Medical policy: Hematopoietic Cell Transplantation for Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Policy number: MP 9.038

Effective date: 5/1/2026

Policy

Allogeneic hematopoietic cell transplantation may be considered medically necessary to treat chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in individuals with markers of poor-risk disease (see Policy Guidelines).

Autologous hematopoietic cell transplantation is considered investigational to treat CLL or SLL. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Policy guidelines

Staging and prognosis of chronic lymphocytic leukemia or small lymphocytic lymphoma

Two scoring systems are used to determine stage and prognosis of patients with CLL or SLL. As outlined in Table 1 and Table 2, the Rai and Binet staging systems classify patients into risk groups with different prognoses and are used to make therapeutic decisions.

Table 1. Rai classification for chronic lymphocytic leukemia/small lymphocytic lymphoma

Table 2. Binet classification for chronic lymphocytic leukemia/small lymphocytic lymphoma

Because prognosis of patients varies within the different Rai and Binet classifications, other prognostic markers are used in conjunction with staging to determine clinical management. These are summarized in Table 2, according to availability in clinical centers.

The National Comprehensive Cancer Network guideline on CLL/SLL stated the following as unfavorable prognostic factors: DNA sequencing with mutated TP53 or ≤2% immunoglobulin heavy-chain variable (IGHV) mutation, interphase cytogenetics with del17p or deletion of 11q (del11q), or complex karyotype (≥3 unrelated chromosome abnormalities in more than 1 cell on karyotype).

Reduced-intensity conditioning for allogeneic HCT

Use of a myeloablative or reduced-intensity pretransplant conditioning regimen should be individualized based on factors that include age, the presence of comorbidities, and disease burden.

Some patients for whom a conventional myeloablative allotransplant could be curative may be considered as candidates for reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (allo-HCT). These include those patients whose age (typically over 60 years old) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen.

A patient who relapses following a conventional myeloablative allo-HCT could undergo a second myeloablative procedure if a suitable donor is available and his or her medical status would permit it. However, this type of patient would likely undergo RIC before a second allogeneic HCT if a complete remission could be reinduced with chemotherapy.

The ideal allogeneic donors are human leukocyte antigen (HLA)–identical siblings, matched at the HLA-A, -B, and -DR 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, haploidentical donors — typically a parent or a child of the patient — with sharing of only 3 of the 6 major histocompatibility antigens, have been under investigation as a stem cell source. Most patients will have such a donor; however, the risk of graft-versus-host disease (GVHD) and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as with matched donors.

Cross-references

• MP 9.001 Placental Umbilical Cord Blood as a Source of Stem Cells
• MP 9.042 Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO - Refer to FEP Medical Policy Manual.

Description/background

Chronic lymphocytic leukemia and small lymphocytic lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are neoplasms of hematopoietic origin characterized by the accumulation of lymphocytes that are mature, generally well-differentiated morphologically. In CLL, these cells accumulate in blood, bone marrow, lymph nodes, and spleen; in SLL they are generally confined to lymph nodes. The Revised European-American/World Health Organization Classification of Lymphoid Neoplasms considers B-cell CLL and SLL a single disease entity.

CLL and SLL share many common features and are often referred to as blood and tissue counterparts of each other, respectively. Both tend to present as asymptomatic enlargement of the lymph nodes, tend to be indolent in nature, but can undergo transformation to a more aggressive form of disease (e.g., Richter transformation). The median age at diagnosis of CLL is approximately 72 years, but it may present in younger individuals, often with poor-risk disease with significantly reduced life expectancy.

Treatment regimens used for CLL are generally the same as those used for SLL, and treatment outcomes are comparable for both diseases. Both low- and intermediate-risk CLL and SLL demonstrate relatively good prognoses, with median survivals of 6 to 10 years; however, the median survival of high-risk CLL or SLL may only be 2 years. Although typically responsive to initial therapy, CLL and SLL are rarely cured by conventional therapy, and nearly all patients ultimately die of their disease. This natural disease history prompted investigation of HCT as a possible curative regimen.

Hematopoietic cell transplantation

Hematopoietic cell transplantation (HCT) is a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow-toxic doses of drugs with or without whole-body radiotherapy. Hematopoietic stem cells may be obtained from the transplant recipient (autologous HCT) or from a donor (allogeneic HCT [allo-HCT]). These cells 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” and thus are associated with a lower incidence of rejection and graft-versus-host disease (GVHD). Cord blood is discussed in detail in evidence review MP 9.001.

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 critical for achieving a good outcome of allo-HCT. Compatibility is established by typing of human leukocyte antigens (HLA) using cellular, serologic, or molecular techniques. HLA refers to the tissue type expressed at the HLA-A, -B, and -DR loci on each arm of chromosome 6. Depending on the disease being treated, an acceptable donor will match the patient at most of the HLA loci.

