Prior Authorization Review Panel MCO Policy Submission...Person has a haploidentical to fully HL...

Prior Authorization Review Panel MCO Policy Submission

A separate copy of this form must accompany each policy submitted for review. Policies submitted without this form will not be considered for review.

Plan: Aetna Better Health Submission Date:10/01/2019

Policy Number: 0494 Effective Date: Revision Date: 09/09/2015

Policy Name: Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma

Type of Submission – Check all that apply:

New Policy Revised Policy*Annual Review – No Revisions Statewide PDL

*All revisions t o the p olicy must be hi ghlighted using track c hanges t hroughout the d ocument.

Please prov ide a ny clarifying information for the p olicy below:

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

Clinical content was last revised on 09/09/2015. No additional non-clinical updates were made by Corporate since the last PARP submission.

Name of Authorized Individual (Please t ype or print):

Dr. Bernard Lewin, M.D.

Signature o f Authorized Individual:

Revised July 22, 2019

Proprietary

http://www.aetna.com/cpb/medical/data/400_499/0494.html 09/23/2019

Page 1 of 39

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

Hematopoietic Cell Transplantation for NonHodgkin's Lymphoma

Clinical Policy Bulletins Medical Clinical Policy Bulletins

Policy History

Last

Review

08/30/2018

Effective: 02/01/200

Next Review:

05/09/2019

Review

History

Definitions

Additional

Number: 0494

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

I. Autologous Hematopoietic Cell Transplantation

Aetna considers autologous hematopoietic cell transplantation for the

treatment of persons with relapsed or primary refractory (see "Note" below)

non-Hodgkin's lymphoma (NHL) medically necessary if the person meets

the transplanting institution's protocol eligibility criteria. In the absence of a

protocol, Aetna considers autologous hematopoietic cell transplantation

medically necessary for the treatment of NHL when all of the following

selection criteria are met:

A. Person has relapsed or refractory NHL. * Note : Upon clinical review,

Aetna may also consider autologous hematopoietic cell

transplantation medically necessary for persons in first clinical remission

with lymphoblastic NHL, Burkitt’s lymphoma, mediastinal B-cell

lymphoma, mantle cell lymphoma, high-risk diffuse large B-cell

lymphoma and other NHLs that are associated with poor prognosis.

http://www.aetna.com/cpb/medical/data/400_499/0494.html

https://www.aetna.com/


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and

B. Evidence of chemotherapy responsive (see note below) disease.*

* Note: Upon medical review, autologous hematopoietic cell

transplantation may be considered medically necessary for persons with

chemoresistant disease where disease is relapsed and widely metastatic

and allogeneic transplantation can not be offered.

and

C. No evidence of serious organ dysfunction based up on the transplanting

institution's evaluation.

Notes:

Responsiveness is defined as a tumor demonstrating either a complete or partial

remission. Partial remission (response) is defined as at least a 50 % decrease in tumor

burden.

Refractory disease is a failure to attain a complete or partial response. The

refractoriness can be primary (failure to respond to initial therapy) or secondary (initial

response but failure to respond after disease relapse).

Aetna considers autologous hematopoietic cell transplantation experimental and

investigational for persons with any of the following contraindications to autologous

hematopoietic cell transplantation for the treatment of NHL:

A. Co-morbid diseases (e.g., uncontrolled hypertension)

B. Evidence of serious organ dysfunction.

II. Allogeneic Hematopoietic Cell Transplantation

Aetna considers allogeneic hematopoietic cell transplantation medically necessary for

the treatment of persons with relapsed NHL (including persons who have relapsed after

autologous hematopoietic cell transplantation) or primary refractory (see "Note" below)



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NHL (low-grade, intermediate-grade, and high-grade) if the person meets the

transplanting institution's protocol eligibility criteria. In the absence of a protocol, all of

the following medical necessity criteria must be met:

A. Person has relapsed or refractory NHL. *Note: Upon clinical review, Aetna

may also consider allogeneic hematopoietic cell transplantation medically

necessary for persons in first clinical remission with lymphoblastic NHL,

Burkitt’s lymphoma, mediastinal B-cell lymphoma, mantle cell lymphoma and

other NHLs that are associated with poor prognosis.

