0627 hematopoietic cell transplantation for aplastic anemia ......2018/09/06 · allogeneic bone...

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

Hematopoietic CellTransplantation for AplasticAnemia and other Bone Marrow Failure Syndromes

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last

Review

09/06/2018

Effective: 06/28/200

Next Review:

06/27/2019

Review History

Definitions

Number: 0627

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

Aetna considers allogeneic hematopoietic cell transplantation medically necessary

for the treatment of severe aplastic anemia, Diamond-Blackfan anemia, Fanconi's

anemia, paroxysmal nocturnal hemoglobinuria, and pure red cell aplasia when

members meet the transplanting institution's selection criteria.

In the absence of a institution's selection criteria, Aetna considers allogeneic

hematopoietic cell transplantation medically necessary for the treatment of severe

aplastic anemia when the member has at least 3 of the 4 following features:

Bone marrow cellularity less than 25 % (markedly hypocellular)

Neutrophil count less than 0.5 x 109/L

Reticulocyte count less than 1 % or less than 20 x 109/L (corrected for

hematocrit)

Untransfused platelet count less than 20 x 109/L

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In the absence of a institution's selection criteria, Aetna considers allogeneic

hematopoietic cell transplantation medically necessary for the treatment of pure red

cell aplasia when the member has the following features.

Bone marrow cellularity less than 25 % (markedly hypocellular); and

Reticulocyte count less than 1 % or less than 20 x 109/L (corrected for

hematocrit).

In the absence of an institution's selection criteria, Aetna considers allogeneic

hematopoietic cell transplantation medically necessary for the treatment of

Diamond-Blackfan anemia in persons who are refractory to corticosteroids.

In the absence of an institution's selection criteria, Aetna considers allogeneic

hematopoietic cell transplantation medically necessary for Fanconi's anemia in

persons with severe bone marrow failure, myelodysplastic syndrome, or acute

myelogenous leukemia.

In the absence of an institution's selection criteria, Aetna considers

allogeneic hematopoietic cell transplantation medically necessary in persons with

paroxysmal nocturnal hemoglobinuria with ongoing transfusion requirements and a

suitable HLA-matched donor.

Aetna considers repeat allogeneic stem cell transplantation medically necessary for

primary graft failure, failure to engraft or rejection in severe aplastic anemia,

Diamond-Blackfan anemia, Fanconi's anemia, paroxysmal nocturnal

hemoglobinuria, and pure red cell aplasia.

Aetna considers autologous hematopoietic cell transplantation experimental and

investigational for the treatment of severe aplastic anemia, Diamond-Blackfan

anemia, Fanconi's anemia, paroxysmal nocturnal hemoglobinuria, and pure red cell

aplasia because its effectiveness for these indications has not been established.

Background

Aplastic anemia (AA) is characterized by peripheral blood pancytopenia, resulting

from a failure of the bone marrow to produce blood cells. In the United States, it

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has an age-adjusted incidence of 2.2 per million populations per year. Pathogenic

mechanisms for AA vary and include intrinsic defects of hematopoietic stem cells,

defects in the marrow micro-environment, and abnormal humoral or cellular

immune control of hematopoiesis. In most patients, AA is of unknown etiology

(idiopathic), whereas in some, the disease can be secondary to infections, drugs or

toxin exposure, and hereditary causes (e.g., Fanconi's anemia or Diamond-

Blackfan syndrome). Severe AA is defined by the presence of neutrophils less than

0.5 x 109/L, platelets less than 20 x 109/L, reticulocytes less than 1 %, and bone

marrow cellularity less than 20 %. When 3 of 4 of these symptoms are present, the

median survival without therapy is about 3 months, with only 20 % of patients

surviving for 12 months. Currently, 2 definitive treatments are available for patients

with severe AA: (i) immuno-suppressive therapy (IST) that includes the use of

anti-thymocyte globulin, cyclosporine, and c yclophosphamide; and (ii)

allogeneic bone marrow transplantation (ABMT). The benefits of each are

comparable. However, certain subsets of patients derive superior benefit from one

or the other.

