Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy Bull... Page 1 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
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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.
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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)
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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
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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 %.
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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.
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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
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%) 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.
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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.
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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.
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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
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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
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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
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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
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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-
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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-
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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.
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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
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 19 of 32
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
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 20 of 32
% 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).
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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
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 22 of 32
Code Code Description
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:
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 23 of 32
Code Code Description
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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Allogeneic bone marrow transplantation for relapsed
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and refractory lymphoma using genotypically HLA-
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14. Yuen AR, Rosenberg SA, Hoppe RT, et al. Comparison
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Hodgkin's disease. Blood. 1997;89(3):814-822.
15. Horning SJ, Chao NJ, Negrin RS, et al. High-dose
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18. Laurence AD, Goldstone AH. High-dose therapy with
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 26 of 32
19. Hale GA, Phillips GL. Allogeneic stem cell
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22. Lazarus HM, Loberiza FR Jr, Zhang MJ, et al.
Autotransplants for Hodgkin's disease in first relapse
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blood and marrow transplant registry (ABMTR). Bone
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23. Reece DE. Hematopoietic stem cell transplantation in
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24. Carella AM, Cavaliere M, Lerma E, et al. Autografting
followed by nonmyeloablative immunosuppressive
chemotherapy and allogeneic peripheral-blood
hematopoietic stem-cell transplantation as treatment
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25. Federico M, Bellei M, Brice P, et al,
EBMT/GISL/ANZLG/SFGM/GELA Intergroup HD01 Trial.
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26. Schmitz N, Sureda A, Robinson S. Allogeneic
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 27 of 32
27. Ahmed T, Rashid K, Waheed F, et al. Long-term survival
of patients with resistant lymphoma treated with
tandem stem cell transplant. Leuk Lymphoma. 2005;46
(3):405-414.
28. Papadopoulos KP, Noguera-Irizarry W, Wiebe L, et al.
Pilot study of tandem high-dose chemotherapy and
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combination of regimens in patients with poor risk
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29. Seftel M, Rubinger M. The role of hematopoietic stem
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Transfus Apher Sci. 2007;37(1):49-56.
30. Sureda A, Robinson S, Canals C, et al. Reduced-
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allogeneic stem-cell transplantation in relapsed or
refractory Hodgkin's lymphoma: An analysis from the
Lymphoma Working Party of the European Group for
Blood and Marrow Transplantation. J Clin Oncol.
2008;26(3):455-462.
31. Anderlini P, Saliba R, Acholonu S, et al. Fludarabine
melphalan as a preparative regimen for reduced-
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lymphoma: The updated M.D. Anderson Cancer Center
experience. Haematologica. 2008;93(2):257-264.
32. Morschhauser F, Brice P, Fermé C, et al; GELA/SFGM
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single or tandem autologous stem-cell transplantation
for first relapse/refractory Hodgkin's lymphoma:
Results of the prospective multicenter H96 trial by the
GELA/SFGM study group. J Clin Oncol. 2008;26
(36):5980-5987.
33. Devetten MP, Hari PN, Carreras J, et al. Unrelated
donor reduced-intensity allogeneic hematopoietic
stem cell transplantation for relapsed and refractory
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 28 of 32
Hodgkin lymphoma. Biol Blood Marrow Transplant.
2009;15(1):109-117.
34. Robinson SP, Sureda A, Canals C, et al; Lymphoma
Working Party of the EBMT. Reduced intensity
conditioning allogeneic stem cell transplantation for
Hodgkin's lymphoma: Identification of prognostic
factors predicting outcome. Haematologica. 2009;94
(2):230-238.
35. Freytes CO, Lazarus HM. Second hematopoietic SCT
for lymphoma patients who relapse after
autotransplantation: Another autograft or switch to
allograft? Bone Marrow Transplant. 2009;44(9):559
569.
36. Brusamolino E, Bacigalupo A, Barosi G, et al. Classical
Hodgkin's lymphoma in adults: Guidelines of the
Italian Society of Hematology, the Italian Society of
Experimental Hematology, and the Italian Group for
Bone Marrow Transplantation on initial work-up,
management, and follow-up. Haematologica. 2009;94
(4):550-565.
