Latest Review Date: January 2024

Category: Surgery                                                                 

POLICY:

Allogeneic hematopoietic cell transplantation (HCT) using a myeloablative conditioning regimen may be considered medically necessary to treat:

• Poor- to intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1), OR
• AML that is refractory to standard induction chemotherapy but can be brought into CR with intensified induction chemotherapy; or
• AML that relapses following chemotherapy-induced CR1 but can be brought into CR2 or beyond with intensified induction chemotherapy; or
• AML in individuals, who have relapsed following a prior autologous HCT, but can be brought into CR with intensified induction chemotherapy and may be medically able to tolerate the procedure.

Allogeneic HCT using a reduced-intensity conditioning regimen may be considered medically necessary as a treatment of AML in individuals who are in complete marrow and extramedullary remission (CR1 or beyond), and who for medical reasons would be unable to tolerate a myeloablative conditioning regimen.

Autologous HCT may be considered medically necessary to treat AML in first or second remission or relapsed AML if responsive to intensified induction chemotherapy in individuals who are not candidates for allogeneic HCT. 

Allogeneic and autologous HCT are investigational in individuals not meeting any of the above criteria.

POLICY GUIDELINES:

Primary refractory acute myeloid leukemia (AML) is defined as leukemia that does not achieve a complete remission after conventionally dosed (nonmarrow ablative) chemotherapy.

In the French-American-British criteria, the classification of AML is solely based on morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.

Clinical features that predict poor outcomes of AML therapy include, but are not limited to, the following:

• Treatment-related AML (secondary to prior chemotherapy and/or radiotherapy for another malignancy)
• AML with antecedent hematologic disease (e.g., myelodysplasia)
• Presence of circulating blasts at the time of diagnosis
• Difficulty in obtaining first complete remission with standard chemotherapy
• Leukemias with monocytoid differentiation (French-American-British classification M4 or M5).

The newer, currently preferred, World Health Organization classification of AML incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers. It attempts to construct a classification that is universally applicable and prognostically valid. The World Health Organization system was adapted by National Comprehensive Cancer Network to estimate individual  prognosis to guide management, as shown in Table PG1.

Table PG1. Risk Status of Acute Myeloid Leukemia Based on Genetic Factors

Risk Category	Genetic Abnormality
Favorable	t(8;21)(q22;q22.1); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Biallelic mutated CEBPA Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
Intermediate	Mutated NPM1 and FLT3-ITDhigh Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions) t(9;11)(p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse
Poor/Adverse	t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23.3); KMT2A rearranged t(9;22)(q34.1;q11.2); BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) -5 or del(5q); -7; -17/abn(17p) Complex karyotype, monosomal karyotype Wild-type NPM1 and FLT3-ITDhigh Mutated RUNX1 (if not co-occurring with favorable-risk AML subtypes) Mutated ASXL1 (if not co-occurring with favorable-risk AML subtypes) Mutated TP53

AML: acute myeloid leukemia; ITD: internal tandem duplication.

The relative importance of cytogenetic and molecular abnormalities in determining prognosis and guiding therapy is under investigation.

The ideal allogeneic donors are human leukocyte antigen (HLA)-identical siblings, matched at the HLA-A, -B, and -DR loci (6 of 6). Related donors mismatched at one locus are also considered suitable donors. A matched, unrelated donor identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the individual, for which there usually is sharing of only three of the six major histocompatibility antigens. Most individuals will have such a donor; however, the risk of graft-versus-host disease and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors.

DESCRIPTION OF PROCEDURE OR SERVICE:

Acute myeloid leukemia (AML) (also called acute nonlymphocytic leukemia) refers to leukemia’s that arise from a myeloid precursor in the bone marrow.  There is a high incidence of relapse, which has prompted research into a variety of post-remission strategies using either allogeneic or autologous hematopoietic cell transplantation (HCT). HCT refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer individuals who receive bone-marrow-toxic doses of drugs with or without whole body radiotherapy.

Treatment

Complete remission of acute  myeloid leukemia (AML) can be achieved initially using induction therapy, consisting of conventional doses of combination chemotherapy. A complete response is achieved in 60% to 80% of adults younger than 60 years of age and in 40% to 60% in individuals older than 60 years of age. However, the high incidence of disease relapse has prompted research into a variety of post remission (consolidation) strategies, typically using high-dose chemotherapy with autologous HCT or high-dose or reduced-intensity chemotherapy with allogeneic HCT. The two treatments, autologous HCT and allogeneic HCT, represent two different strategies. The first, autologous HCT is a “rescue,” but not therapeutic procedure; the second, allogeneic HCT is a “rescue” plus therapeutic procedure.

