hematopoietic cell transplantation for hodgkin's disease

Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy Bull... of 32

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

Hematopoietic Cell Transplantation for Hodgkin's Disease

Policy History

Last Review

10/23/2019

Effective: 02/01/2002

Next

Review: 05/08/2020

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0495

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

I. Autologous Hematopoietic Cell Transplantation

Aetna considers autologous hematopoietic cell

transplantation medically necessary for the treatment of

Hodgkin's disease (HD) when the member meets the

transplanting institution's selection criteria. In the

absence of such criteria, Aetna considers autologous

hematopoietic cell transplantation medically necessary

for the treatment of HD when both of the following

selection criteria are met:

A. The member is in primary induction failure or

beyond first remission; and

B. The member is without serious organ dysfunction

based on the transplanting institution's evaluation.

II. Allogeneic Hematopoietic Cell Transplantation

PPrropoprrietietaarryy

https://www.aetna.com/


Aetna considers allogeneic hematopoietic cell

transplantation medically necessary for the treatment of

members with relapsed HD (including members who

have relapsed or have had persistent disease from an

autologous hematopoietic cell transplant) or primary

refractory HD when the member meets the

transplanting institution's selection criteria. In the

absence of such criteria, Aetna considers allogeneic

hematopoietic cell transplantation medically necessary

for the treatment of members with relapsed or primary

refractory HD when both of the following selection

criteria are met:

A. The member is in primary induction failure or beyond

first remission; and

B. The member is without serious organ dysfunction

based on the transplanting institution's evaluation.

Note: Aetna considers non-myeloablative

allogeneic hematopoietic cell transplantation ("mini-transplant,"

reduced intensity conditioning transplant) medically necessary

for the treatment of members with relapsed HD (including

members who have relapsed or have had persistent disease after

an autologous hematopoietic cell transplant) or primary

refractory HD when they are eligible for conventional

allografting.

III. Tandem Transplants

Aetna considers tandem (also known as sequential) transplants

experimental and investigational for the treatment of HD because

insufficient evidence of its effectiveness and safety for this

indication.

Note: Relapse is the re-appearance of disease in regions of

prior disease (recurrence) and/or in new regions (extension)

after initial therapy and attainment of complete response.



See also

CPB 0823 - Brentuximab (Adcetris) (../800_899/0823.html).

Background

Hodgkin's disease (HD) is an enigmatic lymphoid malignancy

whose cell of origin has remained a mystery since the disease

was first described in 1825. The hallmark of the disease is

effacement of the normal lymph node architecture by a

heterogeneous infiltration of normal appearing lymphocytes,

plasma cells, eosinophils and fibroblasts. The one

characteristic component, and presumably the malignant

component, is the Reed Sternberg cell (or one of its variants),

a large binucleate cell with prominent nucleoli. Hodgkin's

disease is subdivided into 4 subtypes: (i) lymphocytic

predominant (15 % of cases), (ii) nodular sclerosing (70 %),

(iii) mixed cellularity (10 %), and (iv) lymphocyte depleted (5

%). Both the lymphocyte predominant and nodular sclerosing

variants are more common in adolescents and young adults.

Mixed cellularity and lymphocyte depleted are more common

in older patients and frequently present with advanced

disease.

The following staging system for HD recognizes the fact that

HD is thought to typically arise in a single lymph node and

spread to contiguous lymph nodes with eventual involvement

of extranodal sites. The staging system attempts to distinguish

patients with localized HD who can be treated with extended

field radiation from those who require systemic chemotherapy.

Staging for Hodgkin's Disease

Stage I:

Involvement of a single lymph node region or a lymphoid

structure such as the spleen, thymus, Waldeyer's ring (I) or

involvement of a single extra-lymphatic organ or site (IE)



Stage II:

Involvement of 2 or more lymph node regions on the same

side of the diaphragm (hilar nodes, when involved on both

sides, constitute Stage II); localized contiguous involvement of

only 1 extra-nodal organ or site and lymph node region on the

same side of the diaphragm (IIE). The number of lymph node

regions involved should be indicated by a subscript (e.g., II3)

Stage III:

Involvement of lymph node regions or structures on both sides

of the diaphragm (III), which may also be accompanied by

involvement of the spleen (IIIS) or by localized contiguous

involvement of only 1 extra-nodal organ site (IIIE) or both

(IIIE+S). These patients are further subdivided as follows:

III1: with or without involvement of splenic, hilar, celiac,

or portal lymph nodes

III2: with involvement of paraaortic, iliac, and/or

mesenteric lymph nodes

Stage IV:

Diffuse or disseminated Involvement of 1 or more extra-nodal

organs or tissues, with or without associated lymph node

involvement, or isolated extra-lymphatic organ involvement

with distant (non-regional) nodal involvement

Additional Designations Applicable to any Disease Stage

A: No symptoms

B: Unexplained fever (temperature greater than 38° C),

drenching night sweats, unexplained weight loss of greater

than 10 % body weight within the preceding 6 months.