Conditioning for HCT

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 destroy endogenous hematopoietic capability in the recipient. The beneficial treatment effect is due to a combination of initial eradication of malignant cells and subsequent graft-versus-malignancy (GVM) effect that develops after engraftment of allogeneic stem cells within the patient’s bone marrow space. The slower GVM effect is considered the potentially curative component, but it may be overwhelmed by extant disease without the use of pretransplant conditioning.

However, intense conditioning regimens are limited to patients who are sufficiently fit to tolerate substantial adverse effects, including opportunistic infections secondary to loss of endogenous bone marrow function and organ damage or failure caused by cytotoxic drugs. Furthermore, in any allo-HCT, immunosuppressant drugs are required to minimize graft rejection and GVHD, which also increases susceptibility of the patient to opportunistic infections.

The success of autologous HCT is predicated on the ability of cytotoxic chemotherapy with or without radiation to eradicate cancerous cells from the blood and bone marrow. This permits subsequent engraftment and repopulation of the bone marrow with hematopoietic stem cells obtained from the patient before undergoing bone marrow ablation. As a consequence, autologous HCT is typically performed as consolidation therapy when the patient’s disease is in complete remission. Patients who undergo autologous HCT are 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 of cytotoxic drugs or less intense regimens of cytotoxic drugs or radiation than those used in conventional full-dose myeloablative conditioning treatments. The goal of RIC is to reduce disease burden but also to minimize as much as possible associated treatment-related morbidity and nonrelapse mortality (NRM) in the period during which the beneficial graft-versus-malignancy effect of allogeneic transplantation develops.

Although the definition of RIC remains arbitrary, with numerous versions employed, all regimens seek to balance the competing effects of NRM and relapse due to residual disease. RIC regimens can be viewed as a continuum in effectiveness, from nearly myeloablative to minimally myeloablative with lymphoablation, with intensity tailored to specific diseases and patient condition. Patients who undergo RIC with allo-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 this evidence review, the term reduced-intensity conditioning will refer to all conditioning regimens intended to be nonmyeloablative, as opposed to fully myeloablative regimens.

National Comprehensive Cancer Network guidelines

Current National Comprehensive Cancer Network guidelines (v.2.2026) for CLL and small lymphocytic lymphoma (SLL) state the following regarding HCT:

• Given the favorable outcome of patients with del(17p) or TP53 mutation treated with covalent BTKi as first-line therapy and the availability of venetoclax as an effective treatment option for relapsed or refractory CLL, allogeneic HCT is not considered a reasonable treatment option for relapsed/refractory CLL after initial purine analogue–based therapy.
• Allogeneic HCT can be considered for relapsed/refractory disease after prior therapy with BTKi- and venetoclax-based regimens in patients without significant comorbidities.
• In patients with histologic transformation (Richter’s) and progression, allogeneic HCT can be considered for certain patients with disease responding to initial chemoimmunotherapy. In addition, autologous HCT may also be appropriate for patients with disease responding to initial therapy but who are not candidates for allogeneic HCT due to age, comorbidities, or lack of a suitable donor.

American Society for Transplantation and Cellular Therapy

In 2025, the American Society for Transplantation and Cellular Therapy (ASTCT) updated guidelines on the role of HCT and chimeric antigen receptor T-cell therapy (CAR T). The updated guidelines include reduced recommendations for allogeneic HCT compared with earlier guideline versions in favor of CAR T-cell therapy for several indications.

Allogeneic HCT is recommended:

• If CLL is relapsed and/or refractory to CAR T-cell therapy when an objective response is demonstrated prior to the allograft.
• In patients with clonally-related Richter transformation (RT) after demonstrating an objective response to front-line chemoimmunotherapy or other treatments.

The guidelines are uncertain about recommending autologous HCT in patients with RT that achieve an objective response to chemoimmunotherapy.

Regulatory status

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 Code of Federal Regulation title 21, parts 1270 and 1271. Hematopoietic cells are included in these regulations.

Rationale

Summary of evidence

For individuals who have CLL/SLL and markers of poor-risk disease who receive allo-HCT, the evidence includes single-arm prospective and registry-based studies. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related mortality and morbidity. Data suggest that allo-HCT can provide long-term disease control and overall survival in patients with poor-risk CLL/SLL. High rates of treatment-related morbidity discourage this approach in lower risk disease, particularly among older patients whose health status typically precludes the use of myeloablative conditioning. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have CLL/SLL who receive autologous HCT, the evidence includes randomized controlled trials and a systematic review. Relevant outcomes are overall survival, disease-specific survival, change in disease status, and treatment-related mortality and morbidity. Autologous HCT is feasible in younger patients but is not curative, particularly in those with poor-risk CLL. Studies of autologous HCT published to date have not shown improvement in overall survival in patients with CLL/SLL. Furthermore, evidence suggests that quality-of-life issues are important in selecting patients for autologous HCT and may dictate the management course for patients who are otherwise candidates for this approach. The evidence is insufficient to determine the effects of the technology on health outcomes.