37. Imrie K, Rumble RB, Crump M; Advisory Panel on Bone
Marrow and Stem Cell Transplantation, and the
Hematology Disease Site Group of Cancer Care
Ontario’s Program in Evidence-based Care. Cancer
Care Ontario. Stem cell transplantation in adults.
Recommendation Report 1. Toronto, ON: Cancer Care
Ontario; January 30, 2009.
38. Freed J, Kelly KM. Current approaches to the
management of pediatric Hodgkin lymphoma.
Paediatr Drugs. 2010;12(2):85-98.
39. IQWiG. Unrelated donor allogeneic stem cell
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Summary. A09-04. Cologne, Germany: Institut fuer
Qualitaet und Wirtschaftlichkeit im Gesundheitswesen
(IQWiG); 2010.
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 29 of 32
40. Daw S, Wynn R, Wallace H. Management of relapsed
and refractory classical Hodgkin lymphoma in children
and adolescents. Br J Haematol. 2011;152(3):249-260.
41. Corradini P, Sarina B, Farina L. Allogeneic
transplantation for Hodgkin's lymphoma. Br J
Haematol. 2011;152(3):261-272.
42. Rancea M, Monsef I, von Tresckow B, et al. High-dose
chemotherapy followed by autologous stem cell
transplantation for patients with relapsed/refractory
Hodgkin lymphoma. Cochrane Database Syst Rev.
2013;6:CD009411.
43. Harker-Murray PD, Drachtman RA, Hodgson DC, et al.
Stratification of treatment intensity in relapsed
pediatric Hodgkin lymphoma. Pediatr Blood Cancer.
2014;61(4):579-586.
44. Messer M, Steinzen A, Vervolgyi E, et al. Unrelated and
alternative donor allogeneic stem cell transplant in
patients with relapsed or refractory Hodgkin
lymphoma: A systematic review. Leuk Lymphoma.
2014;55(2):296-306.
45. Rashidi A, Ebadi M, Cashen AF. Allogeneic
hematopoietic stem cell transplantation in Hodgkin
lymphoma: A systematic review and meta-analysis.
Bone Marrow Transplant. 2016;51(4):521-528.
46. Martino M, Festuccia M, Fedele R, et al. Salvage
treatment for relapsed/refractory Hodgkin lymphoma:
Role of allografting, brentuximab vedotin and newer
agents. Expert Opin Biol Ther. 2016;16(3):347-364.
47. von Tresckow B, Moskowitz CH. Treatment of relapsed
and refractory Hodgkin lymphoma. Semin Hematol.
2016;53(3):180-185.
48. Gauthier J, Castagna L, Garnier F, et al. Reduced-
intensity and non-myeloablative allogeneic stem cell
transplantation from alternative HLA-mismatched
donors for Hodgkin lymphoma: A study by the French
Society of Bone Marrow Transplantation and Cellular
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Hematopoietic Cell Transplantation for Hodgkin's Disease - Medical Clinical Policy B... Page 30 of 32
Therapy. Bone Marrow Transplant. 2017;52(5):689
696.
49. Smith EP, Li H, Friedberg JW, et al. Tandem autologous
hematopoietic cell transplantation for patients with
primary progressive or recurrent Hodgkin lymphoma:
A SWOG and Blood and Marrow Transplant Clinical
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53. Hsu J, Artz A, Mayer SA, et al. Combined haploidentical
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54. Gauthier J, Poiré X, Gac AC, et al. Better outcome with
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56. Peggs KS. Should all patients with Hodgkin lymphoma
who relapse after autologous SCT be considered for
allogeneic SCT? Blood Adv. 2018;2(7):817-820.
57. Moskowitz CH. Should all patients with HL who relapse
after ASCT be considered for allogeneic SCT? A consult,
yes; a transplant, not necessarily. Blood Adv. 2018;2
(7):821-824.
58. Kanate AS, Kumar A, Dreger P, et al. Maintenance
therapies for Hodgkin and non-Hodgkin lymphomas
after autologous transplantation: A consensus project
of ASBMT, CIBMTR, and the Lymphoma Working Party
of EBMT. JAMA Oncol. 2019 Feb 28 [Epub ahead of
print].
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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 © 2001-2020 Aetna Inc.
PPrropoprrietietaarryy
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