Pruritus alone does not qualify for B classification, nor does a



short febrile illness associated with an infection

X: Bulky disease (a widening of the mediastinum by greater

than 1/3 or the presence of a nodal mass with a maximal

dimension greater than 10 cm)

E: Involvement of a single extra-nodal site that is contiguous

or proximal to a known nodal site

CS: Clinical stage

PS: Pathological stage (as determined by laparotomy)

Staging of HD includes not only the sites of involvement, but

also other factors described by the letters A, B, X, E above,

i.e., a patient could have Stage IIB HD, indicating involvement

of 2 or more lymph node groups on the same side of the

diaphragm with the presence of systemic symptoms. Those

patients initially considered candidates for radiation therapy

alone may undergo a staging laparotomy to determine if the

disease is truly localized or not.

Treatment of HD involves the use of radiation therapy alone

(for Stage I and II disease), the use of chemotherapy (for

Stage IIIB and IV), or combined radiation and chemotherapy

(for patients with bulky disease and for some patients with

Stage IIIA disease). Radiation therapy typically consists of

treatment not only of the involved sites, but also lymphoid

regions adjacent to the involved areas and prophylactic

treatment to uninvolved areas. This frequently takes the form

of mantle irradiation to the mediastinum and an "inverted Y"

irradiation of the periaortic lymph nodes, extending down to

encompass the pelvic lymph nodes. Prolonged relapse free

survival in patients with Stage IA or IIA treated with total nodal

irradiation is estimated at 82 %.



Despite the generally favorable results of irradiation and

chemotherapy, relapses can occur in up to 40 % of those

patients with advanced (Stage III or IV) disease treated with

chemotherapy. In many instances, relapsed HD remains

sensitive to the original chemotherapy used, indicating that

relapses may not be related to the development of

chemoresistance, but instead point to the importance of

adequate dosing of chemotherapy. This observation also

forms the rationale for high dose chemotherapy (HDC).

High dose chemotherapy bone marrow or peripheral stem cell

transplant (autologous or allogeneic) is a treatment option for

selected patients with HD. The basic concept behind HDC is a

combination regimen of marrow ablative drugs which have

different mechanism of action to maximally eradicate the

malignant cells, and non-overlapping toxicity such that the

doses can be maximized as much as possible. Total body

irradiation (TBI) is an additional variable. Patients with the

disease who are responsive to standard doses of

chemotherapy, and are either asymptomatic or have a good

performance status and who do not have any serious co-

morbidities are considered optimal candidates for HDC.

Autologous bone marrow transplant (ABMT) or peripheral stem

cell transplant (ASCT) permits the use of chemotherapeutic

agents at doses that exceed the myelotoxicity threshold;

consequently, a greater tumor cell kill might be anticipated. It

has been suggested that the resultant effect is greater

response rate and possibly an increased cure rate.

Autologous bone marrow transplant entails the patient acting

as his/her own bone marrow donor. The patient's marrow is

harvested via aspiration from the iliac crests under general or

regional anesthesia. The marrow is then preserved and re-

infused following completion of a potent chemotherapy

regimen. This process provides pluripotent marrow stem cells

to reconstitute (i.e., rescue) the patient's marrow from the

myeloablative effects of high dose cytotoxic chemotherapeutic

agents.



Allogeneic bone marrow transplant refers to the use of

functional hematopoietic stem cells from a healthy donor to

restore bone marrow function following HDC. For patients with

marrow-based malignancies, the use of allogeneic stem cells

offers the advantage of lack of tumor cell contamination.

Furthermore, allogeneic stem cells may be associated with a

beneficial graft versus tumor effect.

Tandem (sequential) transplant protocols utilize a cycle of

HDC with ASCT followed in approximately 6 months by a

second cycle of HDC and/or TBI with another ASCT. This is

done in an attempt to obtain greater and extended response

rates. To date, there have been no definitive studies showing

that tandem transplants improve response rates, event-free

survival (EFS) or overall survival (OS) more than single

transplants for patients with HD. Therefore, tandem transplant

protocols are considered experimental and investigational.

In a clinical trial, Papadoupoulos and coleagues (2005)

assessed the effectiveness of a novel regimen of tandem HDC

(THDC) with autologous stem cell transplantation in the

treatment of patients with poor risk lymphoma. A total of 41

patients (median age of 40 years, range of 15 to 68 years) with

poor risk non-Hodgkin's lymphoma and HD were enrolled.