B. Person has a haploidentical to fully HL A-matched related donor or well-

matched unrelated donor (i.e., meets National Marrow Donor Program

(NMDP) criteria for selecting unrelated donors) or single or double cord

blood matched for at least 4 of 6 HLA ABDR antigens; and

C. No serious organ dysfunction based upon the transplanting institution's

evaluation.

Notes:

Aetna considers non-myeloablative allogeneic hematopoietic cell transplantation

medically necessary ("mini-transplant", reduced intensity conditioning transplant)

for the treatment of persons with relapsed NHL (including persons who have

relapsed after ABMT) or primary refractory (see note below) NHL (low-grade,

intermediate-grade, and high-grade) when they are eligible for conventional

allografting or a reduced intensity regimen is preferred by the transplant center.

Tandem Transplant

Aetna considers tandem autologous hematopoietic cell transplantion (auto-auto) or

tandem autologous hematopoietic cell transplantation followed by allogenic

hematopoietic cell transplantation (auto-allo) experimental and investigational for

NHL due to a lack of adequate evidence in the peer-reviewed published medical

literature of their safety and effectiveness.

Background



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Non-Hodgkin's lymphoma (NHL) is an extremely heterogeneous group of lymphoid

malignancies whose diversity relates to their epidemiology, natural history,

morphology, immunology, cytogenetics and response to standard doses of

chemotherapy.

There have been various attempts at classification schemes for NHL resulting in

confusing and overlapping terminology in the literature. Historically, the most

common scheme has been the Rappaport classification, which subdivided

lymphomas based on their resemblance to normal appearing lymphocytes. In

1982, this classification scheme was supplanted in the literature by a National

Cancer Institute Working Formulation (IWF), which was an attempt at providing a

common language for classification. The following table summarizes the two

systems.

Rappaport and International Working Formulation Classification of Lymphomas:

Rappaport System Grade/Histologic Type (IWF Class)

Low Grade

Diffuse, well differentiated Small lymphocytic (A)

Nodular poorly differentiated Predominantly small-cleaved cell, follicular; diffuse

areas, sclerosis (B)

Nodular, mixed histiocytic and

lymphocytic

Mixed, small-cleaved and large-cell, follicular; diffuse

areas (C)

Intermediate Grade

Nodular histiocytic Predominantly large-cell, follicular; diffuse areas,

sclerosis (D)

Diffuse, poorly differentiated

lymphocytic

Small-cleaved cell, diffuse (E)

Diffuse mixed histiocytic and

lymphocytic

Mixed small and large-cell cell, diffuse; sclerosis,

epithelioid cell component (F)

Diffuse histiocytic Large-cell cleaved or non-cleaved, diffuse; sclerosis

(G)

High Grade

Diffuse histiocytic Large-cell, immunoblastic; plasmacytoid, epithelioid

cell component (H)

Lymphoblastic Lymphoblastic, convoluted or non-convoluted cell (I)



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Lymphomas are often typically staged according to the extent of their

dissemination. The Ann Arbor Staging System, specifically developed for

Hodgkin's disease, has been adapted for use in lymphomas.

Ann Arbor Staging System for Lymphomas:

Stages I, II, III, and IV can be sub-classified into A or B category. Category “B” is

for patients with well-defined, generalized symptoms such as unexplained fever

(temperature greater than 38°C), drenching night sweats, and unexplained weight

loss of more than 10 % of body weight in the 6 months prior to diagnosis, while

category “A” is for patients without these symptoms.

In 1994, the Revised European-American Classification of Lymphoid Neoplasms

(REAL) was constructed to define a particular NHL by incorporating all available

tumor information-morphologic, immunotypic, genetic, and clinical features. A

project to update and revise the REAL system was initiated by the World Health

Organization (WHO) in 1995; its consensus was published in 1999. The WHO

classification, like REAL, incorporates a number of tumor characteristics and is

designed to enable disease identification by pathologic examination while



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maintaining clinical relevance. With use of the WHO classification, treatment is

determined by identifying the specific lymphoma type and, if relevant, by

considering tumor grade and other prognostic factors.

