Latest Review Date: January 2024

Category: Surgery                                                                

POLICY:

Childhood Acute Lymphoblastic Leukemia

Allogeneic or autologous hematopoietic cell transplantation (HCT) may be considered medically necessary to treat childhood acute lymphoblastic leukemia (ALL) in first complete remission but at high risk of relapse. (For definition of high-risk factors, see Description section).

Autologous or allogeneic HCT may be considered medically necessary to treat childhood ALL in second or greater remission or refractory ALL.

Allogeneic HCT may be considered medically necessary to treat relapsing ALL after a prior autologous HCT.

Adult Acute Lymphoblastic Leukemia

Autologous HCT may be considered medically necessary to treat adult ALL in first complete remission but at high risk of relapse. (For definition of high-risk factors, see Description section).

Allogeneic HCT may be considered medically necessary to treat ALL in first complete remission for any risk level (for definition of risk factors, see Description section).

Allogeneic HCT may be considered medically necessary to treat adult ALL in second or greater remissions, or in individuals with relapsed or refractory ALL.

Allogeneic HCT may be considered medically necessary to treat relapsing ALL after a prior autologous HCT.

Reduced-intensity conditioning allogeneic HCT may be considered medically necessary as a treatment of ALL in individuals who are in complete marrow and extramedullary first or second remission, and who, for medical reasons would be unable to tolerate a standard myeloablative conditioning regimen.

Autologous HCT is considered investigational to treat adult ALL in second or greater remission or those with refractory disease.

POLICY GUIDELINES:

Relapse Risk Prognostic Factors

Childhood Acute Lymphoblastic Leukemia

Adverse prognostic factors in children include the following: age younger than 1 year or more than 9 years, male gender, white blood cell count at presentation above 50,000/μL, hypodiploidy (<45 chromosomes), translocation involving chromosomes 9 and 22 (t[9;22]) or BCR/ABL fusion, t(4;11) or MLL/AF4 fusion, and ProB or T-lineage immunophenotype.

Several risk-stratification schema exist, but, in general, the following findings help define children at high risk of relapse: (1) poor response to initial therapy including poor response to prednisone prophase defined as an absolute blast count of 1000/μL or greater, or poor treatment response to induction therapy at 6 weeks with high risk having ≥1% minimal residual disease measured by flow cytometry; (2) all children with T-cell phenotype; and (3) individuals with either the t(9;22) or t(4;11) regardless of early response measures.

Adult Acute Lymphoblastic Leukemia

Risk factors for relapse are less well-defined in adults, but an individual with any of the following may be considered at high risk for relapse: age older than 35 years, leukocytosis at presentation of greater than 30,000/μL (B-cell lineage) or greater than 100,000/μL (T-cell lineage), “poor prognosis” genetic abnormalities like the Philadelphia chromosome (t[9; 22]), extramedullary disease, and time to attain complete remission longer than 4 weeks.

Reduced Intensity Conditioning

Some individuals for whom a conventional myeloablative allogeneic HCT could be curative may be considered candidates for reduced-intensity conditioning allogeneic HCT. Such individuals include those whose age (typically >60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy including autologous or allogeneic HCT, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen.

The ideal allogeneic donors are human leukocyte antigen (HLA) identical siblings, matched at the HLA-A, -B, and DR (antigen-D related) loci on each arm of chromosome 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 patient, where usually there is sharing of only three of the six major histocompatibility antigens. Most individuals will have such a donor. The risk of morbidity (e.g., graft-versus-host disease [GVHD]) may be higher than with HLA matched donors; however, as medical treatments improve, the risks of GVHD with haploidentical donors are approaching those similar to HLA-matched donors.

Note: The use of killer cells in the treatment of malignancies is addressed separately Medical Policy #105: Adoptive Immunotherapy.