Tandem HDC consisted of melphalan (180 mg/m2) and

escalating dose mitoxantrone (30 to 50 mg/m2) (MMt) for the

1st conditioning regimen, and thiotepa (500 mg/m2),

carboplatin (800 mg/m2), and escalating dose etoposide

phosphate (400 to 850 mg/m2), (ETCb) as the 2nd regimen. In

all, 31 patients (76 %) completed both transplants, with a

median time between transplants of 55 days (range of 26 to

120 days). The maximum tolerated dose was determined as

40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide

phosphate. The overall toxic death rate was 12 %. Following

HDC, 10 of 24 evaluable patients (42 %) were in complete

remission. The 2-year OS and EFS is 67 % (95 % confidence

interval (CI): 52 % to 81 %) and 45 %, (95 % CI: 29 % to 61 %)

for the 41 patients enrolled; and 69 % (95 % CI: 525 % to 586



%) and 48 % (95 % CI: 30 % to 67 %) for the 31 patients

completing both transplants. This THDC regimen is feasible

but with notable toxicity in heavily pre-treated patients; its role

in the current treatment of high-risk lymphoma remains to be

determined.

Prior to HDC-ABMT, patients generally undergo induction

therapy with vincristine, doxorubicin and dexamethasone,

melphalan and prednisone or other combination salvage

regimens. Conventional dosages of these drugs can typically

be given on an outpatient basis. Hospitalization may be

required due to neutropenic fever, nausea and vomiting,

mucositis, diarrhea, or inadequate oral intake. Standard

severity of illness/intensity of service criteria should be applied

to these admissions.

Prior to peripheral stem cell collection, an apheresis catheter

may be inserted during an ambulatory surgical procedure.

The apheresis catheter can be placed during the same

anesthesia procedure if a bone marrow harvest is also

planned. Apheresis is usually performed daily on an

outpatient basis until adequate stem cells are collected.

Typically, from 5 to 10 procedures are necessary.

Stem cell mobilization, in which cyclophosphamide and/or GM-

CSF are used to flush the critical stem cells from the bone

marrow into the peripheral circulation, may also be part of the

stem cell collection. Protocols vary -- some institutions

administer intermediate doses of cyclophosphamide (4 g/m2)

as an outpatient procedure, followed by apheresis in 5 to 14

days when the blood counts have recovered. When high dose

cyclophosphamide (6 g/m2) is used, a hospitalization of about 4

days is required for pre- and post-chemotherapy hydration.

After completion of the cyclophosphamide regimen, the patient

can usually be discharged; apheresis can be administered on

an outpatient basis once the acute period of bone marrow

hypoplasia has resolved.



Hospitalization for the HDC component of the procedure

depends on the regimen. High-dose melphalan (140 to 200

mg/m2) can usually be given as an outpatient with home

hydration therapy. This outpatient HDC is the exception.

Other high-dose combination therapies, such as EDAP

(etoposide, dexamethasone, ara-C and cisplatin) usually

require hospitalization due to nausea and vomiting, mucositis,

diarrhea and inadequate oral intake. Any regimen that

includes TBI is likely to require a prolonged hospital stay,

usually averaging about 30 days. Patients receiving HDC with

or without TBI are usually initially treated in a private room for

about 1 week until the blood counts start to drop. Then,

patients are typically transferred to a specialized laminar flow

room for the duration of their hospital stay.

Usual length of stay for patients undergoing peripheral stem

cell collection with high- dose cyclophosphamide mobilization

is 4 days. Other stem cell mobilization protocols normally do

not require a hospital stay.

Usual length of stay for patients hospitalized for complications

related to HDC depend on resolution of fever (i.e., fever-free

for 48 hours while off all antibiotics), maintenance of adequate

blood counts (i.e., WBC greater than 500), and resolution of

other morbidities such as mucositis and diarrhea. The patient

must also be able to maintain adequate oral intake. Hospital

stays usually range from 2 to 4 weeks. Patients may be

discharged even if an adequate platelet count is transfusion

dependent; platelet transfusions can be given on an outpatient

basis.

Usual length of stay for patients undergoing HDC in

conjunction with TBI is 30 days. Discharge parameters are

similar to above: fever-free for 48 hours, adequate blood

counts (WBC greater than 1,000). Patients may be discharged

even if an adequate platelet count if transfusion dependent;

platelet transfusions can be given on an outpatient basis.


Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... of 32

Studies on Autologous Transplant

Gribben and colleagues (1989) reported the findings of a non-

randomized study in which a high-dose combination

chemotherapy regimen was followed by autologous bone

marrow rescue (ABMR). The study was comprised of 44

patients with active HD who were resistant to standard

regimen therapy. Previous treatments of the patients involved

in the study were reported as follows: 2 patients had received

front-line, alternating chemotherapy and failed to respond; they

progressed to ABMR. The remainder of the patients had

received at least 2 regimens of chemotherapy. In addition, 28

patients had also received radiotherapy. Of these 44 patients,

22 had never achieved a complete remission (CR), while the

other 22 had achieved a CR in response to first-line therapy

but relapsed. After the use of HDC and ABMR the following

results were described -- 23 patients achieved a partial

response (PR); 2 patients (initially classified as having a PR)

who presented with a residual mediastinal mass at 3 months

had slow resolution of the mass, and were classified as having

a CR 6 months after ABMR; 4 patients had demonstrated a

progressive decrease in the size of a residual mediastinal

mass over 10 to 33 months without receiving further treatment;

7 patients (initially classified as having a PR) underwent post-

ABMR radiotherapy to sites of residual disease, and 5 of these

patients subsequently achieved a CR; 4 patients did not

respond to HDC and ABMR, 3 of whom died within 6 months

of the procedure; and 2 patients died of complications related

to sepsis. In summary, 22 patients (50 %) achieved a CR 6

months after ABMR, and 4 other patients were free of disease

progression. Two patients relapsed from CR at 7 and 9

months following ABMR; they subsequently died from

progressive disease. According to the authors, the remaining

20 patients who achieved a CR remain in remission. They

concluded that the use of HDC followed by ABMR appears to

be an efficacious salvage regimen for patients with refractory

HD.



Chopra and associates (1993) reported the results of 155

patients with relapsed or resistant HD who were treated with

HDC followed by ABMR. At the time of transplant, 46 patients

were primarily refractory to induction therapy, 7 were good

partial responders, and 52 were in first relapse, 37 in second

relapse, and 13 in third relapse. At 3 months 43 (28 %)

patients were assessed as complete responders. Seventy-two

(46 %) patients were assessed to have partial responses

(PR). Twenty-four patients (16 %) showed no response or

progression. At 6 months, 53 patients were assessed as

complete responders. Thirteen patients in PR at 3 months had

achieved a CR by 6 months, this occurring in 8 patients after

radiotherapy to residual masses, and 5 patients without any

further treatment indicative of slow resolution of their tumor

masses. Fifty-one patients still had non-progressive disease

with persistent CT abnormalities, 26 patients had relapsed with

progressive disease, and 8 patients had died of progressive

HD. Overall, 104 of 155 (67 %) had a good response to

ABMR. By 6 months, there were 17 procedure-related

deaths. The actuarial OS at 5 years was 55 %, with a

progression-free survival (PFS) of 50 %. The authors found

that patients undergoing ABMR in second and third relapse

were faring significantly better than patients in first relapse and

primary refractory disease.

Bierman and co-workers (1993) examined the influence of pre-

transplant prognostic factors and evaluated long-term follow-

up in a group of 128 patients with HD. All patients in the study

were refractory to primary therapy, or had relapsed after

attaining a remission, and underwent HDC followed by ABMR.

Following transplantation, 57 (45 %) patients achieved CR; 9

(7 %) patients who were transplanted without evidence of

disease continued in remission following the transplant.

Seven (5 %) patients received localized radiation following

transplantation to areas of apparent residual disease, and they

converted to CR. In total, 73 (57 %) patients were in CR

following transplantation, 23 (18 %) patients achieved a PR,

and 21 (16 %) had no response. There were 11 (9 %) early



deaths. Among the 73 patients in CR following

transplantation, 34 have subsequently died; including 6 who

died without evidence of disease between 6 and 59 months

following transplantation. At the time of the report, 43 patients

were alive, including 28 who remain free from progression.

The median survival time for the entire patient group is 31.5

months, and the median failure-free survival time is 7.3

months. The estimated 4-year OS is 45 % and the 4-year

failure-free survival is estimated as 25 %. The authors

concluded that superior results were seen in patients without

extensive prior chemotherapy and in those with a good

performance status.

In a review, Mink and Armitage (2001) stated that ASCT has

proven to be beneficial in selected patients with HD.

Transplantation appeared to increase EFS in patients who

failed to enter complete remission with initial therapy. When a

patient relapses after a complete remission, transplantation is

probably the best option and particularly so if the remission

lasted less than 1 year. Transplantation as part of primary

therapy for very high-risk patients may be beneficial, but is not

standard therapy at this time. Lazarus et al (2001) reviewed

data from the Autologous Blood and Marrow Transplant

Registry (n = 414) to determine relapse, disease-free survival,

OS, and prognostic factors in patients with relapsed HD. They

concluded that autologous hematopoietic stem cell

transplantation (autotransplantation) should be considered for

patients with HD in first relapse or second remission.