REAL/WHO Classification System:

MALT

Splenic marginal zone lymphoma

Nodal marginal zone lymphoma

Lymphoplasmacytoid lymphoma/immunocytoma

Grade 2 (6 - 15 centroblasts/hpf)

Grade 3† (greater than 15 centroblasts/hpf)

Aggressive

Mediastinal large cell lymphoma

Primary effusion lymphoma

Key: CLL = chronic lymphocytic leukemia; MALT = mucosa-associated lymphoid

tissue; hpf = high-powered field.

† Subtype may exhibit either indolent or aggressive clinical behavior.



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A staging system of the extent of disease is only useful if it reflects a patient's

prognosis and can be used to select appropriate therapy. The Ann Arbor Staging

System is based on the pattern of contiguous nodal spread that is typically

observed in Hodgkin's disease and it is assumed that a higher stage is associated

with a worse prognosis. However, in indolent lymphomas, the majority of patients

present with disseminated disease that would be classified as Stage IV and except

for the rare patient who truly has Stage I disease, there is little difference in

prognosis among the other stages. In addition, the Ann Arbor System gives no

consideration to tumor size, which is prognostically significant in lymphomas.

Furthermore, the diaphragm is an arbitrary anatomic reference point, dictated by

convenience and by the standard size of radiation fields. Thus, Stage II disease

represents an extremely heterogeneous group of patients, who may have from 2 to

12 sites of involvement. They will all be classified as Stage II if their disease is

located entirely on one side of the diaphragm. Similarly, Stage II could include

patients with isolated disease on both sides of the diaphragm, and patients with

bulky widely disseminated disease. The following staging system proposed by the

National Cancer Institute modifies the Ann Arbor Staging System in order to reflect

the natural history of lymphomas and to provide more prognostically useful

information.

Modified Ann Arbor Staging System:

High-Dose Chemotherapy

High-dose chemotherapy (HDC) involves the administration of cytotoxic agents

using doses several times greater than the standard therapeutic dose. In some

cases, whole body or localized radiotherapy is also given and is included in the

term HDC when applicable. The most significant side effect of HDC is marrow



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ablation and thus HDC is accompanied by a re-infusion of hematopoietic stem cells

in order to repopulate the bone marrow. The potential source of stem cells and

harvesting techniques are described below.

High-dose chemotherapy bone marrow or peripheral stem cell transplant

(autologous or allogeneic) is a treatment option for selected patients with NHL. 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 entails the patient acting as his/her own bone

marrow donor. Stem cells may be harvested from the patient's bone marrow or

more commonly, peripheral blood. Peripheral stem cells are harvested via 1 or

more pheresis procedures. The patient's bone 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. A prior course of chemotherapy (typically

cyclophosphamide) or growth factors or both can increase the number of circulating

stem cells.

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.

Allogeneic bone marrow transplant refers to the use of functional hematopoietic

stem cells from a healthy donor to restore bone marrow function following HDC.

Allogeneic stem cells can be harvested from either the bone marrow or peripheral

blood. For patients with marrow-based malignancies, the use of allogeneic stem

cells offers the advantage of lack of tumor cell contamination, particularly if the



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stem cells are harvested from the bone marrow, as opposed to from the peripheral

blood. Furthermore, allogeneic stem cells may be associated with a potentially

beneficial graft versus tumor effect.

Syngeneic stem cells refer to genetically identical bone marrow or peripheral stem

cells harvested from an identical twin. Syngeneic cells can be harvested from

either the bone marrow or peripheral blood.

Tandem (sequential) transplant protocols utilize a cycle of HDC with ASCT followed

in approximately 6 months by a 2nd 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 or overall survival more than single transplants

for patients with NHL. Ahmed et al (2005) reported that the median disease-free

survival of patients with resistant/refractory NHL treated with tandem stem cell

transplant was only 2 months.

Oliansky and colleagues (2011) presented clinical research published since the

2001 evidence-based review on the role of hematopoietic stem cell transplantation

(HSCT) in the treatment of diffuse large B cell lymphoma (DLBCL) in adults.

