Non-myeloablative Hematopoietic Cell Transplantation (Mini-Allograft / Reduced Intensity Conditioning Transplant)

Number: 0634

Policy

  1. Aetna considers non-myeloablative hematopoietic cell transplantation (mini-allograft) medically necessary for members with any of the following diseases for which conventional allogeneic hematopoietic cell transplantation is considered an established alternative.  Persons who are unable to tolerate a conventional allogeneic hematopoietic cell transplant may be able to tolerate a milder, non-myeloablative conditioning regimen.  In these cases, mini-allografting represents a technical modification of an established procedure.

  2. Aetna considers non-myeloablative hematopoietic cell transplantation (mini-allograft) experimental and investigational for any of the following diseases because it has not been established that a conventional allogeneic hematopoietic cell transplant is effective in treating these conditions (not an all-inclusive list):

Background

Conventional allogeneic stem cell transplant is an effective therapeutic option for some malignancies and hematological disorders such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), aplastic anemia (AA), chronic myelogenous leukemia (CML), Hodgkin's disease (HD), multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), myelodysplasia, neuroblastoma, sickle cell anemia, and thalassemia major.  However, high-dose conditioning regimens designed both to control the malignancy and to prevent graft rejection are associated with a high incidence of transplant-related organ toxicity and mortality.  This results in the preclusion of the use of allografting for patients older than 55 years or for younger patients with certain pre-existing organ damage.  Thus, studies have been ongoing to develop safer allografting procedures that can be extended to older patients or patients with pre-existing organ dysfunction who are currently excluded from consideration for allografting.  New strategies for allografting entail the use of less intensive conditioning therapy that is administered with the sole purpose of facilitating allogeneic engraftment.  Pre-clinical studies in a canine model have demonstrated that conditioning regimens for allografting can be markedly reduced in intensity yet still attain the goal of engraftment.  This reduced intensity conditioning transplant, also known as non-myeloablative transplant or mini-allograft, is usually based on low dose total body irradiation or fludarabine alone or in combination with other drugs followed by a short course of immunosuppression with post-grafting cyclosporine and methotrexate or mycophenolate mofetil.  Mini-allograft, however, may be associated with severe side effects since non-myeloablative regimens used in this procedure rely on immunosuppressive treatment to prevent graft-versus-host disease (GVHD) following transplantation.  Such treatment predisposes patients to infections and may also lower the anti-malignancy effects of donor cells.

For patients with ALL, AML, AA, CML, HD, MM, NHL, myelodysplasia, neuroblastoma, sickle cell anemia, or thalassemia major who are eligible for conventional ASCT, mini-allograft is a technical variation of an established procedure. On the other hand, for patients with ALL, AML, AA, CML, HD, MM, NHL, myelodysplasia, neuroblastoma, sickle cell anemia, or thalassemia major as well as patients with other malignancies, who are ineligible for conventional ASCT, mini-allograft is still considered an investigational procedure.

Nagler et al (2000) reported that fludarabine-based conditioning with reduced amounts of chemotoxic drugs before allogeneic transplant appeared to be beneficial for patients with high-risk malignant lymphoma (n = 23).  Engraftment was fast.  There was no rejection or non-engraftment.  Organ toxicity was moderate with no hepatic or renal toxicity higher than grade II.  Four patients developed higher than grade II GVHD.  Seven patients died -- 4 of grade III-IV GVHD and severe infections, 2 of bacterial sepsis, 1 of respiratory failure.  Ten patients were alive after 22.5 (range of 15 to 37) months.  Survival and disease-free survival at 37 months were both 40 %.  Probability of relapse was 26 %.  The authors concluded that these encouraging findings suggested that allogeneic transplant following fludarabine-based low intensity conditioning in high-risk malignant lymphoma patients warranted further investigation.

In a prospective multi-center study (n = 71), Martino and associates (2001) concluded that reduced intensity conditioning regimens resulted in low early toxicity following allografting, with stable donor hematopoietic engraftment, with an apparent low-risk of acute GVHD.  However, chronic GVHD developed in a significant number of patients.  These findings suggested that reduced intensity conditioning allogeneic peripheral blood stem cell transplantation might lower the risk of dying from an opportunistic infection and reduce the occurrence of cytomegalovirus infection and disease.  Overall, the development of GVHD (acute or chronic) was an important risk factor for these complications.  Other infections continued to pose a significant threat to recipients of reduced intensity conditioning allografts.  Kroger and co-workers (2001) reported that fludarabine dose-reduced conditioning prior to allogeneic stem cell transplantation in high-risk myelodysplastic syndrome patients (n = 12), who were ineligible for standard transplantation, resulted in stable engraftment with complete chimerism, but the toxicity and relapse rate were considerable.