DESCRIPTION OF PROCEDURE OR SERVICE:

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia is a heterogeneous disease with different genetic alterations resulting in distinct biologic subtypes. Patients are stratified by certain clinical and genetic risk factors that predict an outcome, with risk-adapted therapy tailoring treatment based on the predicted risk of relapse. Two of the most important factors predictive of risk are patient age and white blood cell count at diagnosis. Certain genetic characteristics of leukemic cells strongly influence prognosis.

Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children and represents nearly 25% of cancer diagnoses in children younger than 15 years. Complete remission (CR) of disease is now typically achieved with pediatric chemotherapy regimens in approximately 98% of children with ALL, with long-term survival rates of up to 85%. Survival rates have improved with the identification of effective drugs and combination chemotherapy through large randomized trials, integration of presymptomatic central nervous system prophylaxis, and intensification and risk-based stratification of treatment. The prognosis after first relapse is related to the length of the original remission. For example, leukemia-free survival is 40% to 50% for children whose first remission was longer than 3 years, compared with only 10% to 15% for those who relapse less than 3 years following treatment. Thus, HCT may be a strong consideration in those with short remissions. At present, comparative outcomes with either autologous or allo-HCT are unknown.

Adult Acute Lymphoblastic Leukemia

In adults, ALL accounts for 20% of acute leukemias. Between 60% and 80% of adults with ALL can be expected to achieve complete remission after induction chemotherapy; however, patients who experience a relapse after remission usually die within 1 year. Differences in the frequency of genetic abnormalities that characterize adult ALL versus childhood ALL help, in part, explain the outcome differences between the two groups. For example, the “good prognosis” genetic abnormalities such as hyperdiploidy and translocation (t) of chromosomes 12 and 21, are seen much less commonly in adult ALL, whereas they are some of the most common in childhood ALL. Conversely, “poor prognosis” genetic abnormalities such as the Philadelphia chromosome (translocation of chromosomes 9 and 22) are seen in 25% to 30% of adult ALL but infrequently in childhood ALL. Other adverse prognostic factors in adult ALL include age greater than 35 years, poor performance status, male sex, and leukocytosis at presentation of greater than 30,000/μL (B-cell lineage) or greater than 100,000/μL (T-cell lineage).

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation is a procedure in which hematopoietic stem cells are intravenously infused to repair bone marrow and immune function in cancer patients who receive bone marrow-toxic doses of cytotoxic drugs with or without whole-body irradiation. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or a donor (allo-HCT). They can be harvested from bone marrow, peripheral blood, or umbilical cord blood shortly after delivery of neonates. The use of cord blood is discussed in Medical Policy #439: Placental/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. In allogeneic stem cell transplantation, immunologic compatibility between donor and patient is a critical factor for achieving a successful outcome. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the gene complex 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.

Conditioning for Hematopoietic Cell Transplantation

Conventional Conditioning

The conventional (“classical”) practice of allo-HCT involves administration of cytotoxic agents (e.g., cyclophosphamide, busulfan) with or without existing disease in the absence of pretransplant conditioning. Intense conditioning regimens are limited to patients whose health status is sufficient to tolerate the procedure of 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 the initial eradication of malignant cells and subsequent graft-versus-malignancy effect mediated by non-self-immunologic effector cells. While the slower graft-versus-malignancy effect is considered the potentially curative component, it may be overwhelmed by substantial adverse effects. These include opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. After graft infusion in allo-HCT, immunosuppressant drugs are required to minimize graft rejection and graft-versus-host disease (GVHD), which increases susceptibility to opportunistic infections.

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

Reduced-Intensity Conditioning for Allo-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 NRM and relapse due to residual disease. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and non-relapse mortality (NRM) in the period during which the beneficial GVM effect of allogeneic transplantation develops. These RIC regimens can be viewed as a continuum in effects, from nearly totally myeloablative, to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Individuals who undergo RIC with allogeneic HCT initially demonstrate donor cell engraftment and bone marrow mixed chimerism. Most will subsequently convert to full-donor chimerism, which may be supplemented with donor lymphocyte infusions to eradicate residual malignant cells. For the purposes of this policy, the term “reduced-intensity conditioning” will refer to all conditioning regimens intended to be non-myeloablative.