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) may use stem cells are infused to restore bone marrow function in cancer individuals who receive bone marrow toxic doses of drugs with or without whole body radiotherapy. HCT may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve”; thus are associated with a lower incidence of rejection or graft-versus-host disease (GVHD). Cord blood is discussed in greater detail in Medical Policy # 439: Placenta/Umbilical Cord Blood as a Source of Stem Cells.

Immunologic compatibility between infused hematopoietic stem cells and the recipient is not an issue in autologous HCT. However, immunologic compatibility between donor and patient is a critical factor for achieving a good outcome of allogeneic HCT. Immunologic compatibility is established by typing human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA A, B, and DR (antigen-D related) loci on each arm of chromosome 6.  An acceptable donor will match the patient at all or most of the HLA loci.

Conventional Conditioning for HCT

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

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

Reduced-Intensity Conditioning for Allogeneic HCT

Reduced-intensity conditioning (RIC) refers to the pretransplant use of lower doses or less intense regimens of cytotoxic drugs or radiation than are used in conventional full-dose myeloablative conditioning treatments. Although the definition of RIC remains arbitrary, with numerous versions employed, all seek to balance the competing effects of nonrelapse mortality and relapse due to residual disease. The goal of RIC is two-fold: to reduce disease burden, and to minimize treatment-related morbidity and nonrelapse mortality in the period during which the beneficial GVM effect of allogeneic transplantation develops. RIC regimens range from nearly totally myeloablative to minimally myeloablative with lymphoablation—with intensity tailored to specific diseases and individual condition. Individuals who undergo RIC with allo-HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism. In this evidence review, RIC refers to all conditioning regimens intended to be nonmyeloablative. 

A 2015 review in the New England Journal of Medicine summarized advances in the classification of acute myeloid leukemia (AML), the genomics of AML and prognostic factors, and current and new treatments. The National Comprehensive Cancer Network guidelines provide updated information on genetic markers for risk stratification, and additional recent reviews summarize information on novel therapies for AML.

KEY POINTS:

The most recent literature review was performed through December 5, 2023.

Summary of Evidence

For individuals who have cytogenetic or molecular intermediate- or poor-risk acute myeloid leukemia (AML) in first complete remission who receive allogeneic hematopoietic cell transplantation (allo-HCT) with myeloablative conditioning, the evidence includes systematic reviews, randomized controlled trials (RCTs) and matched cohort studies. Relevant outcomes are overall survival (OS) and disease-specific survival. The majority of the evidence has revealed that allo-HCT is better at improving overall and disease-specific survival rates in individuals with AML in first complete remission than conventional chemotherapy. All trials employed natural randomization based on donor availability and an intention-to-treat analysis. Survival rates appear to be associated with presence of minimal residual disease and risk category. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have AML refractory to standard induction chemotherapy who receive allo-HCT with MAC, the evidence includes retrospective data compiled from individuals entered in phase 3 trials and registry data. Relevant outcomes are overall survival and disease-specific survival. The evidence would suggest that allo-HCT improves overall and disease-specific survival rates in individuals who are refractory to induction chemotherapy better than conventional chemotherapy. While there are some limitations to the evidence, which include its retrospective nature, lack of rigorous randomization, and general pitfalls of registry data, these results may provide clinically meaningful benefit for individuals who do not have other treatment options. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have AML who relapsed after standard induction chemotherapy-induced first complete remission who receive allo-HCT or autologous HCT with myeloablative conditioning, the evidence includes retrospective data compiled from individuals entered in phase 3 trials and registry data. Relevant outcomes are OS and disease-specific survival. The evidence has shown that allo-HCT improves OS rates in patients with relapsed AML better than conventional chemotherapy. Limitations of the evidence include its retrospective nature, lack of rigorous randomization, and pitfalls of registry data. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have cytogenetic or molecular intermediate- or poor-risk AML in first complete remission and for medical reasons cannot tolerate myeloablative conditioning who receive allo-HCT with reduced-intensity conditioning, the evidence includes two RCTs, 3 meta-analyses, and other comparative and noncomparative studies. Relevant outcomes are OS, disease-specific survival, and treatment-related morbidity. The RCTs compared reduced-intensity conditioning with myeloablative conditioning and reported similar rates in nonrelapse mortality, relapse, and OS though one of the trials was stopped prematurely due to a slow accrual of individuals. Two retrospective comparative studies found no difference in OS or leukemia-free survival between the conditioning regimens. It appears unlikely that additional comparative evidence will be generated. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have AML in first complete remission or beyond without a suitable allo-HCT donor who receive autologous HCT, the evidence includes prospective cohort studies in which individuals with an available sibling donor were offered allo-HCT (biologic randomization) with random assignment of all others to autologous HCT or chemotherapy (or no further treatment); and randomized trials comparing autologous HCT with chemotherapy in all individuals. Relevant outcomes are OS and disease-specific survival. Compared with chemotherapy, individuals undergoing autologous HCT experienced reduced relapse and improved disease-free survival rates. The OS did not differ between the groups. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements

American Society for Transplantation and Cellular Therapy

In 2020, the American Society for Transplantation and Cellular Therapy published expert panel recommendations on the role of hematopoietic cell transplant (HCT) in newly-diagnosed adult acute myeloid leukemia. Recommendations were generated based on findings from a systematic review and graded based on prespecified criteria. Expert panel recommendations regarding allogeneic HCT (allo-HCT) and autologous HCT and the grades of the recommendations are as follows:

• Individuals with unfavorable-risk in first remission (CR1) should undergo allo-HCT. (Grade A)
• Individuals with intermediate-risk in CR1 should undergo allo-HCT. (Grade B)
• Individuals with favorable-risk in CR1 should not undergo allo-HCT. (Grade C)
• The role of secondary mutational abnormalities in selecting an individual for allo-HCT is unclear. (Grade N/A)
• The presence of measurable residual disease at the end of induction therapy should be considered an indication to offer allo-HCT. (Grade C)
• The role of allo-HCT is unclear in individuals with induction failure. (Grade N/A)
• Individuals with secondary acute myeloid leukemia in CR1 should undergo allo-HCT. (Grade D)
• Individuals with therapy-related acute myeloid leukemia in CR1 should undergo allo-HCT. (Grade D)
• Individuals ≥ 60 years in CR1 should undergo allo-HCT. (Grade B)
• Autologous HCT is a good alternative to chemotherapy consolidation in individuals who are not eligible for allo-HCT. (Grade B)
• Myeloablative conditioning should be the preferred type of conditioning in individuals who are fit for myeloablative conditioning, but reduced-intensity conditioning is an acceptable alternative in unfit individuals. (Grade D)

In 2015, the American Society for Transplantation and Cellular Therapy (formerly The American Society for Blood and Marrow Transplantation) published guidelines on indications for autologous HCT and allo-HCT. An updated guideline was published in 2020. Table 2 summarizes recommendations for HCT in acute myeloid leukemia from the most recent guideline iteration.

Table 2. Recommendations for the Use of Hematopoietic Cell Transplantation to Treat Acute Myeloid Leukemia

Indication	Allo-HCTa	Autologous HCTa
AML, age <18 years
First CR, low risk	N	N
First CR, intermediate risk	C	N
First CR, high risk	S	N
Second or greater CR	S	N
Not in remission	S	N
AML, age ≥18 years
First CR, low risk	N	C
First CR, intermediate risk	S	C
First CR, high risk	S	N
Second CR	S	C
Third or greater CR	S	N
Not in remission	S	N

a Recommendations were classified as follows: S, standard of care (well-defined and generally supported by evidence in the form of high quality clinical trials and/or observational studies); C, standard of care, clinical evidence available (large clinical trials are not available; however, sufficiently large cohort studies have shown efficacy with acceptable risk of morbidity and mortality); N, not generally recommended. allo-HCT: allogeneic hematopoietic cell transplantation; AML: acute myeloid leukemia; CR: complete remission HCT: hematopoietic cell transplantation

In 2022, the American Society of Transplantation and Cellular Therapy published guidance on the role of HCT in pediatric AML and myelodysplastic syndrome. The guidelines state that HCT is recommended for individuals in CR1 with unfavorable mutations/cytomolecular abnormalities but not for individuals with favorable-risk lesions. HCT should also be considered for individuals with primary induction failure, refractory disease after 2 to 3 cycles of chemotherapy, and relapse.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network clinical guidelines (v.6.2023) for acute myeloid leukemia state that allo-HCT is recommended for individuals aged <60 years after standard-dose cytarabine induction with induction failure or significant residual disease without a hypocellular marrow. It is also recommended after high-dose cytarabine induction with induction failure, or as post-remission therapy in those with intermediate-risk or poor-risk cytogenetics. Allo-HCT is identified as a "reasonable option" for individuals aged ≥60 years after standard-dose cytarabine induction with residual disease or induction failure or following complete response (preferably in a clinical trial). In addition, allo-HCT is recommended for relapsed or refractory disease.

According to the guidelines, the role of autologous HCT is diminishing due to improvements in allo-HCT that have expanded the pool of potential donors outside the family setting. Autologous HCT should not be a recommended consolidation therapy outside the setting of a clinical trial.