Definitions

Allogeneic refers to having a different genetic constitution but belonging to the same species, i.e., involves a donor and a recipient. These cells are harvested from a donor; after verifying the donor and the recipient are well matched with respect to human leukocyte antigens (HLA). Allogeneic cells provide two theoretical advantages: the lack of tumor contamination associated with autologous stem cells and the possibility of a beneficial graft-versus-tumor effect. Their disadvantage is the risk of graft-versus-host disease (GVHD), which increases with great HLA disparity and recipient age.

Autologous refers to originating within an individual, i.e., self-donation. These stem cells are harvested from patients prior to myeloablative therapy.

Reduced-intensity allogeneic stem cell transplantation uses lower doses of chemotherapy than standard allogeneic transplant; it does not completely inactivate the patient’s immune system or treat the CLL as aggressively. Older, sicker patients may be helped with this type of treatment.

Relapsed refers to patients who have achieved remission but later have decreased numbers of normal blood cells and a return of leukemia in their bone marrow.

Refractory refers to patients who have residual leukemia cells in their bone marrow even after they receive intensive treatment.

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the member’s benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Covered when medically necessary

Investigational; therefore, not covered, when used to treat chronic lymphocytic leukemia or small lymphocytic lymphoma

References

1. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 2.2026.
2. Giné E, Moreno C, Esteve J, et al. The role of stem-cell transplantation in chronic lymphocytic leukemia risk-adapted therapy. Best Pract Res Clin Haematol. Sep 2007;20(3):529-43. PMID 17707838.
3. Gribben JG. Role of allogeneic hematopoietic stem-cell transplantation in chronic lymphocytic leukemia. J Clin Oncol. Oct 20 2008;26(30):4864-5. PMID 18794537.
4. Kharfan-Dabaja MA, Anasetti C, Santos ES. Hematopoietic cell transplantation for chronic lymphocytic leukemia: an evolving concept. Biol Blood Marrow Transplant. Apr 2007;13(4):373-85. PMID 17382245.
5. Gladstone DE, Fuchs E. Hematopoietic stem cell transplantation for chronic lymphocytic leukemia. Curr Opin Oncol. Mar 2012;24(2):176-81. PMID 22234253.
6. Delgado J, Milligan DW, Dreger P. Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time? Blood. Sep 24 2009;114(13):2581-8. PMID 19641189.
7. Dreger P. Allotransplantation for chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program. 2009:602-9. PMID 20008245.
8. Brown JR, Kim HT, Li S, et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Blood. Mar 15 2006;107(6):1056-64. PMID 17084369.
9. Delgado J, Thomson K, Russell N, et al. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. Feb 15 2006;107(4):1724-30. PMID 16239425.
10. Dreger P, Brand R, Hansz J, et al. Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning. Leukemia. May 2003;17(5):841-8. PMID 12750695.
11. Khouri IF, Saliba RM, Admirand J, et al. Graft-versus-leukemia effect after nonmyeloablative hematopoietic transplantation can overcome the unfavorable expression of ZAP-70 in refractory chronic lymphocytic leukemia. Br J Haematol. May 2007;137(4):355-63. PMID 17456058.
12. Schetelig J, Thiede C, Bornhäuser M, et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol. Jul 15 2003;21(14):2747-53. PMID 12860954.
13. Sorror ML, Storer BE, Sandmaier BM, et al. Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol. Oct 20 2008;26(30):4912-20. PMID 18794548.
14. Dreger P, Döhner H, Ritgen M, et al. Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood. Oct 07 2010;116(14):2438-47. PMID 20595516.
15. Reljic T, Kumar A, Djulbegovic B, et al. High-dose therapy and autologous hematopoietic cell transplantation as front-line consolidation in chronic lymphocytic leukemia: a systematic review. Bone Marrow Transplant. Aug 2015;50(8):1144. PMID 26242579.
16. Michallet M, Dreger P, Sutton L, et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. Feb 03 2011;117(5):1516-21. PMID 21069805.
17. De Wreede LC, Watson M, van Os M, et al. Improved relapse-free survival after autologous stem-cell transplantation does not translate into better quality of life in chronic lymphocytic leukemia: lessons from the randomized European Society for Blood and Marrow Transplantation-Intergroup study. Am J Hematol. Feb 2014;89(2):174-80. PMID 24123244.
18. 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. PMID 26256941.
19. Kharfan-Dabaja MA, Kumar A, Hamadani M, et al. Clinical practice recommendations for use of allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia on behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant. Dec 2016;22(12):2117-2125. PMID 27660167.
20. 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. PMID 32165328.
21. National Cancer Institute. Chronic lymphocytic leukemia treatment (PDQ®)–Health Professional Version. Updated April 25, 2025.