Treatment recommendations that remain unchanged from the original review

include: (i) ASCT as salvage therapy is recommended for patients with chemo

sensitive relapsed D LBCL; and ( ii) ASCT is not recommended f or patients who

achieve a p artial response to an abbreviated ind uction regimen. New

treatment recommendations based on new published data include:

(i) ASCT as first-line therapy is not recommended f or any international

prognostic index (IPI) group; (ii) planned tandem or multiple sequential ASCT is

not recommended; (iii) peripheral blood i s the standard s tem cell source for

ASCT; (iv) age is not a c ontraindication for ASCT, although outcomes in older

adults are not as good as in younger adults.

There are insufficient data to make recommendations on the routine use of

rituximab maintenance after ASCT, autologous versus allogeneic SCT, fewer

versus more cycles of induction therapy prior to ASCT, or the use of reduced

intensity versus myeloablative conditioning regimens.



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Prior to HDC-ABMT, the literature indicates that 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.

Prior to peripheral stem cell collection, the literature states that 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 an outpatient procedure, which is done on a

daily basis until adequate stem cells are collected. From 5 to 10 procedures may

be 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 4-day

hospitalization is usually required for pre- and post-chemotherapy hydration. After

completion of the cyclophosphamide regimen, the literature indicates that the

patient can usually be discharged; apheresis can usually 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) is typically given on an outpatient basis

with home hydration therapy. Other high dose combination therapies, such as

EDAP (etoposide, dexamethasone, ara-C and cisplatin) require hospitalization due

to nausea and vomiting, mucositis, diarrhea and inadequate oral intake. Any

regimen that includes TBI will require a prolonged hospital stay, typically lasting

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.



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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),

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

morbidity such as mucositis and diarrhea. The patient must also be able to

maintain adequate oral intake. Hospital stays typically range from 2 to 4 weeks.

Patients may be discharged even if they require transfusions to maintain an

adequate platelet count; platelet transfusions can be given on an outpatient basis.

Usual length of stay for patients undergoing HDC in conjunction with TBI is about

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 the continue to require platelet transfusions, as these transfusions can be

given on an outpatient basis.

Studies on Autologous Transplant

Takvorian and colleagues (1987) studied 49 patients with either high-grade (n =

29), intermediate-grade (n =14) or low-grade (n = 6) lymphoma. All patients were

considered to have a poor prognosis either due to relapse (n = 41) or poor

prognostic factors (n = 8). These latter 8 patients were in at least partial remission

but were considered to be at high-risk for relapse due to a bulky tumor mass, or

multiple sites of extra-nodal involvement. All patients had a good performance

status. The common feature of all these patients was that they were responsive to

conventional induction therapy such that at the time of HDC, all patients had a

minimal disease burden. In fact, 23 patients were considered to be in complete

remission. A total of 34 of the 49 patients remained in complete remission for 2 to

52 months post-HDC, which translated into a 65 % probability that patients would

remain disease free for greater than 11 months. Two patients died from treatment-

related toxicity and relapse occurred in 13 others. All relapses occurred before 11

months. Other earlier studies of HDC had included all patients relapsing from

disease, regardless of their performance status or whether the lymphoma was

chemo-resistant. In these studies the mortality rate ranged from 20 to 40 % and long

term disease survival was seen in only 20 % of patients. Considering their



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improved results, the authors suggested that HDC should be a treatment option for

patients with relapsing disease but with a minimal tumor burden that is still

responsive to chemotherapy.

Schouten et al (1994) reported their findings of 92 patients with low-grade NHL

treated with HDC and ASCT. At the time of ASCT, the majority of patients had

chemo-sensitive disease in first or subsequent remission (37 %) or disease with a

good response to chemotherapy (49 %). At a median follow-up of 19 months, the

progression free survival is 52 %. Patients with complete remission or responding

relapse at the time of ASCT had a significantly better progression-free survival

compared to patients with refractory disease. Patients with transformed low-grade

NHL at ASCT had a very poor outcome. Despite the relatively short follow-up of

this study, the data suggested that chemo-sensitive disease responded better to

HDC followed by stem cell transplant than refractory disease at the time of ASCT.