In a recent review, Schanz (2001) stated that although mini-allograft is feasible, less toxic than conventional stem cell grafting, severe side effects have been reported and are not uncommon.  Realistic outcome estimations cannot be made yet due to the still short follow-up periods.  Nevertheless, mini-allograft is a treatment option and its position in the management of hematological and oncological diseases will become clearer in the future.  This observation was echoed by Feinstein and Storb (2001) who stated that preliminary results of mini-allograft were encouraging.  If long-term effectiveness of this approach were demonstrated, such strategies would expand therapeutic options for patients who would otherwise be excluded from receiving conventional allografts.

In a review of the chemotherapy effects in patients with AML, Kimby et al (2001) stated that allogeneic stem cell transplantation following mini-allograft induced a host-versus-graft tolerance and an immune graft-versus-leukemia effect.  This new approach of immunotherapy appears to result in a low procedure-related mortality, however, long-term effects are unknown and evaluation in controlled clinical studies is needed.  van Besien and colleagues (2001) noted that mini-allograft has been examined as a means to lower treatment-related mortality in patients with CLL, however extended follow-up is needed to establish the cure rate obtained with this procedure.

Some of the conclusions from the 1999 European Group for Blood and Marrow Transplantation (EBMT) Workshop on allogeneic hematopoietic stem cell transplantation (HSCT) following non-myeloablative conditioning, also known as reduced intensity (RI) conditioning regimen were as follows (Bacigalupo, 2000):

  • RI-HSCT may be appropriate in chronic disorders such as chronic lymphoproliferative diseases.  Chronic myeloid leukemia should be studied.  
  • It remains to be determined whether RI-HSCT is beneficial in patients with solid tumors. 

Some of the findings/conclusions from the 2nd EMBT Workshop on allogeneic transplantation following non-myeloablative conditioning held in 2001 were as follows (Bacigalupo, 2002):

  • It is probably too early to give a clear message on the role of allogeneic RI-HSCT in patients with solid tumors.  Some responses have been recorded in breast cancer and renal cell carcinoma, but results in melanoma appear to be less encouraging. 
  • There are very little data on the use of RI-HSCT for patients with myeloma.  
  • A high relapse rate (60 % at 2 years) suggested that RI-HSCT in advanced and/or high-grade lymphomas is unlikely to be successful. 
  • There are little data on the use of RI-HSCT for patients with high-risk leukemia or myelodysplasia (e.g., patients with acute leukemia in relapse or patients with transformed myelodysplasia).  
  • There was no specific program described for patients with ALL.  
  • Reducing intensity programs are being optimized and tested in selected indications including unrelated donor transplants.  
  • The comparison with conventional programs will probably be tested. 

In an updated technology assessment on "Non-myeloablative bone marrow and peripheral stem cell transplantation" by the Wessex Institute for Health Research and Development, Muthu (2001) stated that the updated search has not altered the conclusions of the review.  The patient populations of the reviewed studies consisted mainly of individuals who are considered unsuitable for conventional allograft.  The research regarding safety and effectiveness of mini-transplant is still in an early phase.  Studies are heterogeneous in terms of their populations and interventions, and are uncontrolled.  Results are promising, especially if it may be assumed that prognosis is consistently worse with alternative treatment strategies in the studied patient groups.  However, the conclusion remains tentative pending larger, preferably controlled-studies with consistent and explicit inclusion and exclusion criteria, consistent co-interventions and longer follow-up.

Shaughnessy and colleagues (2006) carried out a phase I and pharmacokinetic study of once-daily, intravenously administered busulfan in the setting of a reduced-intensity preparative regimen and matched sibling donor allogeneic stem cell transplantation for treatment of metastatic renal cell carcinoma.  Seven male patients with metastatic renal cell carcinoma received intravenously administered busulfan at 3.2 mg/kg once daily on day -10 and day -9, fludarabine at 30 mg/m2 on day -7 through day -2, and equine anti-thymocyte globulin at 15 mg/kg per day on day -5 through day -2.  The mean area under the plasma concentration-time curve (AUC) and the half-life of the first dose of intravenously administered busulfan were 6,253 microM x minute (range of 5,036 to 7,482 microM x minute) and 3.37 hours (range of  2.54 to 4.00 hours), respectively.  The AUC was higher than predicted from extrapolation of AUC data for the same total dose of intravenously administered busulfan divided into four doses daily.  Patients experienced greater than expected regimen-related toxicity for a reduced-intensity preparative regimen, and the study was stopped.  The authors concluded that this preparative regimen was associated with unacceptable regimen-related toxicity among patients with metastatic renal cell carcinoma.