 

KEY POINTS:

The most recent literature update was performed through November 17, 2023.

Summary of Evidence

For individuals who have childhood ALL in first complete remission (CR1) at high-risk of relapse, remission, or refractory ALL who receive autologous HCT, the evidence includes RCTs and systematic reviews. Relevant outcomes are overall survival (OS), disease-specific survival (DSS), and treatment-related mortality (TRM) and morbidity. For children with high-risk ALL in CR1 or with relapsed ALL, studies have suggested that HCT is associated with fewer relapses but higher death rates due to treatment-related toxicity. However, for a subset of high-risk patients in second complete remission or beyond or with relapsed disease, autologous HCT is a treatment option. This conclusion is further supported by an evidence-based systematic review and position statement from the American Society for Blood and Marrow Transplantation (ASBMT). The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have childhood ALL in CR1 at high-risk of relapse, remission, or refractory ALL who receive allogeneic HCT (allo-HCT), the evidence includes RCTs and systematic reviews. Relevant outcomes are OS, DSS, and TRM and morbidity. For children with high-risk ALL in CR1 or with relapsed ALL, studies have suggested that allo-HCT is associated with fewer relapses but higher death rates due to treatment-related toxicity. However, for a subset of high-risk patients in second complete remission or beyond or with relapsed disease, allo-HCT is a treatment option. This conclusion is further supported by an evidence-based systematic review and position statement from the ASBMT. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have adult ALL in CR1, subsequent remission, or refractory ALL who receive autologous HCT, the evidence includes RCTs and systematic reviews. Relevant outcomes are OS, DSS, and TRM and morbidity. Current evidence supports the use of autologous HCT for adults with high-risk ALL in CR1, whose health status is sufficient to tolerate the procedure. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have adult ALL in CR1 or subsequent remission or refractory ALL who receive allo-HCT, the evidence includes RCTs, systematic reviews, and observational studies. Relevant outcomes are OS, DSS, and TRM and morbidity. Current evidence supports the use of myeloablative allo-HCT for adults with any risk level ALL, whose health status is sufficient to tolerate the procedure. Reduced-intensity conditioning allo-HCT may be considered for patients who demonstrate complete marrow and extramedullary first or second remission and who could be expected to benefit from a myeloablative allo-HCT, but for medical reasons would not tolerate a myeloablative conditioning regimen. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have relapsed after a prior autologous HCT for ALL adult or childhood who receive allo-HCT, the evidence includes case series. Relevant outcomes are OS, DSS, and TRM and morbidity. Evidence reviews have identified only small case series with short-term follow-up, which was considered inadequate evidence of benefit. However, clinical input has been obtained from specialty societies and academic medical centers which had a general agreement that allogeneic hematopoietic cell transplantation is considered medically necessary to treat relapsed acute lymphoblastic leukemia (ALL) after a prior autologous HCT in either children or adults.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines (v.3.2023) for ALL indicate allo-HCT is appropriate for consolidation treatment of most poor risk (e.g., the Philadelphia chromosome positive, relapsed, or refractory) patients with ALL. The guidelines state that for appropriately fit older adults with ALL who are achieving remission, “consideration of autologous or reduced-intensity allogeneic stem cell transplantation may be appropriate.” In addition, the guidelines note that chronologic age is not a good surrogate for fitness for therapy and that patient should be evaluated on an individual basis.

Current National Comprehensive Cancer Network guidelines (v.3.2024) for pediatric ALL say that "Allogeneic HCT has demonstrated improved clinical outcomes in pediatric ALL patients with evidence of certain high-risk features and/or persistent disease. In addition, survival rates appear to be comparable regardless of the stem cell source (matched related, matched unrelated, cord blood, or haploidentical donor)." The guidelines state that the benefit of allo-HCT in infants is still controversial. 