Studies on Allogeneic Transplant

Lundberg and associates (1991) performed a non-randomized,

prospective study to ascertain whether HDC followed by

allogeneic bone marrow transplantation is an effective

treatment in relapsed or refractory lymphoma. The study

group consisted of 22 patients with relapsed or refractory

lymphoma. Seven patients had HD; the remaining 15 patients

had non-Hodgkin's lymphoma (NHL). The median age was 30



years. The treatment regimen consisted of the following:

cytarabine, cytoxan, TBI, and methylprednisolone. Seven

patients with significant bulky disease received localized

radiotherapy prior to the preparative regimen. Total body

irradiation was begun 48 hours after the last dose of

chemotherapy. Patients who had undergone radiotherapy

treatments were precluded from the use of standard TBI-

based regimens; thus, only myeloablative chemotherapy was

used in those patients. Patients who were treated with TBI

received graft-versus-host-disease prophylaxis with T-cell

depletion and cyclosporine. The authors recounted the

following results in the 7 patients with HD: 4 patients were

alive; 3 in CR (19 to 43 months post-transplant) and 1 with

recurrent lymphoma. The remaining 3 patients died due to the

following complications; (i) aspergillus, (ii) hepatic veno

occlusive-disease, and (iii) recurrent lymphoma. The

authors concluded that, allogeneic bone marrow

transplantation appeared superior to salvage chemotherapy

for the achievement of long-term, lymphoma-free survival and

may be preferable to autologous bone marrow transplantation

for selected patients.

Anderson and colleagues (1993) carried out a non-

randomized, prospective study on 127 patients undergoing

myeloablative therapy for relapsed or refractory HD. The

purpose of the study was to determine efficacy of transplant

(autologous or allogeneic) post-failure of MOPP

(mechlorethamine, vincristine, procarbazine, and prednisone) -

and ABVD (adriamycin, bleomycin, vinblastine, and

dacarbazine)-like regimens. The study group consisted of the

following: (i) 23 patients with primary refractory disease, (ii)

34 in early first relapse or second CR, and (iii) 70 with

refractory first relapse or disease beyond second CR. The

median age was 29. Disease stage at diagnosis was I to IV.

A total of 68 patients received autologous marrow, 6

syngeneic marrow, and 53 allogeneic marrow. The

preparative regimen in 94 of the 127 patients consisted of



cytoxan and TBI, or cytoxan, carmustine (BCNU) and

etoposide. The remaining patients received busulfan and

cytoxan or other regimens. Twelve of the 53 patients who

received an allogeneic transplant have survived for a median

of 1,661 days, all free of relapse (20 % actuarial survival and

22 % actuarial EFS at 5 years). Twenty-four of 68 patients

who underwent an autologous transplant were alive (median

survival time of 758 days; 5-year actuarial survival, 13 %), 14

of whom survived without evidence of relapse (median survival

time of 740 days; 5-year actuarial EFS, 14 %). The authors

determined that the EFS rate did not differ statistically when

comparing allogeneic to autologous transplants. However,

there was a trend toward decreased relapse rates in the

allogeneic recipients. The authors state that, although

autologous bone marrow transplantation is often preferred

over allogeneic transplantation in HD because of perceived

lower mortality, few studies have had sufficient numbers of

patients to study the effect of marrow source on outcome.

Moreover, their results demonstrated a lower relapse rate for

HLA-identical compared with autologous marrow recipients,

despite more frequent poor prognostic features among the

allogeneic group. The authors concluded that, the use of HLA-

identical marrow should be considered in patients who have

features that suggest a higher risk for relapse, such as the

presence of bulky disease and history of a short first CR, and

who also have features that suggest a lower risk of non-

relapse mortality.

Mendoza and co-workers (1995) studied 23 patients with

relapsed or resistant aggressive lymphoma. The purpose of

this study was to determine if HDC followed by allogeneic

bone marrow transplant is an effective means of treatment for

relapsed or aggressive Hodgkin's or NHL. The study group

consisted of 23 patients -- 9 patients with stage III or IV HD

and 14 patients with NHL. In the HD group, patients were

accepted for transplant if they met the following criteria: (i)

failure to attain a CR despite prior chemotherapy (with



MOPP or ABVD), (ii) tumor progression despite

chemotherapy, or (iii) relapse within 1 year of achieving

remission with the MOPP and/or ABVD regimen. Patients

were under age 50. The following treatment protocols were

used: TBI combined with cytoxan; TBI, cytoxan and

vinblastine; TBI, cytoxan and etoposide; and busulfan and

cytoxan. The authors recounted the following results: 4 of the

9 patients with HD were alive and disease-free at 1.3 to 94.8

months post-transplant. There was significant toxicity

associated with the treatment such as infection, hepatotoxicity,

interstitial pneumonitis, hemorrhage, and graft-versus-host

disease (GVHD). However, the authors stated that allogeneic

bone marrow transplantation is an effective salvage treatment

for relapsed or refractory lymphoma.