Allogeneic bone marrow transplantation from human leukocyte antigen (HLA)

-matched, related donors is generally accepted as the initial treatment of choice for

young patients (less than 20 years old). It results in the complete reconstitution of

hematopoiesis, whereas autologous hematopoietic remissions after IST are more

susceptible to relapse. The literature indicates that survival rates after ABMT, in

patients between the ages of 20 and 40, are comparable to those reported for IST.

Better survival rates after ABMT have been attained with improved conditioning

regimens and graft-versus-host disease (GVHD) prophylaxis. Best current results

demonstrate long-term, event-free survivals with successful allografts on the order

of 90 %. Long-term complications after ABMT include GVHD and secondary

neoplasms. The role of ABMT from an unrelated donor is being investigated.

For patients older than 40, the generally accepted treatment of choice is IST, which

entails the combination of anti-thymocyte globulin and cyclosporin A. A variable

proportion of patients (ranging from 20 to 80 %) respond to IST. However, although

responses may be frequent, long-term outcome is guarded because some patients

may relapse and others may develop a clonal disorder, including myelodysplasia,

leukemia, or paroxysmal nocturnal hemoglobinuria. Long-term complications of IST

include recurrence and development of clonal myeloid disorders.


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In a review on ABMT for the treatment of AA, Horowitz (2000) stated that long-term

survival rates ranged from less than 40 to more than 90 % in reported series.

These rates have improved over the past 20 years due to significant reductions in

GVHD, interstitial pneumonitis, and early transplant-related mortality. Most long

term survivors have excellent performance status. Late complications such as

cataracts, thyroid disorders, joint problems, and therapy-related cancers are

observed, especially in patients who received radiation for pre-transplant

conditioning. Results are best in young patients transplanted with bone marrow

from a HLA-identical sibling; early transplantation is appropriate in this group. For

older patients or those without an HLA-identical related donor, transplants are

better reserved for those who fail to respond to IST.

Kojima and co-workers (2000a) compared the long-term outcome of acquired AA in

children treated with IST or ABMT. They recommended ABMT as first-line therapy

in pediatric severe AA patients with an HLA-matched family donor. Alternative

donor ABMT was recommended as salvage therapy in patients who relapsed or did

not respond to initial IST. In a Consensus Conference on the Treatment of Aplastic

Anemia, the participants recommended that the number of courses of IST for non-

responders before unrelated ABMT consideration to be 1 for children and 2 for

adults (Kojima et al, 2000b).

Bone marrow failure (BMF) syndromes entail a broad group of diseases of varying

etiologies, in which hematopoeisis is abnormal or completely arrested in one or

more cell lines. Bone marrow failure syndromes can be an acquired AA or can be

congenital, as part of such syndromes as Fanconi anemia (FA), Diamond Blackfan

anemia (DBA), and Schwachman Diamond syndrome. Hematopoietic bone

marrow/stem cell transplantation is a therapeutic option for patients with BMF

syndromes (Steele et al, 2006, Myers and Davies, 2009, Mehta et al, 2010).

In a report from the Aplastic Anemia Committee of the Japanese Society of

Pediatric Hematology on hematopoietic stem cell transplantation (HSCT) for DBA,

Mugishima et al (2007) stated that transfusion-dependent DBA patients opt for

allogeneic HSCT as curative therapy. These investigators analyzed clinical

outcomes of 19 transplanted Japanese patients. Prior to HSCT, 10 patients (53 %)

suffered hemosiderosis with organ dysfunction, and all 8 with short stature (42 %)

had adverse effects of prednisolone. Median age at the time of HSCT was 56

months. Transplantation sources were 13 bone marrow (6 HLA-matched siblings,

and 6 HLA-matched and 1 HLA-mismatched unrelated donors), 5 cord blood (2


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HLA-matched siblings and 3 HLA-mismatched unrelated donors), and 1 peripheral