Norton and Roberts (2006) noted that Evans syndrome is an uncommon condition defined by the combination (either simultaneously or sequentially) of immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) with a positive direct antiglobulin test (DAT) in the absence of known underlying etiology.  This chronic disorder is characterized by frequent exacerbations and remissions.  First-line therapy usually entails corticosteroids and/or intravenous immunoglobulin, to which most patients respond; however, relapse is frequent.  Second-line treatments include immunosuppressive drugs, especially ciclosporin or mycophenolate mofetil; vincristine; danazol or a combination of these agents.  More recently a small number of patients have been treated with rituximab, which induces remission in the majority although such responses are often sustained for less than 12 months and the long-term effects in children are unclear.  Splenectomy may also be considered although long-term remissions are less frequent than in uncomplicated ITP.  For very severe and refractory cases stem cell transplantation (SCT) offers the only chance of long-term cure.  The limited data available suggested that ASCT may be superior to autologous SCT but both carry risks of severe morbidity and of transplant-related mortality.  Cure following RI conditioning has now been reported and should be considered for younger patients in the context of controlled clinical trials.

In a phase I/II clinical trial, Burt and colleagues (2009) evaluated the safety and clinical outcome of autologous non-myeloablative hemopoietic SCT in patients with relapsing-remitting multiple sclerosis (MS) who had not responded to treatment with interferon beta.  Eligible patients had relapsing-remitting MS, and despite treatment with interferon beta had had two corticosteroid-treated relapses within the previous 12 months, or one relapse and gadolinium-enhancing lesions seen on MRI and separate from the relapse.  Peripheral blood hemopoietic stem cells were mobilized with 2 g/m2 cyclophosphamide and 10 microg/kg/day filgrastim.  The conditioning regimen for the hemopoietic stem cells was 200 mg/kg cyclophosphamide and either 20 mg alemtuzumab or 6 mg/kg rabbit anti-thymocyte globulin.  Primary outcomes were progression-free survival and reversal of neurological disability at 3 years post-transplantation.  These researchers also examined the safety and tolerability of autologous non-myeloablative hemopoietic SCT.  A total of 21 patients were treated.  Engraftment of white blood cells and platelets was on median day 9 (range of day 8 to 11) and patients were discharged from hospital on mean day 11 (range of day 8 to 13).  One patient had diarrhea due to clostridium difficile and 2 patients had dermatomal zoster; 2 of the 17 patients receiving alemtuzumab developed late immune thrombocytopenic purpura that remitted with standard therapy.  Overall, 17 of 21 patients (81 %) improved by at least 1 point on the Kurtzke expanded disability status scale (EDSS), and 5 patients (24 %) relapsed but achieved remission after further immunosuppression.  After a mean of 37 months (range of 24 to 48 months), all patients were progression-free (no deterioration in EDSS score), and 16 were relapse-free.  Significant improvements were noted in neurological disability, as determined by EDSS score (p < 0.0001), neurological rating scale score (p = 0.0001), paced auditory serial addition test (p = 0.014), 25-foot walk (p < 0.0001), and quality of life, as measured with the short form-36 questionnaire (p < 0.0001).  The authors concluded that non-myeloablative autologous hemopoietic SCT in patients with relapsing-remitting MS reverses neurological deficits, but these results need to be confirmed in a randomized trial.

Burdach and colleagues (2000) compared outcome after autologous and allogeneic stem-cell transplantation (SCT) in patients with advanced Ewing's tumors.  These investigators analyzed the results of 36 patients who were treated with the myeloablative Hyper-ME protocol (hyper-fractionated total body irradiation, melphalan, etoposide +/- carboplatin).  Minimal follow-up for all patients was 5 years.  All subjects underwent remission induction chemotherapy and local treatment before myeloablative therapy.  Seventeen of 36 patients had multi-focal primary Ewing's tumor, 18 of 36 had early, multiple or multi-focal relapse, 1 of 36 patients had unifocal late relapse.  Twenty-six of 36 were treated with autologous and 10 of 36 with allogeneic hematopoietic stem cells.  These researchers analyzed the following risk factors, which could possibly influence the event-free survival (EFS): number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis.  Event-free survival for the 36 patients was 0.24 (0.21) +/- 0.07.  Eighteen of 36 patients suffered relapse or died of disease, 9 of 36 died of treatment related toxicity (DOC).  Nine of 36 patients are alive in complete remission (CR).  Age greater than or equal to 17 years at initial diagnosis significantly deteriorated outcome (p < 0.005).  According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT.  Incidence of DOC was more than twice as high after allogeneic (40 %) compared to autologous (19 %) SCT, even though the difference did not reach significance (p = 0.08, Fisher's exact test).  The authors concluded that because of the rather short observation period, secondary malignant neoplasms may complicate the future clinical course of some of the patients who were viewed as event-free survivors.  Event-free survival in patients with advanced Ewing's tumors is not improved by allogeneic SCT due to a higher complication rate.  Furthermore, Capitini and colleagues (2009) noted that further clinical trials are needed to evaluate the role for allogeneic SCT for Ewing's sarcoma.

