaluation are considered ineligible due to age, comorbidities, or other factors and should be considered for clinical trial or symptom-directed therapies (Wolfe, et al., 2022). Non-Hodgkin Lymphoma: The peer-reviewed published scientific literature supports the safety and effectiveness of high-dose chemotherapy with autologous HSCT as a standard treatment option for selected adults with aggressive or advanced indolent, aggressive or recurrent chemosensitive disease. There is a clear survival benefit for compared with conventional chemotherapy (Song, 2007; Oyan, 2006). Although pediatric data are not robust, there is evidence in the published peer-reviewed scientific literature supporting improvement in overall survival (OS) with autologous HSCT compared with standard chemotherapy for the treatment of stage II, stage III or stage IV NHL (Won, 2006; Sandlund, 2002). Although data are not robust, myeloablative allogeneic HSCT is considered an acceptable treatment option for selected adults and children with NHL (Kim, 2006; Laudi, 2006; Kasamon, 2005). Non-myeloablative allogeneic HSCT may result in improved OS and is considered an acceptable treatment option for selected adults with NHL (Tomblyn , 2011; Rezvani, 2008; Vigouroux, 2007). POEMS Syndrome: POEMS (Polyneuropathy, organomegaly, endocrinopathy, M- protein, skin changes) syndrome is a rare plasma cell disorder. Jurczyszyn et al. (2022) retrospectively reported on a multi-country registry of 108 patients with POEMS.A total of 15 hematology centers from 9 countries from the period of 1992 to 2019 were included in the analysis. Median follow up was 2.6 years. High dose chemotherapy with autologous stem cell transplant (ASCT) was incorporated into front line treatment in 25 patients (30%). Fifty-two percent ASCT patients achieved complete remission/very good partial remissions (CR/VGPR), compared to 35% in the non-ASCT group (p=.003). The authors concluded that proteasome inhibitors (PI) as single agents, the combination of a proteasome inhibitors with immunomodulatory agents (IMiDs), and ASCT all demonstrate high responses and should be considered standard options for a newly diagnosed POEMS patient. Primary Central Nervous System (CNS) Lymphoma: Peer-reviewed published data are limited to small prospective case series and retrospective reviews and support the use of autologous HSCT in the treatment of relapsed or refractory primary CNS lymphoma (Alnahhas, et al., 2019; DeFilipp, 2017; Stephanoni, et al., 2023). Systemic Mastocytosis: Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra-cutaneous organs. Broadly, patients either have Medical Coverage Policy: 0533 indolent/smoldering SM (ISM/SSM) or advanced SM, including aggressive SM (ASM), SM with associated myeloid neoplasm (SM-AMN), and mast cell leukemia. Identification of poor-risk mutations (i.e., ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease-related organ dysfunction. Tyrosine kinase inhibitors (TKI) (midostaurin, avapritinib) have changed the treatment landscape in SM. While deep biochemical, histological and molecular responses have been documented with avapritinib treatment, its efficacy as monotherapy against a multimutated AMN disease component in SM-AMN patients remains unclear. Cladribine continues to have a role for MC debulking, whereas interferon-α has a diminishing role in the TKI era. Treatment of SM-AMN primarily targets the AMN component, particularly if an aggressive disease such as acute leukemia is present. Allogeneic stem cell transplant has a role in such patients. Imatinib has a therapeutic role only in the rare patient with an imatinib-sensitive KIT mutation (Pardanani, et al., 2023).