blood from haploidentical mother. All 13 patients with BMT and 2 with sibling cord

blood transplantation (CBT) had successful engraftment. Of 3 patients who

underwent unrelated CBT, 1 died after engraftment, and the other 2 had graft

failure but succeeded in a second BMT from an HLA-disparate father and unrelated

donor, respectively. One died shortly after haploidentical PBSCT. The 5-year failure-

free survival rate after BMT was higher than CBT (100 %: 40 %, p = 0.002). Platelet

recovery was slower in 7 unrelated BMT than in 6 sibling BMT (p = 0.030). No other

factors were associated with engraftment and survival. These results suggested that

allogeneic BMT, but not unrelated CBT, is an effective HSCT for refractory DBA.

In a report from the Italian pediatric group, Locatelli and colleagues (2007) noted

that HSCT represents the only treatment potentially able to prevent/rescue the

development of marrow failure and myeloid malignancies in patients with FA. While

in the past HSCT from an HLA-identical sibling was proven to cure many patients, a

higher incidence of treatment failure has been reported in recipients of an unrelated

donor (UD) or HLA-partially matched related allograft. These researchers

analyzed the outcome of 64 FA patients (age range of 2 to 20 years) who

underwent HSCT between January 1989 and December 2005. Patients were

transplanted from either an HLA-identical sibling (n = 31), an UD (n = 26), or an

HLA-partially matched relative (n = 7). T-cell depletion of the graft was performed

in patients transplanted from an HLA-disparate relative. The 8-year estimate of

overall survival (OS) for the whole cohort was 67 %; it was 87 %, 40 % and 69 %

when the donor was an HLA-identical sibling, an UD, and a mis-matched relative,

respectively (p < 0.01). The outcome of recipients of grafts from an UD improved

over time, the probability of survival being 10 % and 72 % for patients transplanted

before and after 1998, respectively (p < 0.05). The OS probability of children who

did or did not receive fludarabine in preparation for the allograft was 86 % and 59

%, respectively (p < 0.05). These data provided support to the concept that a

relevant proportion of FA patients undergoing HSCT can now be successfully

cured, even in the absence of an HLA-identical sibling, especially if the conditioning

regimen includes fludarabine.

Roth and colleagues (2009) stated that paroxysmal nocturnal hemoglobinuria

(PNH) is characterized by the clinical triad of corpuscular hemolytic anemia,

thrombophilia, and cytopenia. This is caused by an acquired mutation of the PIG

(phosphatidylinositol glycan)-A gene of the pluripotent hematopoetic stem cell. This

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results in a deficiency of GPI (glycosylphosphatidylinositol)-anchors and GPI-

anchored proteins on the surface of affected blood cells. Flow cytometry is the

standard for diagnosis and measurement of type and size of the PNH clone.

Treatment of PNH is mainly symptomatic. Allogeneic BMT is the only curative

option in case of severe complications during the course of the diseases.

Li and colleagues (2013) noted that although high-dose cyclophosphamide seems

to achieve durable complete remission, there are still concerns about its too much

early toxicity. Thus, these researchers designed a clinical study to examine the

effects of high-dose cyclophosphamide/anti-thymocyte globulin (ATG) combined

with cord blood infusion as first-line therapy for patients with severe AA. Between

January 2003 and September 2007, these investigators treated 16 treatment-naive

patients with severe AA with cord blood infusion after high-dose cyclophosphamide

(50 mg/kg/day × 2) and rabbit ATG (3 mg/kg/day × 5) therapy. Although only 1

patient had durable full donor engraftment, 14 of the enrolled 16 patients had rapid

autologous hematopoietic recovery. The median recovery time for neutrophils and

platelets was only 23 and 37 days after infusion of cord blood. Of the 15

responding patients, all patients achieved treatment-free remission: 9 patients met

the criteria for a complete remission; 6 patients achieved a partial remission. The

authors concluded that infusion of cord blood after high-dose

cyclophosphamide/ATG resulted in a rapid autologous hematologic recovery and a

high response rate in patients with treatment-naive patients with severe AA. They

stated that these promising results merit further investigation and confirmation on a

larger number of patients.