Mills and colleagues (1995) reported the main prognostic factors in 107 patients

with relapsed or resistant intermediate- or high-grade NHL who underwent HDC

with ASCT. All patients had failed to achieve a complete remission to conventional

chemotherapy or had subsequently relapsed. Additionally, there was no bone

marrow involvement in any of the patients. Forty-two patients (40 %) had

chemoresistant disease at the time of HDC, 55 (51 %) had chemo-sensitive

disease, and 10 (9 %) had untested relapse. At 3 months, 44 patients (41 %) were

assessed to be in complete remission, 34 (32 %) were in partial remission and 22

(21 %) showed no response or had progressive disease. There were 7 early

procedure-related deaths. Overall survival rate at 5 years is 41 % and progression

free survival rate is 35 %. None of the patients who were unresponsive to HDC

survived beyond 18 months, whereas at a median follow-up of 34 months, 50 % of

the partial responders were alive. Patients with chemo-sensitive disease, small

masses, and ASCT after one line of chemotherapy had the best outcome.

In a randomized clinical trial (The European CUP trial), Schouten et al (2003)

examined if high-dose therapy (HDT) followed by ASCT is more effective than

standard treatment with regard to progression-free survival (PFS) and overall

survival (OS) in patients with relapsed follicular NHL; and evaluated the additional

value of B-cell purging of the stem-cell graft with regards to PFS and OS. Patients

received three cycles of chemotherapy. Responding patients with limited bone

marrow infiltration were eligible for random assignment to 3 further cycles of

chemotherapy (C), unpurged HDT (U), or purged HDT (P). A total of 140 patients



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were registered from 36 centers internationally, and 89 were randomly assigned.

Reasons for not randomizing included patient refusal, early progression, or death

on induction therapy. With a 69-month median follow-up, the log-rank P value for

PFS and OS were 0.0037 and 0.079, respectively. The authors concluded that

HDT significantly improves PFS and OS in patients under age of 60 years with

recurrent chemosensitive disease. Furthermore, there is no clear evidence of

benefit through purging. This is in agreement with the observations of Alvarnas and

Forman (2004) who stated that data to justify routine use of hematopoietic stem cell

graft purging are insufficient.

In a recent review on stem cell transplantation in follicular lymphoma, Tse et al

(2004) stated that ASCT or allogeneic stem cell transplantation in first remission

remains an investigational procedure.

A review (Sweetenham, 2001) states that the role of stem cell transplantation

(autologous/allogeneic) in patients with mantle cell lymphoma is unclear. In

particular, there is no justification for autologous stem cell transplantation in

patients who have failed multiple lines of therapy, and its role in first remission is

unproven. Furthermore, the role of allogeneic stem cell transplantation in mantle

cell lymphoma is also unclear and unproven. Thus, the study concludes that stem

cell transplantation for the treatment of mantle cell lymphoma should only be used

as part of a clinical trial.

High-dose chemotherapy with ASCT has been proven effective in relapsed

aggressive NHL. However, conflicting results of HDT as part of first-line treatment

have been reported in randomized controlled trials (RCTs). In a Cochrane review,

Greb et al (2008) examined if HDC with ASCT as part of first-line treatment

improves survival in patients with aggressive NHL. Randomized controlled trials

comparing conventional chemotherapy versus HDC in the first-line treatment of

adults with aggressive NHL were included in this review. Eligibility and quality

assessment, data extraction and analysis were done in duplicate. All authors were

contacted to obtain missing data and asked to provide individual patient data. A

total of 15 RCTs (n = 3079) were eligible for this meta-analysis. Overall treatment-

related mortality was 6.0 % in the HDT group and not significantly different

compared to conventional chemotherapy (odds ratio [OR] 1.33; 95 % confidence

interval [CI]: 0.91 to 1.93, p = 0.14). A total of 13 studies (n = 2,018) showed

significantly higher complete remission (CR) rates in the group receiving HDT (OR

1.32; 95 % CI: 1.09 to 1.59, p = 0.004). However, HDT did not have an effect on



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OS, when compared to conventional chemotherapy. The pooled hazard ratio (HR)

was 1.04 (95 % CI: 0.91 to 1.18, p = 0.58). There was no statistical heterogeneity

among the trials. Sensitivity analyses underlined the robustness of these results.