Duvic et al (2010) examined the safety and effectiveness of total skin electron beam with allogeneic HSCT in patients with cutaneous T-cell lymphoma (CTCL).  A total of 19 patients with advanced CTCL (median age of 50 years; 4 prior therapies) underwent total skin electron beam radiation followed by allogeneic HSCT; 16 patients were conditioned with fludarabine (125 mg/m(2)) and melphalan (140 mg/m(2)) plus thymoglobulin (for mis-matched donors).  Graft-versus-host disease prophylaxis was with tacrolimus/mini methotrexate.  Eighteen patients experienced engraftment, and 1 died as a result of sepsis on day 16.  Median time to recovery of absolute neutrophil count (ANC) was 12 days.  Fifteen achieved full donor chimerism, 12 had acute GVHD, and 12 were treated for chronic GVHD.  The overall intent-to-treat response was 68 %, and the complete response rate was 58 %.  Four of 6 patients died in complete remission as a result of bacterial sepsis (n = 2), chronic GVHD and fungal infection (n = 1), or lung cancer (n = 1); only 2 died as a result of progressive disease.  Eight subjects experienced relapse in skin; 5 regained complete response with reduced immunosuppression or donor lymphocyte infusions.  Eleven of 13 are currently in complete remissions, with median follow-up of 19 months (range of 1.3 to 8.3 years).  Median overall survival has not been reached. The authors concluded that total skin electron beam followed by allogeneic HSCT is a promising treatment for selected patients with refractory CTCL and merits additional evaluation in high-risk patients with advanced disease who had poor survival and matched donors.

Acquired Angioedema:

Zegers and colleagues (2015) stated that acquired angioedema is a rare disorder causing recurrent life-threatening angioedema, due to decreased activity of C1 esterase inhibitor. These researchers reported on the case of a 57-year old man presented to the authors’ hospital with recurrent swelling of the hands, lips, tongue, scrotum and throat.  Laboratory examination showed the presence of an IgM kappa monoclonal antibody; additional analysis showed that in the IgM fraction autoantibody activity against C1 esterase inhibitor was present.  This confirmed the diagnosis of acquired angioedema in the presence of lympho-plasmacytic lymphoma.  Despite standard therapy, there was an increase in the episodes of laryngeal edema.  Therefore it was decided to perform a non-myeloablative allogeneic HSCT, with his HLA-identical brother as donor.  The post-transplantation course was without complications; 5 years following allo-SCT he is in CR without symptoms and with increased C1 esterase inhibitor activity.  The authors concluded that this was the first case describing treatment of severe acquired angioedema, that had failed all known therapeutic options, with an allo-SCT.

Furthermore, UpToDate reviews on “Acquired C1 inhibitor deficiency: Management and prognosis” (Cicardi, 2016) and “An overview of angioedema: Clinical features, diagnosis, and management” (Zuraw and Bingham, 2016) do not mention the use of non-myeloablative hematopoietic cell transplantation/mini-allograft as a therapeutic option.

Inherited Hemophagocytic Lymphohistiocytosis:

Kuriyama and associates (2016) noted that inherited hemophagocytic lymphohistiocytosis (HLH) is a genetic anomaly disorder in which abnormally activated cytotoxic T lymphocytes cannot induce the apoptosis of target cells and antigen-presenting cells, leading to hemophagocytosis, pancytopenia, and a variety of symptoms such as a high fever. These investigators presented the case of a patient with adult-onset HLH developed refractory disease despite receiving immunosuppressive treatments.  He underwent a reduced-intensity conditioning (RIC) regimen that comprised anti-thymocyte globulin (ATG) followed by cord blood transplantation (RIC-CBT).  He achieved and maintained a complete donor type.  The authors concluded that the incorporation of ATG into RIC-CBT may prevent graft failure and control hemophagocytosis, however, they stated that further efforts are needed to reduce infectious complications.

Furthermore, an UpToDate review on “Treatment and prognosis of hemophagocytic lymphohistiocytosis” (McClain, 2016) does not mention the use of non-myeloablative hematopoietic cell transplantation/mini-allograft as a therapeutic option.

Mucopolysaccharidosis Types II, III and IV:

Yokoi and associates (2015) stated that mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficient activity of the iduronate-2-sulfatase (IDS) resulting in the  accumulation of glycosaminoglycans (GAGs) in the lysosomes of various cells.  Although it has been proposed that BMT may have a beneficial effect for patients with MPS II, the requirement for donor-cell chimerism to reduce GAG levels is unknown.  To address this issue, these investigators transplanted various ratios of normal and MPS II bone marrow cells in a mouse model of MPS II and analyzed GAG accumulation in various tissues.  Chimerism of whole leukocytes and each lineage of BMT recipients' peripheral blood was similar to infusion ratios; GAGs were significantly reduced in the liver, spleen, and heart of recipients.  The level of GAG reduction in these tissues depended on the percentage of normal-cell chimerism.  In contrast to these tissues, a reduction in GAGs was not observed in the kidney and brain, even if 100 % donor chimerism was achieved.  The authors concluded that these results suggested that a high degree of chimerism is needed to attain the maximum effect of BMT, and donor lymphocyte infusion (DLI) or enzyme replacement therapy (ERT) might be considered options in cases of low-level chimerism in MPS II patients.