An UpToDate review on “Aplastic anemia: Prognosis and treatment” (Schrier, 2013)

states that “Only a fraction of patients with severe aplastic anemia in first or second

complete remission are able to mobilize sufficient stem cells to undergo autologous

hematopoietic cell transplantation (HCT). Accordingly, patients with relapsing or

resistant disease, who have even fewer mobilizable stem cells than those in

remission, are not candidates for autologous HCT". Furthermore, an UpToDate

review on “Hematopoietic cell transplantation in aplastic anemia” (Negrin, 2013)

recommends the use of allogeneic HCT; it does not mention the use of autologous

HCT as a therapeutic option.


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UpToDate reviews on “Hematopoietic cell transplantation for Diamond-Blackfan

anemia and the myelodysplastic syndromes in children” (Khan, 2013) and

“Hematopoietic cell transplantation for idiopathic severe aplastic anemia and

Fanconi anemia in children” (Khan and Negrin, 2013) do not mention the use of

autologous HCT as a therapeutic option.

An UpToDate review on “Diagnosis and treatment of paroxysmal nocturnal

hemoglobinuria” (Rosse, 2013) states that “autologous transplantation is unlikely to

be successful because of the difficulty in obtaining sufficient numbers of normal

stem cells”.

In a Cochrane review, Peinemann and associates (2013) evaluated the

effectiveness and adverse events of first-line allogeneic HSCT of HLA-matched

sibling donors compared to first-line immunosuppressive therapy including

cyclosporine and/or anti-thymocyte or anti-lymphocyte globulin in patients with

acquired severe AA. The authors concluded that there are insufficient and biased

data that do not allow any conclusions to be made about the comparative

effectiveness of first-line allogeneic HSCT of an HLA-matched sibling donor and

first-line treatment with cyclosporine and/or anti-thymocyte or anti-lymphocyte

globulin (as first-line immunosuppressive therapy). These investigators stated that

they were unable to make firm recommendations regarding the choice of

intervention for treatment of acquired severe AA.

Williams and colleagues (2014) noted that randomized clinical trials in pediatric AA

are rare and data to guide standards of care are scarce. Eighteen pediatric

institutions formed the North American Pediatric Aplastic Anemia Consortium

(NAPAAC) to foster collaborative studies in AA. The initial goal of NAPAAC was to

survey the diagnostic studies and therapies utilized in AA. The survey indicated

considerable variability among institutions in the diagnosis and treatment of AA.

There were areas of general consensus, including the need for a bone marrow

evaluation, cytogenetic and specific fluorescent in-situ hybridization assays to

establish diagnosis and exclude genetic etiologies with many institutions requiring

results prior to initiation of IST; uniform referral for HSCT as first line therapy if an

HLA-identical sibling is identified; the use of first-line IST containing horse anti

thymocyte globulin and cyclosporine A (CSA) if an HLA-identical sibling donor is not

identified; supportive care measures; and slow taper of CSA after response. Areas

of controversy included the need for telomere length results prior to IST, the time

after IST initiation defining a treatment failure; use of hematopoietic growth factors;


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the preferred rescue therapy after failure of IST; the use of specific hemoglobin and

platelet levels as triggers for transfusion support; the use of prophylactic antibiotics;

and follow-up monitoring after completion of treatment. The authors concluded that

these initial survey results reflected heterogeneity in diagnosis and care amongst

pediatric centers and emphasized the need to develop evidence-based diagnosis

and treatment approaches in this rare disease.

Aplastic anemia is a disorder characterized by the presence of pancytopenia and a

hypo-cellular bone marrow. Acquired pure red cell aplasia (PRCA), a part of a

unique form of AA, is a rare condition of profound anemia characterized by the

absence of reticulocytes and the virtual absence of erythroid precursors in the bone

marrow.