U.S. Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

Bone Marrow Transplant, High-Dose Chemotherapy, Acute Myeloid Leukemia (AML), Stem-Cell Transplant, HSCT, Hematopoietic Cell Transplant, HCT

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration regulate human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, parts 1270 and 1271. Hematopoietic stem cells are included in these regulations.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group-specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP: Special benefit consideration may apply.  Refer to member’s benefit plan.  

CURRENT CODING:

CPT Codes:

38204	Management of recipient hematopoietic cell donor search and cell acquisition
38205	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic
38206	Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, autologous
38208	Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest, without washing; per donor
38209	; thawing of previously frozen harvest, with washing; per donor
38210	; specific cell depletion with harvest, T-cell depletion
38211	; tumor cell depletion
38212	; red blood cell removal
38213	; platelet depletion
38214	; plasma (volume) depletion
38215	; cell concentration in plasma, mononuclear, or buffy coat layer
38220	Diagnostic bone Marrow; aspiration(s)
38221	; biopsy (ies)
38222	Diagnostic bone marrow; biopsy (ies) and aspiration(s)
38230	Bone marrow harvesting for transplantation; allogeneic
38232	Bone marrow harvesting for transplantation; autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	; autologous transplantation
38242	Allogeneic donor lymphocyte infusions

           

HCPCS:

S2140	Cord blood harvesting for transplantation; allogeneic
S2142	Cord blood derived stem-cell transplantation; allogeneic
S2150	Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic, and emergency services)

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53. Valcarcel D, Martino R, Caballero D, et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: Chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol. Feb 01 2008; 26(4):577-584.
54. Vellenga E, van Putten W, Ossenkoppele GJ et al. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. Blood. Dec 01 2011; 118(23):6037-6042.
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POLICY HISTORY:

Medical Policy Group, September 2009 (3)

Medical Policy Administration Committee, September 2009

Available for comment September 18-November 2, 2009

Medical Policy Group, June 2010 (2)

Medical Policy Panel, August 2011

Medical Policy Group, September 2011 (2) Key Points, References updated

Medical Policy Group, December, 2011 (3): 2012 Code Updates: Updated Codes 38208, 38209, and 38230 and added 38232 effective January 1, 2012

Medical Policy Group, August 2012 (3): 2012 Updates to Key Points and References

Medical Policy Panel, August 2013

Medical Policy Group, August 2013 (3): 2013 Updates to Description, Key Points and References; no change in policy statement

Medical Policy Panel, August 2014

Medical Policy Group, September 2014 (3): 2014 Updates to Key Points & References; no change in policy statement.

Medical Policy Panel, August 2015

Medical Policy Group, October 2015 (2): 2015 Updates to Description, Key Points, Approved by Governing Bodies, Current Coding, and policy statement updated with no change to intent.

Medical Policy Panel, January 2016

Medical Policy Group, February 2016 (2): 2016 Updates to Key Points, Key Words, and References; no change in policy statement.

Medical Policy Panel, July 2017

Medical Policy Group, August 2017 (7): Updates to Key Points, Key Words, and References. Removed “stem” from Policy Statement; no change in intent.

Medical Policy Group, December 2017. Annual Coding Update 2018.  Added new CPT code 38222 effective 1/1/18 to the Current coding section.  Updated verbiage for revised CPT codes 38220 and 38221.

Medical Policy Panel, January 2018

Medical Policy Group, February 2018 (7): Updates to Description, Key Points, and References.

Medical Policy Panel, January 2019

Medical Policy Group, February 2019 (3): Updates to Key Points, Practice Guidelines and Position Statements, References and Key Words: added: HCT and Hematopoietic Cell Transplant. Policy statement regarding medical necessity for autologous HCT changed to clarify that it applies to patients that are not candidates for allogeneic HCT. Investigational statements added for patients not meeting MN criteria.

Medical Policy Panel, January 2020

Medical Policy Group, February 2020 (3): 2020 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References.  No changes to policy statement or intent. Policy Guidelines section added to policy.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points, Practice Guidelines and Position Statements and References. Policy statement updated to remove “not medically necessary, “no other changes to policy statement or intent. This policy was placed on biannual review/literature updates.

Medical Policy Panel, January 2022

Medical Policy Group, January 2022 (3): 2022 Updates to Key Points and References. No changes to policy statement or intent.

Medical Policy Panel, January 2023

Medical Policy Group, February 2023 (3): 2023 Updates to Key Points, Practice Guidelines and Position Statements and References. No changes to policy statement or intent.

Medical Policy Panel, January 2024

Medical Policy Group, January 2024 (3): Updates to Description, Key Points, Benefit Applications, References, Policy statement and Policy Guidelines verbiage updated-patient to individual. No changes to policy statement or intent.

This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

 

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.