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):

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):

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".

Scope of Policy

This Clinical Policy Bulletin addresses non-myeloablative hematopoietic cell transplantation (mini-allograft / reduced intensity conditioning transplant).

Medical Necessity

Experimental and Investigational

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):