An UpToDate review on “Determining eligibility for allogeneic hematopoietic cell

transplantation” (Deeg and Sandmaier, 2014) states that “In general, allo-HCT may

be considered in the following settings …. Nonmalignant inherited and acquired

marrow disorders -- Treatment of sickle cell anemia, beta-thalassemia major,

refractory Diamond-Blackfan anemia, myelodysplastic syndrome, idiopathic severe

aplastic anemia, paroxysmal nocturnal hemoglobinuria, pure red cell aplasia,

Fanconi anemia, amegakaryocytosis, or congenital thrombocytopenia”.

Second Hematopoietic Stem Cell Transplantation for Graft Failure in Adult Patients with Severe Aplastic Anemia

Yahng and colleagues (2018) stated that data regarding the optimal approach for

2nd allogeneic HSCT (allo-HSCT) after graft failure (GF) in acquired severe AA

(SAA) are still limited and heterogeneous. These researchers examined 24

patients who underwent 2nd HLA-matched sibling donor (MSD) peripheral blood

HSCT for GF. The re-conditioning regimen (TNI-750/ATG) consisted of a single-

dose of total nodal irradiation (TNI, 750 cGy) and anti-thymocyte globulin (ATG;

Thymoglobulin, 1.25 mg/kg/day for 3 days). All but 1 patient achieved successful

engraftment of neutrophils (median of 12 days, range of 5 to 21) and platelets

(median of 15 days, range of 9 to 316); 2 patients with subsequent secondary GF

achieved successful engraftment after a 3rd HSCT from the same MSD. After a

median follow-up of 57.4 months (range of 11.2 to 155.2), the 5-year OS and

failure-free survival were 95.7 % (95 % confidence interval [CI]: 87.7 % to 100 %)

and 87.5 % (95 % CI: 75.2 % to 100 %), respectively; 1 patient developed grade II

acute GVHD, and the 2-year cumulative incidence of chronic GVHD was 23.5 %


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(95 % CI: 8.1 % to 43.5 %). The authors concluded that the findings of this study

demonstrated successful outcomes following a 2nd MSD HSCT in SAA after GF,

and the results suggested TNI-750/ATG is a feasible re-conditioning option.

CPT Codes / HCPCS Codes / ICD-10 Codes

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

Transplantation - Allogeneic:

CPT codes covered if selection criteria are met:

38230 Bone marrow harvesting for transplantation; allogeneic

38240 Hematopoietic progenitor cell (HPC); allogeneic transplantation per

donor

86813 HLA typing; A, B or C multiple antigens

86817 DR/DQ, multiple antigens

86821 lymphocyte culture, mixed (MCL)

86822 lymphocyte culture, primed (PLC)

Other CPT codes related to the CPB:

38204 - 38215 Bone marrow or stem cell services/procedures

85004 - 85049 Blood count

85055 Reticulated platelet assay

85060 Blood smear, peripheral, interpretation by physician with written report

85097 Bone marrow, smear interpretation

86920 - 86923 Compatibility test each unit

HCPCS codes covered if selection criteria are met:

ICD-10 codes covered if selection criteria are met:


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D59.5

D60.0 - D61.9

T86.5

Z94.84

Transplantation - Autologous:

CPT codes not covered for indications listed in the CPB:

The above policy is based on the following references:

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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

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

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Copyright © 2001-2019 Aetna Inc.

http://www.aetna.com/cpb/medical/data/600_699/0627.html 09/24/2019 Proprietary


AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0627 Hematopoietic

Cell Transplantation for Aplastic Anemia and other Bone Marrow Failure Syndromes

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania annual 10/01/2019

http://www.aetnabetterhealth.com/pennsylvania

0627 hematopoietic cell transplantation for aplastic anemia ......2018/09/06 · allogeneic bone...

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