Yokoi and colleagues (2016) noted that although ERT is available as a treatment of MPS II, there are some limitations, such as the requirement of weekly administration for the entire life.  To avoid such limitations, HSCT is a possible alternative.  In fact, some report suggested positive effects of HSCT for MPS II.  However, HSCT has also some limitations since strong conditioning regimens can cause severe side effects.  To overcome this obstacle, these researchers studied the effectiveness of ACK2, an antibody that blocks KIT, followed by low-dose irradiation as a pre-conditioning regimen for HSCT using a murine model of MPS II.  This protocol achieved 58.7 ± 4.92 % donor chimerism at 16 weeks after transplantation in the peripheral blood of recipient mice; GAG levels were significantly reduced in liver, spleen, heart and intestine.  The authors concluded that these findings showed that ACK2-based pre-conditioning might be one of the choices for MPS II patients who receive HSCT.

Furthermore, an UpToDate review on “Mucopolysaccharidoses: Complications and management” (Wynn, 2017) stated that “HCT has also improved the clinical outcomes of patients with milder MPS I and II, and MPS VI and VII.  However, HCT has not prevented the central nervous system (CNS) decline in patients with severe MPS II in most series and has not been successful in other types of MPS.  MPS III A to D patients usually do not benefit and may worsen after the procedure.  HCT does not correct the bony abnormalities in MPS IV A and IV B or MPS I.  The reason for the lack of success of HCT in some types of MPS is uncertain, although it is possible that the transplanted cells do not secrete sufficient enzyme, or the enzyme may not be taken up sufficiently to correct the deficiency.  It is possible outcomes in some of these populations may improve with early HCT with full donor engraftment from a non-carrier donor.  This question warrants further study”.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:
38204 - 38205, 38207 - 38215, 38230 - 38240 Bone marrow or stem cell services/procedures-allogenic and transplantation and post-transplantation cellular infusions
38242 Allogeneic lymphocyte infusions

HCPCS codes covered if selection criteria are met:
S2150 Bone marrow or blood-derived stem cells (peripheral or umbilical), allogenic 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

Other HCPCS codes related to the CPB:
J7502 Cyclosporine, oral, 100 mg
J7515 Cyclosporine, oral 25 mg
J7516 Cyclosporine, parenteral 250 mg
J7517 Mycophenolate mofetil, oral, 250 mg
J8610 Methotrexate, oral, 2.5 mg
J9185 Fludarabine phosphate, 50 mg
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg

ICD-10 codes covered if selection criteria are met:
C74.00 - C74.92 Malignant neoplasm of adrenal gland
C81.00 - C81.99 Hodgkin's lymphoma
C82.50 - C82.59, C84.a0 - C84.z9
C84.90 - C84.99 - C85.10 - C85.99		 Other lymphoma
C83.10 - C83.19 Mantle cell lymphoma
C83.30 - C83.39 Diffuse large B-cell lymphoma
C83.80 - C83.89, C88.4 Other non-follicular lymphoma
C84.40 - C84.49 Peripheral T-cell lymphoma, not classified
C84.60 - C84.79 Anaplastic large cell lymphoma, ALK-positive, ALK-negative
C90.00 - C90.01 Multiple myeloma [in remission and not having achieved remission]
C91.00 - C91.01 Acute lymphoblastic leukemia [in remission and not have achieved remission]
C91.10 - C91.11 Chronic lymphocytic leukemia of B-cell type [in remission and not having achieved remission]
C92.00 - C92.01 Acute myeloblastic leukemia [in remission and not having achieved remission]
D46.0 - D46.9 Myelodysplastic syndromes
D56.1 Beta thalassemia
D57.0 - D57.819 Sickle-cell disorder
D57.40 Sickle-cell thalassemia without crisis
D57.411 - D57.419 Sickle-cell thalassemia with crisis
D59.5 Paroxysmal nocturnal hemoglobinuria (PNH) [Marchiafava-Micheli]
D60.0 - D64.9 Acquired pure red cell aplasia [erythroblastopenia]
D75.81 Myelofibrosis
Q06.0 - Q06.9 Other congenital malformation of spinal cord