Laurence and Goldstone (1999) stated that there is an

increasing tendency to consider allogeneic transplantation in

HD. There may be some limited graft-versus-Hodgkin's

lymphoma effect, but this is outweighed by the greatly

increased treatment toxicity associated with the allogeneic

procedure. It is possible, however, that modern low-intensity

conditioning regimens, the so-called mini-allograft approach,

may increase the use of allogeneic transplantation for poor-

prognosis Hodgkin's lymphoma patients in the future.

In a recent review, Hale and Phillips (2000) stated that some

poor-prognosis patients with HD and NHL, usually with

recurrent and/or refractory disease, are rarely curable with

standard chemoradiotherapy. Autologous hematopoietic stem

cell transplantation has been reported to improve long-term

disease-free survival in some of these patients. Unfortunately,

a number of patients are unsuitable for autologous

transplantation as a consequence of damaged stem cell pool

involvement or other disease processes of the marrow. These

individuals may benefit from allogeneic stem cell

transplantation. In addition to the therapeutic effect of HDC

with or without TBI, an immunologic [namely, graft-versus-



lymphoma (GVLym)] effect may be present in some patients

undergoing allogeneic transplantation, resulting in a lower

relapse rate than autotransplants. However, allografts are

often associated with a higher non-relapse mortality due

primarily to GVHD; unfortunately, GVHD and GVLym are

difficult to differentiate. As a result, full exploitation of this

GVLym effect may necessitate the modification of commonly

employed conditioning regimens. If successful, these

modifications may lead to an additional reduction relapse rate

without additional morbidity. Furthermore, when combined

with low-intensity conditioning, such modifications may allow

patients who otherwise would not be candidates for standard

transplant regimens to be allografted.

Guidelines from Cancer Care Ontario (2009) recommend

autologous stem cell transplantation as a treatment option for

eligible chemosensitive patients with Hodgkin's lymphoma who

are refractory to or who have relapsed after primary

chemotherapy. These guidelines state that allogeneic stem

cell transplantation is an option for chemosensitive patients

with refractory or relapsed Hodgkin's lymphoma who are not

candidates for autologous stem cell transplantation or who

have a syngeneic (identical twin) donor. The guidelines do not

recommend stem cell transplantation as part of primary

therapy for Hodgkin's lymphoma.

Messer et al (2014) stated that allogeneic stem cell transplant

(allo-SCT) is considered a clinical option for patients with

Hodgkin lymphoma (HL) who have experienced at least 2

chemo-sensitive relapses. These investigators determined the

benefits and harms of allo-SCT with an unrelated donor (UD)

versus related donor (RD) allo-SCT for adult patients with HL.

Alternative donor sources such as haplo-identical donor cells

(Haplo) and umbilical cord blood (UCB) were also included.

The available evidence was limited. A total of 10 studies were

included in this assessment; 4 studies provided sufficient data

to compare UD with RD allo-SCT. None of these studies was

a randomized controlled trial (RCT). Additionally, 3 non-



comparative studies, such as registry analyses, which

considered patients with UD transplants were included. The

risk of bias in the studies was high. Results on overall and

PFS showed no consistent tendency in favor of a donor type.

Results on therapy-associated mortality and acute (grade II to

IV) and chronic GVHD were also inconsistent. The study

comparing UCB with RD transplants and 2 non-comparative

studies with UCB transplants showed similar results. One of

the studies comparing additionally Haplo with RD transplants

indicated a benefit in PFS for the Haplo transplant group. The

authors concluded that these findings did not indicate a

substantial outcome disadvantage of UD and alternative donor

sources versus RD allo-SCT for adult patients with advanced

HL.

Gauthier and associates (2017) stated that allo-SCT following

a non-myeloablative (NMA) or reduced-intensity conditioning

(RIC) is considered a valid approach to treat patients with

refractory/relapsed HL. When an HLA-matched donor is

lacking a graft from a familial haploidentical (HAPLO) donor, a

mis-matched unrelated donor (MMUD) or CB might be

considered. In this retrospective study, these investigators

compared the outcome of patients with HL undergoing a RIC

or NMA allo-SCT from HAPLO, MMUD or CB. A total of 98

patients were included. Median follow-up was 31 months for

the whole cohort. All patients in the HAPLO group (n = 34)

received a T-cell replete allo-SCT after a NMA (FLU-CY-TBI, n

= 31, 91 %) or a RIC (n = 3, 9 %) followed by post-transplant

cyclophosphamide (PT-Cy). After adjustment for significant co-

variates, MMUD and CB were associated with significantly

lower GVHD-free relapse-free survival (GRFS; hazard ratio

(HR) = 2.02, p = 0.03 and HR = 2.43, p = 0.009, respectively)

compared with HAPLO donors. The authors concluded that

higher GRFS was observed in HL patients receiving a RIC or

NMA allo-SCT with PT-Cy from HAPLO donors. They stated

that these findings suggested they should be favored over

MMUD and CB in this setting.