The American Society for Transplantation and Cellular Therapy

In 2020, the guidelines from The American Society for Transplantation and Cellular Therapy (previously known as the American Society for Blood and Marrow Transplantation) were published on indications for autologous and allo-HCT. Recommendations were intended to describe the current consensus on the use of HCT in and out of the clinical trial setting. Recommendations on ALL are listed in Table 1.

Table 1: ASBMT Guidelines for Autologous and Allogeneic HCT

Indication	Children (Age <18 Years)		Adults (Age ≥18 Years)
	Allogeneic HCT	Autologous HCT	Allogeneic HCT	Autologous HCT
First complete response, standard-risk	N	N	S	N
First complete response, high-risk	S	N	S	N
Second complete response	S	N	S	N
At least third complete response	C	N	S	N
Not in remission	C	N	S	N

ALL: acute lymphoblastic leukemia; C: clinical evidence available; HCT: hematopoietic cell transplantation; N: not generally recommended; S: standard of care.

U.S. Preventive Services and Task Force Recommendations

Not applicable.

KEY WORDS:

Acute Lymphoblastic Leukemia (ALL), High-Dose Chemotherapy, Stem-Cell Transplant, Hematopoietic Cell Transplantation, HCT

APPROVED BY GOVERNING BODIES:

The U.S. Food and Drug Administration regulates human cells and tissues intended for implantation, transplantation, or infusion through the Center for Biologics Evaluation and Research, under the Code of Federal Regulation title 21, 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	Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest with washing, per donor
38210	Transplant preparation of hematopoietic progenitor cells; specific cell depletion with harvest, T cell depletion
38211	Transplant preparation of hematopoietic progenitor cells; tumor cell depletion
38212	Transplant preparation of hematopoietic progenitor cells; red blood cell removal
38213	Transplant preparation of hematopoietic progenitor cells; platelet depletion
38214	Transplant preparation of hematopoietic progenitor cells; plasma (volume) depletion
38215	Transplant preparation of hematopoietic progenitor cells; cell concentration in plasma, mononuclear, or buffy coat layer
38220	Diagnostic bone marrow; aspiration(s)
38221	Diagnostic bone marrow; biopsy(ies
38222	Diagnostic bone marrow; biopsy(ies) and aspiration(s) (Effective 01/01/2018)
38230	Bone marrow harvesting for transplantation; allogeneic
38232	Bone marrow harvesting for transplantation; autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	Hematopoietic progenitor cell (HPC); autologous transplantation

HCPCS:

S2140	Cord blood harvesting for transplantation, allogeneic
S2142	Cord blood-derived stem-cell transplantation, allogeneic
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre and post-transplant care in the global definition

REFERENCES:

1. Abdul Wahid SF, Ismail NA, Mohd-Idris MR, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev. Nov 1 2014; 23(21):2535-2552.
2. Technology Evaluation Center (TEC). Salvage high-dose chemotherapy with allogeneic stem-cell support for relapse or incomplete remission following high-dose chemotherapy with autologous stem-cell transplantation for hematologic malignancies. TEC Assessments 2000; Volume 15, Tab 9.
3. Technology Evaluation Criteria (TEC) Evaluation 1990; p. 254.
4. Technology Evaluation Criteria (TEC) Evaluation 1987; p. 243.
5. Technology Evaluation Criteria (TEC) Assessment 1997; Volume 12: Tab 25.
6. Carroll WL, Bhojwani D, Min DJ, et al. Pediatric acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program 2003: 102-131..
7. Cho BS, Lee S, Kim YJ et al. Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study. Leukemia. Oct 2009; 23(10):1763-1770.
8. Cornelissen JJ, van der Holt B, Verhoef GE et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood. Feb 5 2009; 113(6):1375-1382.
9. Dinmohamed AG, Szabo A, van der Mark M, et al. Improved survival in adult patients with acute lymphoblastic leukemia in the Netherlands: a population-based study on treatment, trial participation and survival. Leukemia. Feb 2016; 30(2):310-317.
10. Fielding AK, Rowe JM, Richards SM et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. May 07 2009; 113(19):4489-4496.
11. Giebel S, Labopin M, Socie G, et al. Improving results of allogeneic hematopoietic cell transplantation for adults with acute lymphoblastic leukemia in first complete remission: an analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. Jan 2017; 102(1):139-149.
12. Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. Feb 15 2008; 111(4):1827-1833.
13. Gupta V, Richards S, Rowe J et al. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood. Jan 10 2013; 121(2):339-350.
14. Gutierrez-Aguirre CH, Gomez-Almaguer D, Cantu-Rodriguez OG, et al. Non-myeloablative stem cell transplantation in patients with relapsed acute lymphoblastic leukemia: results of a multicenter study. Bone Marrow Transplant. Sep 2007; 40(6):535-539.
15. Harrison G, Richards S, Lawson S, et al. Comparison of allogeneic transplant versus chemotherapy for relapsed childhood acute lymphoblastic leukaemia in the MRC UKALL R1 trial. Ann Oncol. Aug 2000; 11(8):999-1006. 
16. IOM (Institute of Medicine). 2011. Clinical Practice Guidelines We Can Trust. Washington, DC: The National Academies Press.
17. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: Guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant. Jul 2020; 26(7): 1247- 1256.
18. Lawson SE, Harrison G, Richards S, et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaeima: A report on the Medical Research Council UK ALLR1 study. Br J Haematol. Mar 2000; 108(3):531-543.
19. Majhail NS, Farnia SH, Carpenter PA, et al. Indications for autologous and allogeneic hematopoietic cell transplantation: guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Nov 2015; 21(11):1863-1869.
20. Mohty M, Labopin M, Tabrizzi R, et al. Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: A retrospective study from the European Group for Blood and Marrow Transplantation. Haematologica. Feb 2008; 93(2):303-306.
21. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Pediatric Acute Lymphoblastic Leukemia. Version 3.2024. www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf.
22. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute lymphoblastic leukemia. Version 3.2023. www.nccn.org/professionals/physician_gls/pdf/all.pdf. 
23. Oliansky DM, Camitta B, Gaynon P et al. Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: update of the 2005 evidence-based review. Biol Blood Marrow Transplant. Apr 2012; 18(4):505-522.
24. Owattanapanich W, Leelakanok N, Sanpakit K, et al. A Comparison of the Clinical Outcomes of Haploidentical Transplantation and Other Graft Sources in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis. Clin Lymphoma Myeloma Leuk. Mar 2022; 22(3): 174-191.
25. Pidala J, Djulbegovic B, Anasetti C et al. Allogeneic hematopoietic cell transplantation for adult acute lymphoblastic leukemia (ALL) in first complete remission. Cochrane Database Syst Rev. Oct 5 2011; (10):CD008818.
26. Pieters R and Carroll WL. Biology and treatment of acute lymphoblastic leukemia. Pediatr Clin N Am. Feb 2008; 55(1):1-20.
27. Pulsipher MA, Boucher KM, Wall D et al. Reduced-intensity allogeneic transplantation in pediatric patients ineligible for myeloablative therapy: results of the Pediatric Blood and Marrow Transplant Consortium Study ONC0313. Blood. Aug 13 2009; 114(7):1429-1436.
28. Ribera JM, Oriol A, Bethencourt C, et al. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial. Haematologica. Oct 2005; 90(10):1346-1356.
29. Ribera JM, Ortega JJ, Oriol A, et al. Comparison of intensive chemotherapy, allogeneic, or autologous stem-cell transplantation as post remission treatment for children with very high risk acute lymphoblastic leukemia: PETHEMA ALL-93 trial. J Clin Oncol. Jan 01 2007; 25(1):16-24.
30. Rosko A, Wang HL, de Lima M, et al. Reduced intensity conditioned allograft yields favorable survival for older adults with B-cell acute lymphoblastic leukemia. Am J Hematol. Jan 2017; 92(1):42-49.
31. Trujillo AM, Karduss AJ, Suarez G, et al. Haploidentical Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide in Children with High-Risk Leukemia Using a Reduced-Intensity Conditioning Regimen and Peripheral Blood as the Stem Cell Source. Transplant Cell Ther. May 2021; 27(5): 427.e1-427.e7
32. Wheeler KA, Richards SM, Bailey CC, et al. Bone marrow transplantation versus chemotherapy in the treatment of very high-risk childhood acute lymphoblastic leukemia in first remission: Results from Medical Research Council UKALL X and XI. Blood. Oct 01 2000; 96(7):2412-2418.
33. Yanada M, Matsuo K, Suzuki T et al. Allogeneic hematopoietic stem cell transplantation as part of post remission therapy improves survival for adult patients with high-risk acute lymphoblastic leukemia: a metaanalysis. Cancer. Jun 15 2006; 106(12):2657-2663.