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C43.0 - C43.9 Malignant melanoma of skin
C50.011 - M50.929 Malignant neoplasm of breast
C62.00 - C62.92 Malignant neoplasm of testis
C64.1 - C65.9 Malignant neoplasm of kidney and renal pelvis
D03.0 - D03.9 Melanoma in situ [skin]
D45 Polycythemia vera
D47.3 Essential (hemorrhagic) thrombocythemia
D51.0 Vitamin B12 deficiency anemia due to intrinsic factor deficiency
D76.1 Hemophagocytic lymphohistiocytosis
D80.0 - D89.9 Disorders involving the immune mechanism
E05.00 - E05.01 Thyrotoxicosis with diffuse goiter
E06.3 Autoimmune thyroiditis [Hashimoto's thyroiditis]
E10.10 - E10.9 Diabetes mellitus, type I
E27.1 - E27.49 Adrenocortical insufficiency [Addison's disease]
G35 Multiple sclerosis
G70.00 - G70.01 Myasthenia gravis
L93.0 - L93.2 Lupus erythematosus
M02.30 - M02.39 Reiter's disease
M05.00 - M06.9, M08.00 - M08.99, M12.00 - M12.09 Rheumatoid arthritis and other inflammatory polyarthropathies
M32.10 - M32.9 Systemic lupus erythematosus
M33.00 - M33.9, M36.0 Dermatopolymyositis
M34.0 - M34.9 Systemic sclerosis [scleroderma]
M35.00 - M35.9 Sicca syndrome [Sjogren's disease]
T78.3xxA - T78.3xxS Angioneurotic edema

The above policy is based on the following references:

  1. Bacigalupo A. Hematopoietic stem cell transplants after reduced intensity conditioning regimen (RI-HSCT): Report of a workshop of the European group for Blood and Marrow Transplantation (EBMT). Bone Marrow Transplant. 2000;25(8):803-805.
  2. Nagler A, Slavin S, Varadi G, et al. Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for malignant lymphoma. Bone Marrow Transplant. 2000;25(10):1021-1028.
  3. Carella AM, Champlin R, Slavin S, et al. Mini-allografts: Ongoing trials in humans. Bone Marrow Transplant. 2000;25(4):345-350.
  4. Maris M, Sandmaier BM, Maloney DG, et al. Non-myeloablative hematopoietic stem cell transplantation. Transfus Clin Biol. 2001;8(3):231-234.
  5. Slavin S, Nagler A, Shapira M, et al. Non-myeloablative allogeneic stem cell transplantation focusing on immunotherapy of life-threatening malignant and non-malignant diseases. Crit Rev Oncol Hematol. 2001;39(1-2):25-29.
  6. Schanz U. Allogeneic haematopoietic stem cell transplantation with reduced intensity conditioning regimens (“minitransplants”). Swiss Med Wkly. 2001;131(5-6):59-64.
  7. Michallet M, Bilger K, Garban F, et al. Allogeneic hematopoietic stem-cell transplantation after nonmyeloablative preparative regimens: Impact of pretransplantation and posttransplantation factors on outcome. J Clin Oncol. 2001;19(14):3340-3349.
  8. Feinstein L, Storb R. Nonmyeloablative hematopoietic cell transplantation. Curr Opin Oncol. 2001;13(2):95-100.
  9. Kimby E, Nygren P, Glimelius B; et al. A systematic overview of chemotherapy effects in acute myeloid leukemia. Acta Oncol. 2001;40(2-3):231-252.
  10. van Besien K, Keralavarma B, Devine S, et al. Allogeneic and autologous transplantation for chronic lymphocytic leukemia. Leukemia. 2001;15(9):1317-1325.
  11. Kyle RA. Update on the treatment of multiple myeloma. Oncologist. 2001;6(2):119-124.
  12. McSweeney PA, Niederwieser D, Shizuru JA, et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood. 2001;97(11):3390-3400.
  13. Vindelov L. Allogeneic bone marrow transplantation with reduced conditioning (RC-BMT). Eur J Haematol. 2001;66(2):73-82.
  14. Martino R, Caballero MD, Canals C, et al. Allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning: Results of a prospective multicentre study. Br J Haematol. 2001;115(3):653-659.
  15. Martino R, Caballero MD, Canals C, et al. Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant. 2001;28(4):341-347.
  16. Mohty M, Fegueux N, Exbrayat C, et al. Reduced intensity conditioning: Enhanced graft-versus-tumor effect following dose-reduced conditioning and allogeneic transplantation for refractory lymphoid malignancies after high-dose therapy. Bone Marrow Transplant. 2001;28(4):335-339.
  17. Kroger N, Schetelig J, Zabelina T, et al. A fludarabine-based dose-reduced conditioning regimen followed by allogeneic stem cell transplantation from related or unrelated donors in patients with myelodysplastic syndrome. Bone Marrow Transplant. 2001;28(7):643-647.
  18. Champlin R, Khouri I, Anderlini P, et al. Nonmyeloablative preparative regimens for allogeneic hematopoietic transplantation. Bone Marrow Transplant. 2001;27(Suppl 2):S13-S22.
  19. Muthu V. Non-myeloablative bone marrow and peripheral stem cell transplantation. STEER: Succint and Timely Evaluated Evidence Reviews. Bazian, Ltd., eds.. 2001;1(1):1-12. Available at: http://www.soton.ac.uk/~wi/projx/signpost/steers/STEER_2001(1).pdf. Accessed June 20, 2003.
  20. Bacigalupo A. Second EBMT Workshop on reduced intensity allogeneic hemopoietic stem cell transplant (RI-HSCT). Bone Marrow Transplant. 2002;29:191-195.
  21. Rizouli V, Gribben JG. Role of autologous stem cell transplantation in chronic lymphocytic leukemia. Curr Opin Hematol. 2003;10(4):306-311.
  22. Georges GE, Maris M, Sandmaier BM, et al. Related and unrelated nonmyeloablative hematopoietic stem cell transplantation for malignant diseases. Int J Hematol. 2002;76 Suppl 1:184-189.
  23. Nieto Y, Bearman SI, Shpall EJ, et al. Intensive chemotherapy for progressive chronic lymphocytic leukemia administered early after a nonmyeloablative allograft. Bone Marrow Transplant. 2001;28(11):1083-1086.
  24. Champlin R, van Besien K, Giralt S, Khouri I. Allogeneic hematopoietic transplantation for chronic lymphocytic leukemia and lymphoma: Potential for nonablative preparative regimens. Curr Oncol Rep. 2000;2(2):182-191.
  25. Khouri IF, Keating M, Korbling M, et al. Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol. 1998;16(8):2817-2824.
  26. van Besien K, Keralavarma B, Devine S, Stock W. Allogeneic and autologous transplantation for chronic lymphocytic leukemia. Leukemia. 2001;15(9):1317-1325.
  27. Schey SA. Stem cell transplantation for chronic lymphocytic leukaemia: Is this the way forward in the new millennium? Malignancy; Current Clinical Practice. Hematology. 2000;5(4):265-273.
  28. Hamblin TJ. Achieving optimal outcomes in chronic lymphocytic leukaemia. Drugs. 2001;61(5):593-611.
  29. Flinn IW, Vogelsang G. Bone marrow transplantation for chronic lymphocytic leukemia. Semin Oncol. 1998;25(1):60-64.
  30. Khouri I, Giralt S, Saliba R, et al. “Mini”-allogeneic stem cell transplantation for relapsed/refractory lymphomas with aggressive histologies [abstract]. Proc ASCO. 2000;19:47a.
  31. Champlin R, Khouri I, Kornblau S, et al. Allogeneic hematopoietic transplantation as adoptive immunotherapy. Induction of graft-versus-malignancy as primary therapy. Hematol Oncol Clin North Am. 1999;13(5):1041-1057, vii-viii.
  32. University of Texas M.D. Anderson Cancer Center. Allogeneic transplantation for CLL. Leukemia Insights Newsletter. 2003;8(2). Available at: http://www.mdanderson.org/publications/insights/. Accessed June 20, 2003.
  33. Djulbegovic B, Seidenfeld J, Bonnell C, Kumar A. Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: A systematic review. Cancer Control. 2003;10(1):17-41. Available at: http://www.medscape.com/viewarticle/449119. Accessed June 20, 2003.
  34. Childs RW. Immunotherapy of solid tumors: Nonmyeloablative allogeneic stem cell transplantation. Medscape General Med. 2002;4(3). Available at: http://www.medscape.com/viewarticle/436456_1. Accessed June 20, 2003.
  35. BlueCross BlueShield Association (BCBSA), Technology Evaluation Center (TEC). Nonmyeloablative allogeneic stem-cell transplantation for malignancy. TEC Assessment Program. Chicago, IL: BCBSA; May 2001;16(3).