Subgroup analysis of prognostic groups according to IPI did not show any survival

difference between HDT and controls in 12 trials (low and low-intermediate risk IPI:

HR 1.41; 95 % CI: 0.95 to 2.10, p = 0.09; high-intermediate and high risk IPI: HR

0.97; 95 % CI: 0.83 to 1.13, p = 0.71. Event-free survival (EFS) also showed no

significant difference between HDT and CT (HR 0.93; 95 % CI: 0.81 to 1.07, p =

0.31). Other possible risk factors such as the proportion of patient with diffuse large

cell lymphoma, protocol adherence, HDT strategy, response status before HDT,

conditioning regimens and methodological issues were analyzed in sensitivity

analyzes. However, there was no evidence for an association between these

factors and the results of these analyses. The authors concluded that despite

higher CR rates, there is no benefit for HDC with ASCT as a first-line treatment in

patients with aggressive NHL.

In a phase-II clinical trial, Krishnan et al (2008) assessed the safety and

effectiveness of combining yttrium-90 (90Y) ibritumomab tiuxetan (Zevalin) with high-

dose carmustine, cytarabine, etoposide, and melphalan (BEAM) and ASCT in

patients with NHL who were ineligible for TBI because of older age or prior

radiotherapy. A total of 41 patients with received standard-dose 90Y ibritumomab

tiuxetan (14.8 MBq/kg [0.4 mCi/kg]) followed by high-dose BEAM. The median age

was 60 years (range of 19 to 78 years), and the median number of previous

therapies was 2 (range of 1 to 6). Disease histologies were diffuse large B-cell (n =

20), mantle cell (n = 13), follicular (n = 4), and transformed lymphoma (n = 4). With

a median follow-up of 18.4 months (range of 5.5 to 53.3 months), the estimated

2-year OS and PFS were 88.9 % (95 % CI: 75.3 % to 95.2 %) and 69.8 % (95 % CI:

56.4 % to 79.7 %), respectively. The median time to white blood cell engraftment

was 11 days (range of 9 to 26 days) and time to platelet engraftment was 12 days

(range of 3 to 107 days). Adverse events were similar to those seen historically

with high-dose BEAM alone, and included grade 3 or 4 pulmonary toxicity in 10

patients. The authors concluded that adding 90Y ibritumomab tiuxetan to high-

dose BEAM with ASCT is feasible and has a toxicity and tolerability profile similar to

that observed with BEAM alone. They noted that rates of PFS seen in these

patients are promising and warrant additional study.



Page 15 of 39

Seshadri et al (2009) stated that ASCT for relapsed/refractory aggressive NHL

results in long-term disease-free survival in 40 to 50 % of patients. The incidence

of and risk factors for second cancer development in these patients have not been

well studied. These investigators analyzed 372 patients with relapsed/refractory

aggressive NHL who underwent ASCT from 1987 to 2006. Median age at ASCT

was 50 years (range of 19 to 70). Most patients (74 %) received two chemotherapy

regimens before transplant. High-dose chemotherapy consisted of etoposide and

melphalan in 95 % of patients and 16 % received TBI. A total of 32 patients (9 %)

developed a second cancer (19 hematologic, 13 solid tumors). The probability of

second cancer at 3 and 10 years post-ASCT was 4.4 % and 12.9 %, respectively.

When compared with the general population, the relative risk of acute myeloid

leukemia and new solid tumor was 13.2 (p < 0.0001) and 2.3 (p = 0.0013). Salvage

therapy using mini-BEAM was significantly associated with second cancer

development (p = 0.004). The authors concluded that second cancers are a

significant cause of late morbidity and mortality patients treated with ASCT with

curative intent, and appear increased in patients exposed to mini-BEAM

chemotherapy.