Mei and Chen (2018) noted that HL is a highly curable B-cell

lymphoma, and approximately 90 % of patients who present

with early-stage (stage I to II) disease and 70 % of patients

who present with late-stage disease will be cured with

standard front-line treatment. For patients with relapsed or

refractory (r/r) disease after initial therapy, the standard of care

is salvage chemotherapy, followed by autologous SCT (auto-

SCT). Although this approach will cure a significant proportion

of patients, up to 50 % of patients will experience disease

progression after auto-SCT, and this population has

historically had a very poor prognosis. In the past, further

salvage chemotherapy, followed by allo-SCT, has been the

only option associated with a significant probability of long-

term survival, owing to a graft-versus-lymphoma effect.

However, this approach has been complicated by high rates

of treatment-related morbidity and mortality and a high risk of

disease relapse. Furthermore, many patients have been

unable to proceed to allo-SCT because of disease

refractoriness, poor performance status, or the lack of a donor.

However, significant therapeutic advances in recent years

have greatly expanded the options for patients with post-auto-

SCT r/r HL. These include the anti-CD30 antibody-drug

conjugate brentuximab vedotin and the check-point inhibitors

nivolumab and pembrolizumab, as well as increasing

experience with alternative donor allo-SCT, especially from

HAPLO donors.

Haploidentical Versus HLA-Matched Related Donors in Allogeneic Hematopoietic Cell Transplantation

Gauthier and colleagues (2018) noted that the question of the

best donor type between HAPLO and matched-related donors

(MRD) for patients with advanced HL receiving an allo

hematopoietic cell transplantation (allo-HCT) is still debated.

Given the lack of data comparing these 2 types of donor in the

setting of NMA or RIC allo-HCT, these researchers performed

a multi-center, retrospective study using GRFS as the primary

end-point. They analyzed the data of 151 consecutive HL



patients who underwent NMA or RIC allo-HCT from a HAPLO

(n = 61) or MRD (n = 90) between January 2011 and January

2016. GRFS was defined as the probability of being alive

without evidence of relapse, grade 3 to 4 acute GVHD or

chronic GVHD. In multi-variable analysis, MRD donors were

independently associated with lower GRFS compared to

HAPLO donors (HR = 2.95, p < 0.001). Disease status at

transplant other than complete remission was also associated

with lower GRFS in multi-variable analysis (HR = 1.74, p = 0.01).

In addition, the administration of anti-thymocyte globulin

was independently linked to higher GRFS (HR = 0.52, p= 0.009).

The authors concluded that they observed significantly

higher GRFS in HL patients receiving an allo-HCT using the

HAPLO PT-Cy platform compared to MRD.

Tandem Autologous Hematopoietic Cell Transplantation

Based on promising pilot data, Smith and co-workers (2018)

carried out a phase-II clinical trial on the use of tandem

autologous hematopoietic stem cell transplant (AHSCT) for the

treatment of relapsed/refractory HL to determine if long-term

PFS could be improved. Patients were enrolled after salvage

therapy and stem cell collection. Sensitivity to salvage was

defined by 1999 Standardized Response Criteria and did not

include 18F-fluorodeoxyglucose-positron emission tomography

(18F-FDG PET). Cycle 1 consisted of melphalan 150 mg/m2

with 50 % of the stem cells. For stable disease (SD) or better,

patients received cycle 2 consisting of single doses of

etoposide 60 mg/kg and cyclophosphamide 100 mg/kg and

either TBI 12 Gy in 8 fractions over 4 days or BCNU 150mg/m2/day

for 3 days with the remaining stem cells. Of 98

enrolled patients, 89 were eligible and treated: 82 completed

both cycles of AHSCT, 47 (53 %) had primary refractory HL,

and 72 (81 %) were resistant to salvage therapy. There were

no treatment-related deaths (TRDs) in the 1st year after

AHSCT. With a median follow-up of 6.2 years (range of 2 to

7.7) for eligible patients who remained alive, the 2-year and

5-year PFS were 63 % (95 % CI: 52 % to 72 %) and 55 % (95



% CI: 44 % to 64 %) respectively; the 2-year and 5-year OS

were 91 % (95 % CI: 83 % to 95 %) and 84 % (95 % CI: 74 %

to 90 %), respectively. Univariate Cox regression analysis

showed Zubrod performance status and lactate

dehydrogenase levels greater than 1 times upper limit of

normal at the time of enrollment were significantly associated

with PFS. The authors concluded that the observed 5-year

PFS of 55 % suggested that the tandem approach appeared to

be effective in treating HL patients demonstrated to have poor

prognosis in prior single AHSCT trials. These findings need to

be further investigated.

Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma

Hsu and colleagues (2018) stated that limited studies have

reported on outcomes for lymphoid malignancy patients

receiving alternative donor allogeneic stem cell transplants.

These researchers have previously described combining CD34-

selected haploidentical grafts with UCB (haplo-cord) to

accelerate neutrophil and platelet engraftment. These

investigators examined the outcome of patients with lymphoid

malignancies undergoing haplo-cord transplantation. They

analyzed 42 lymphoma and chronic lymphoblastic leukemia

(CLL) patients who underwent haplo-cord allo-SCT. Patients

underwent transplant for HL (n = 9, 21 %), CLL (n = 5, 12 %)

and NHL (n = 28, 67 %), including 13 T cell lymphomas; 24

patients (52 %) had 3 or more lines of therapies; 6 (14 %) and

1 (2 %) patients had prior auto- and allo-SCT, respectively. At

the time of transplant, 12 patients (29 %) were in CR, 18 had

chemotherapy-sensitive disease, and 12 patients had

chemotherapy-resistant disease; 7 (17 %), 11 (26 %), and 24

(57 %) patients had low, intermediate, and high disease risk

index before transplant. Co-morbidity index was evenly

distributed among 3 groups, with 13 (31 %), 14 (33 %), and 15

(36 %) patients scoring 0, 1 to 2, and greater than or equal to

3. Median age for the cohort was 49 years (range of 23 to 71).



All patients received fludarabine/melphalan/anti-thymocyte

globulin conditioning regimen and post-transplant GVHD

prophylaxis with tacrolimus and mycophenolate mofetil. The

median time to neutrophil engraftment was 11 days (range of 9

to 60) and to platelet engraftment 19.5 days (range of 11 to

88). Cumulative incidence of non-relapse mortality was 11.6

% at 100 days and 19 % at 1 year. Cumulative incidence of

relapse was 9.3 % at 100 days and 19 % at 1 year. With a

median follow-up of survivors of 42 months, the 3-year rates of

GVHD relapse free survival (RFS), PFS, and OS were 53 %,

62 %, and 65 %, respectively, for these patients. Only 8 % of

the survivors had chronic GVHD. The authors concluded that

haplo-cord transplantation offered a transplant alternative for

patients with recurrent or refractory lymphoid malignancies

who lack matching donors. Both neutrophil and platelet count

recovery was rapid, non-relapse mortality was limited,

excellent disease control could be achieved, and the incidence

of chronic GVHD was limited. Thus, haplo-cord achieved high

rates of engraftment and encouraging results.

CPT Codes / HCPCS Codes / ICD-10 Codes

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

Code Code Description

CPT codes covered if selection criteria are met:

38204 Management of recipient hematopoietic

progenitor cell donor search and cell acquisition

38205 Blood-derived hematopoietic progenitor cell

harvesting for transplantation, per collection;

allogenic

38206 autologous




38210 Transplant preparation of hematopoietic

progenitor cells; specific cell depletion with

harvest, T-cell depletion

38211 tumor cell depletion

38212 red blood cell removal

38213 platelet depletion

38230 Bone marrow harvesting for transplantation

38232 autologous

38240 Hematopoietic progenitor cell (HPC); allogeneic

transplantation per donor

38241 autologous transplantation

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:

77261 -

77295

Radiation therapy

96401 -

96450

Chemotherapy administration code range

HCPCS code covered if selection criteria are met:




S2150 Bone marrow or blood-derived peripheral stem

cells (peripheral or umbilical), allogeneic or

autologous, harvesting, transplantation, and

related complications; including: pheresis and

cell preparation/storage; marrow ablative

therapy; drugs, supplies, hospitalization with

outpatient follow-up; medical/surgical,

diagnostic, emergency and rehabilitative

services; and the number of days of pre- and

post-transplant care in the global definition

Other HCPCS codes related to the CPB:

J9000 -

J9999

Chemotherapy drugs code range

Q0083 -

Q0085

Chemotherapy administration

ICD-10 codes covered if selection criteria are met: C81.00 -

C81.99

Hodgkin lymphoma

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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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 © 2001-2020 Aetna Inc.


AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0495 Hematopoietic

Cell Transplantation for Hodgkin's Disease

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania annual 09/01/2020

Proprietary

http://www.aetnabetterhealth.com/pennsylvania

hematopoietic cell transplantation for hodgkin's disease

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