  36. Muthu V. Update report: Non-myeloablative bone marrow and peripheral blood stem cell transplant. Bazian Ltd., eds. London, UK: Wessex Institute for Health Research and Development, University of Southampton; 2002.
  37. Ruiz-Arguelles GJ. Non-myeloablative bone marrow transplantation. Arch Med Res. 2003;34(6):554-557.
  38. Baron F, Frere P, Baudoux E, Schaaf, et al. Low incidence of acute graft-versus-host disease after non-myeloablative stem cell transplantation with CD8-depleted peripheral blood stem cells: An update. Haematologica. 2003;88(7):835-837.
  39. Ljungman P, Urbano-Ispizua A, Cavazzana-Calvo M, et al. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: Definitions and current practice in Europe. Bone Marrow Transplant. 2006;37(5):439-449.
  40. Shaughnessy P, Alexander W, Tran H, et al. Phase I and pharmacokinetic study of once-daily dosing of intravenously administered busulfan in the setting of a reduced-intensity preparative regimen and allogeneic hematopoietic stem cell transplantation as immunotherapy for renal cell carcinoma. Mil Med. 2006;171(2):161-165.
  41. Roigas J, Johannsen M, Ringsdorf M, Massenkeil G. Allogeneic stem cell transplantation for patients with metastatic renal cell carcinoma. Expert Rev Anticancer Ther. 2006;6(10):1449-1458.
  42. Norton A, Roberts I. Management of Evans syndrome. Br J Haematol. 2006;132(2):125-137.
  43. Valcárcel 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. 2008;26(4):577-584.
  44. Laport GG, Sandmaier BM, Storer BE, et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant. 2008;14(2):246-255.
  45. Satwani P, Morris E, Bradley MB, et al. Reduced intensity and non-myeloablative allogeneic stem cell transplantation in children and adolescents with malignant and non-malignant diseases. Pediatr Blood Cancer. 2008;50(1):1-8.
  46. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: Systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301(22):2349-2361.
  47. Bensinger WI. Role of autologous and allogeneic stem cell transplantation in myeloma. Leukemia. 2009;23(3):442-448.
  48. Burt RK, Loh Y, Cohen B, et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing-remitting multiple sclerosis: A phase I/II study. Lancet Neurol. 2009;8(3):244-253.
  49. Burdach S, van Kaick B, Laws HJ, et al. Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol. 2000;11(11):1451-1462.
  50. Capitini CM, Derdak J, Hughes MS, et al. Unusual sites of extraskeletal metastases of Ewing sarcoma after allogeneic hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2009;31(2):142-144.
  51. 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. 2009;114(7):1429-1436.
  52. Storb R. Reduced-intensity conditioning transplantation in myeloid malignancies. Curr Opin Oncol. 2009;21 Suppl 1:S3-S5.
  53. Duvic M, Donato M, Dabaja B, et al. Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome. J Clin Oncol. 2010;28(14):2365-2372.
  54. Shevchenko JL, Kuznetsov AN, Ionova TI, et al. Autologous hematopoietic stem cell transplantation with reduced-intensity conditioning in multiple sclerosis. Exp Hematol. 2012;40(11):892-898.
  55. Armeson KE, Hill EG, Costa LJ. Tandem autologous vs autologous plus reduced intensity allogeneic transplantation in the upfront management of multiple myeloma: Meta-analysis of trials with biological assignment. Bone Marrow Transplant. 2013;48(4):562-567.
  56. Velazquez-Sanchez-de-Cima S, Zamora-Ortiz G, Hernandez-Reyes J, et al. Oral versus intravenous fludarabine as part of a reduced-intensity conditioning for allogeneic stem cell transplantation. Acta Haematol. 2014;132(1):125-128.
  57. AlJohani NI, Thompson K, Hasegawa W, et al. Non-myeloablative allogeneic hematopoietic transplantation for patients with hematologic malignancies: 9-year single-centre experience. Curr Oncol. 2014;21(3):e434-e440.
  58. Hong S, Le-Rademacher J, Artz A, et al. Comparison of non-myeloablative conditioning regimens for lymphoproliferative disorders. Bone Marrow Transplant. 2015;50(3):367-374.
  59. Zegers IH, Aaldering KN, Nieuwhof CM, Schouten HC. Non-myeloablative allogeneic stem cell transplantation: A new treatment option for acquired angioedema? Neth J Med. 2015;73(8):383-385.
  60. Cicardi M. Acquired C1 inhibitor deficiency: Management and prognosis. UpToDate Inc., Waltham, MA. Last reviewed May 2016.
  61. Zuraw B, Bingham CO. An overview of angioedema: Clinical features, diagnosis, and management. UpToDate Inc., Waltham, MA. Last reviewed May 2016.
  62. Kuriyama T, Kato K, Sakamoto K, et al. Cord blood transplantation following reduced-intensity conditioning for adult-onset inherited hemophagocytic lymphohistiocytosis. Intern Med. 2016;55(6):667-671.
  63. McClain KL. Treatment and prognosis of hemophagocytic lymphohistiocytosis. UpToDate Inc., Waltham, MA. Last reviewed May 2016.
  64. Choi EJ, Lee JH, Lee JH, et al. Non-myeloablative conditioning for lower-risk myelodysplastic syndrome with bone marrow blasts less than 5 % -- a feasibility study. Ann Hematol. 2016;95(7):1151-1161.
  65. Ahmad I, LeBlanc R, Cohen S, et al. Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation. Bone Marrow Transplant. 2016;51(4):529-535.
  66. Nelson AS, Marsh RA, Myers KC, et al. A reduced-intensity conditioning regimen for patients with dyskeratosis congenita undergoing hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(5):884-888.
  67. Yokoi K, Akiyama K, Kaneshiro E, et al. Effect of donor chimerism to reduce the level of glycosaminoglycans following bone marrow transplantation in a murine model of mucopolysaccharidosis type II. J Inherit Metab Dis. 2015;38(2):333-340.
  68. Nino N, Kozaki A, Hasegawa D, et al. Successful non-myeloablative allogenic bone marrow transplantation in a child with severe congenital neutropenia complicated by chronic pulmonary infection. Rinsho Ketsueki. 2016;57(6):742-747.
  69. Yokoi T, Yokoi K, Akiyama K, et al. Non-myeloablative preconditioning with ACK2 (anti-c-kit antibody) is efficient in bone marrow transplantation for murine models of mucopolysaccharidosis type II. Mol Genet Metab. 2016;119(3):232-238.
  70. Wynn R. Mucopolysaccharidoses: Complications and management. UpToDate Inc., Waltham, MA. Last reviewed April 2017.