Freytes and Lazarus (2009) stated that although ASCT is the only potentially

curative treatment for lymphoma that has relapsed after conventional

chemotherapy, the prognosis of patients with disease recurrence after auto-HSCT

is poor. Some highly selected patients can benefit from second transplants. One-

third with late recurrence after initial auto-HSCT may attain a prolonged remission

after second auto-HSCT. Non-myeloablative or reduced-intensity conditioning

(RIC) allogeneic hematopoietic SCT (allo-HSCT) has been used successfully after

auto-HSCT failures, especially in subjects who have an HLA-compatible donor,

chemo-sensitive disease and good performance status. Patients with chemo

senstive disease recurrence who have completed at least 1 year after their first auto-

HSCT should be considered for a second auto-HSCT. Patients who have chemo

resistant disease are best served by participation in a well-designed clinical trial

examining novel anti-tumor agents.

Al Khabori et al (2012) stated that the impact of HDC and ASCT versus conventional-

dose chemotherapy in the initial management of adults with advanced follicular

lymphoma (FL) on OS remains uncertain. These investigators performed a

systematic review of the RCTs addressing this question. They searched MEDLINE,

EMBASE, CENTRAL, American Society of Hematology, American Society of Clinical

Oncology, BIOSIS, PAPERSFIRST, PROCEEDINGS, clinical



Page 16 of 39

trials registries, and bibliographies of relevant studies for RCTs comparing

myeloablative chemotherapy with ASCT to any chemotherapy in adults with

untreated advanced FL. They performed a meta-analysis using random effects

models to estimate OS, EFS, and risks of adverse outcomes. Statistical

heterogeneity was calculated by using the I(2) statistic. A total of 7 trials proved

eligible, 4 of which provided data from 941 patients that could be included in a meta-

analysis and 3 of which remain unpublished. In 2 of the trials, patients in both arms

received rituximab during the induction treatment. Moderate quality evidence from the

3 trials that reported OS (n = 701 patients) suggests that ASCT did not result in

improved OS (HR of death = 0.99, 95 % CI: 0.73 to 1.33). Low-quality evidence from

the 4 trials of 941 patients suggested improvement in EFS in favor of ASCT (HR of

death = 0.54, 95 % CI: 0.36 to 0.82) with substantial heterogeneity (I

(2) = 80 %). Adverse outcomes of treatment-related mortality (TRM),

myelodysplastic syndrome, acute myeloid leukemia, and solid tumors were not

different between the 2 arms (RR of treatment-related mortality = 1.04, 95 % CI:

0.29 to 3.70; RR of myelodysplastic syndrome/acute myeloid leukemia = 2.19, 95

% CI: 0.45 to 10.55; I(2) = 48 %; and RR of solid tumors = 1.30, 95 % CI: 0.33 to

5.08). The absolute risk of death from treatment was 14 per 1,000 patients for

those who received chemotherapy and 15 per 1,000 for those who received ASCT

(range of 4 to 52). The authors concluded that available evidence suggested that

HDC and ASCT as part of FL initial treatment does not improve OS. They stated

that future trials of ASCT in the context of current chemoimmunotherapy

approaches to FL are needed.

Studies on Allogeneic Transplant

Chopra and associates (1992) used a case-controlled analysis of the European

Bone Marrow Transplant Registry data to compare allogeneic with autologous

transplant for patients with NHL. A total of 101 matched sets of patients were

studied. Although the relapse rate was lower with allogeneic transplant (23 %

compared to 48 % at 31 to 48 months), the overall PFS rate was similar between

the 2 groups (49 % for allogeneic versus 46 % for autologous). As expected the

toxic death rate was higher among allogeneic transplants (28 % versus 14 %).

Among the subgroups of lymphoma, allogeneic transplant only showed a survival

advantage among the 16 patients with lymphoblastic lymphoma, perhaps due to a

graft versus host anti-leukemic effect.



Page 17 of 39

Tan and Bartlett (2000) noted that combination chemotherapy remains the standard

of care for the treatment of aggressive NHL. Major advances in the management of

aggressive lymphomas include validation of the international prognostic index and

clarification of the role of high-dose therapy with bone marrow or stem cell

transplant in patients with relapsed aggressive lymphomas. Many randomized pilot

trials of HDC as initial therapy for aggressive lymphomas have shown conflicting

results and await confirmatory studies.