POLICY HISTORY:

Medical Policy Group, February 2010 (2)

Medical Policy Administration Committee, February 2010

Available for comment February 23-April 8, 2010

Medical Policy Group, December 2011 (3): 2012 Code Updates: Updated codes 38208, 38209 & 38230; Added Code 38323

Medical Policy Group, February 2012 (3): Updated Key Points, Key Words, References

Medical Policy Group, February 2013 (3): Updated Key Points and References; no change in policy statement

Medical Policy Panel, May 2013

Medical Policy Group, May 2013 (3): 2013 Update to Policy Statement, Key Points & References; policy statement updated to include coverage for children and adults for allogeneic HSCT in treating relapsing ALL after a prior autologous HSCT

Available for comment May 21 through July 5, 2013

Medical Policy Group, January 2014 (1): 2014 Coding Update: added current codes Q2049 and Q2050 to coding section; new codes are included in the chemotherapy drug code range

Medical Policy Panel, May 2014

Medical Policy Group, June 2014 (3):  2014 Updates to Description, Key Points & References; corrected policy statement entry to allow additional coverage per any risk for allogeneic HSCT

Medical Policy Administration Committee, July 2014

Medical Policy Panel, May 2015

Medical Policy Group; June 2015 (2): 2015 Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, March 2016

Medical Policy Group, April 2016 (2): 2016 updates to Name of Policy, Description, Key Points, Approved by Governing Bodies, and Coding-removed code 86812-86822; no changes in policy statement.

Medical Policy Panel, January 2017

Medical Policy Group, February 2017 (7): 2017 Updates to Description, Key Points, and References. No changes in policy statement.

Medical Policy Group, December 2017: Annual Coding Update 2018. Added new CPT code 38222 effective 01/01/2018 to the Current Coding section. Updated verbiage for revised codes 38220 and 38221.

Medical Policy Panel, January 2018

Medical Policy Group, February 2018 (7): Updates to Description, Key Points, and References.  No change to policy statements.

Medical Policy Panel, January 2019

Medical Policy group, February 2019 (3): 2019 Updates to Key Points, Practice Guidelines and Position Statements, and Key Words: added: Hematopoietic Cell Transplantation and HCT. No changes to policy statement or intent.

Medical Policy Panel, January 2020

Medical Policy Group, March 2020 (3): 2020 Updates to Description, Key Points and References. Added policy guidelines section. No changes to policy statement or intent.

Medical Policy Panel, January 2021

Medical Policy Group, February 2021 (3): 2021 Updates to Key Points and References. Policy statement updated to remove “not medically necessary, “no other changes to policy statement or intent.

Medical Policy Panel, January 2022

Medical Policy Group, February 2022 (3): 2022 Updates to Description, Key Points, Practice Guidelines and Position Statements, and References. No changes to policy statement or intent.

Medical Policy Panel, January 2023

Medical Policy Group, February 2023 (3): 2023 Updates to Description, 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, Benefits Application and References. 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.