0634 Non-myeloablative Hematopoietic Cell Transplantation ......Transplantation (EBMT) Workshop on allogeneic hematopoietic stem cell transplantation (HSCT) following non-myeloablative

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(https://www.aetna.com/)

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

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last

Review

02/26/2019

Effective: 08/02/200

Next Review:

06/27/2019

Review History

Definitions

Number: 0634

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

I. 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.

Acute lymphoblastic leukemia ( ALL, see

CPB 0640 - Hematopoietic Cell Transplantation for Selected Le ukemias

(0640.html)

Proprietary

http://www.aetna.com/cpb/medical/data/600_699/0634.html 09/24/2019

http://www.aetna.com/cpb/medical/data/600_699/0634.html

https://www.aetna.com/

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Acute myelogenous leukemia (AML,

CPB 0640 - Hematopoietic Cell Transplantation for Selected Leukemias

see (0640.html)

Aplastic anemia ( AA) (including paroxysmal nocturnal hemoglobinuria

(PNH),

CPB 0627 - Hematopoietic Cell Transplantation for Aplastic

see Anemia//Bone Marrow Failure Syndromes (0627.html)

Chronic lymphocytic leukemia (CLL)

CPB 0494 - Hematopoietic Cell Transplantation for Non-Hodgkin's

(see Lymphoma (../400_499/0494.html)

Chronic myelogenous leukemia (CML)

CPB 0674 - Hematopoietic Cell Transplantation for Chronic Myelogenous

(see Leukemia (0674.html)

Hodgkin's disease (HD,

CPB 0495 - Hematopoietic Cell Transplantation for Hodgkin's Disease

see (../400_499/0495.html)

Multiple myeloma (MM,

CPB 0497 - Hematopoietic Cell Transplantation for Multiple Myeloma

see (../400_499/0497.html)

Myelofibrosis (see

CPB 0838 - Hematopoietic Cell Transplantation for Myelofibrosis

(../800_899/0838.html)

Myelodysplasia/myelodysplastic syndrome (see

CPB 0836 - Hematopoietic Cell Transplantation for Myelodysplastic

Syndrome (../800_899/0836.html)

Neuroblastoma

CPB 0496 - Hematopoietic Cell Transplantation for Selected Childhood

(see Solid Tumors (../400_499/0496.html)

Non-Hodgkin's lymphoma (NHL,

CPB 0494 - Hematopoietic Cell Transplantation for Non-Hodgkin's

see Lymphoma (../400_499/0494.html)

Sickle cell anemia

CPB 0626 - Hematopoietic Cell Transplantation for Thalassemia Major

(see and S ickle Cell Anemia (0626.html)

Thalassemia major

CPB 0626 - Hematopoietic Cell Transplantation for Thalassemia Major

(see and S ickle Cell Anemia (0626.html)

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II. 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):

Acquired angioedema

Autoimmune diseases

CPB 0606 - Hematopoietic Cell Transplantation for Autoimmune

(see Diseases and M iscellaneous Indications (0606.html)

Breast cancer

CPB 0507 - Hematopoietic Cell Transplantation for Breast Cancer

(see (../500_599/0507.html)

Essential thrombocythemia and p olycythemia

CPB 0606 - Hematopoietic Cell Transplantation for Autoimmune

vera (see Diseases and M iscellaneous Indications (0606.html)

Inherited hemophagocytic lymphohistiocytosis

Melanoma

CPB 0811 - Hematopoietic Cell Transplantation for Solid T umors in

(see Adults (../800_899/0811.html)

Ovarian cancer

CPB 0635 - Hematopoietic Cell Transplantation for Ovarian Cancer

(see (0635.html)

Renal cancer

CPB 0811 - Hematopoietic Cell Transplantation for Solid T umors in

(see Adults (../800_899/0811.html)

Testicular cancer

CPB 0617 - Hematopoietic Cell Transplantation for Testicular Cancer

(see (0617.html)

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

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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

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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

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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

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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

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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.

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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

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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.

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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

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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”.

CPT Codes / HCPCS Codes / ICD-10 Codes

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

CPT codes covered if selection criteria are met:

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Code Code Description

38204 - 38205,

38207 - 38215,

38230 - 38240

Bone marrow or stem cell services/procedures-allogenic and

transplantation and po st-transplantation cellular i nfusions

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 n umber 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

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Code Code Description

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

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D76.1 Hemophagocytic lymphohistiocytosis

D80.0 - D89.9

L93.0 - L93.2

M02.30 - M02.39

T78.3xxA -

T78.3xxS

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.

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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.

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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.

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.

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Page 18 of 23

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 I nsights 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.

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.

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http://www.medscape.com/viewarticle/436456_1

http://www.mdanderson.org/publications/insights/

Page 19 of 23

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.

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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.

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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 [online serial]. Waltham, MA: UpToDate; reviewed May 2016.

61. Zuraw B, Bingham CO. An overview of angioedema: Clinical features,

diagnosis, and management. UpToDate [online serial]. Waltham, MA:

UpToDate; 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 [online serial]. Waltham, MA:

UpToDate; 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

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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 [online serial]. Waltham, MA: UpToDate; reviewed April 2017.

71. Zhang ZH, Lian XY, Yao DM, et al. Reduced intensity conditioning of

allogeneic hematopoietic stem cell transplantation for myelodysplastic

syndrome and acute myeloid leukemia in patients older than 50 years of

age: a systematic review and meta-analysis. J Cancer Res Clin Oncol.

2017;143(9):1853-1864.

72. Yucel OK, Saliba RM, Rondon G, et al. Cytogenetics and comorbidity predict

outcomes in older myelodysplastic syndrome patients after allogeneic

stem cell transplantation using reduced intensity conditioning. Cancer.

2017;123(14):2661-2670.

73. de Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell

transplantation for MDS and CMML: Recommendations from an

international expert panel. Blood. 2017;129(13):1753-1762.

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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan

benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial,

general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care

services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in

private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible

for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to

change.

Copyright © 2001-2019 Aetna Inc.

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0634 Non

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

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania updated 02/26/2019 Proprietary

http://www.aetnabetterhealth.com/pennsylvania

Documents

0634 Non-myeloablative Hematopoietic Cell Transplantation ......Transplantation (EBMT) Workshop on allogeneic hematopoietic stem cell transplantation (HSCT) following non-myeloablative