Hale and Phillips (2000) mentioned that certain poor-prognosis patients with NHL

and Hodgkin's disease, usually with recurrent and/or refractory disease, are rarely

curable with standard chemoradiotherapy. Autologous hematopoietic stem cell

transplantation has been demonstrated to result in improved long-term disease-free

survival in some of these patients. Unfortunately, a number of patients are not

suitable for autologous transplantation due to a damaged stem cell pool

involvement or other disease processes of the marrow. These patients may benefit

from allogeneic stem cell transplantation. In addition to the therapeutic effect of

HDC with or without TBI, an immunologic (i.e., graft-versus-lymphoma) effect may

be present in some patients undergoing allogeneic transplantation, resulting in a

lower relapse rate than that obtained from autologous transplantation. However,

allogeneic transplantation is often associated with a higher non-relapse mortality

due primarily to graft-versus-host disease.

In a review, Mink and Armitage (2001) stated that ASCT has proven to be beneficial

in selected patients with Hodgkin's disease and NHL. For patients with diffuse large-

cell NHL, transplantation can be considered standard therapy for relapsed patients if

they have chemotherapy-sensitive disease. The use of transplantation for high-risk

patients in complete remission is promising, but definite recommendations can not be

made at this time. For follicular lymphomas, selected patients seem to benefit and

studies are ongoing. Finally, the use of allogeneic stem cell transplantation can be

useful in a select group of younger patients.

Allogeneic SCT is an effective therapy for lymphoma. Reduced-intensity

conditioning (RIC) reduces non-relapse mortality associated with myeloablative

conditioning but relapse rates are high when performed in active disease. Shimoni

et al (2008) examined the safety and outcome of ibritumomab tiuxetan combined

with RIC in patients with advanced lymphoma. The study included 12 patients,

median age 54 years (37 to 62), with a median of 4 prior treatments (2 to 6) and

active disease documented on PET-CT. Zevalin 0.4 mCi/kg was given on day-14



Page 18 of 39

and fludarabine combined with busulfan (n = 6) or melphalan (n = 6) was started on

day-6. Graft-versus-host disease (GVHD) prevention was tapered 3 months after

SCT to augment the graft-versus-lymphoma effect. All patients engrafted, a

median of 14 days after SCT; 83 % achieved CR/partial remission (PR). With a

median follow-up of 21 months (12 to 37), 2-year PFS was 33 %. Only 3 patients

relapsed; cumulative incidence 25 %. Non-relapse mortality was 42 %,

predominantly due to acute GVHD. Zevalin-RIC is feasible with consistent

engraftment, acceptable organ toxicity, but high rates of acute GVHD. The low

incidence of relapse suggested augmented anti-lymphoma effect. The authors

stated that Zevalin-RIC merits further study. Better results may be achieved in

patients earlier in disease course and with longer duration of immune-suppression.

Lazarus and colleagues (2010) compared outcomes of 916 DLBCL patients aged

18 years or older undergoing first autologous (n = 837) or myeloablative (MA)

allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003

reported to the Center for International Blood and Marrow Transplant Research

(CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months

for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk

disease features including higher stage, more prior chemotherapy regimens, and

resistant disease. Allogeneic HCT was associated with a higher 1 year TRM

(relative risk [RR] 4.88; 95 % CI: 3.21 to 7.40, p < 0.001), treatment failure (RR

2.06; 95 % CI: 1.54 to 2.75, p < 0.001), and mortality (RR 2.75; 95 % CI: 2.03 to

3.72, p < 0.001). Risk of disease progression was similar in the 2 groups (RR 1.12;

95 % CI: 0.73 to 1.72, p = 0.59). In fact, for 1-year survivors, no significant

differences were observed for TRM, progression, PFS or OS. Increased risks of

TRM and mortality were associated with older age (greater than 50 years), lower

performance score, chemo-resistance, and earlier year of transplant. The authors

concluded that in a cohort of mainly high-risk DLBCL patients, upfront MA

allogeneic HCT, although associated with increased early mortality, was associated

with a similar risk of disease progression compared to lower risk patients receiving

autologous HCT.

van Kampen et al (2011) analyzed the outcome, including non-relapse mortality

(NRM), relapse rate (RR), PFS, and OS, of patients with diffuse large B-cell non

Hodgkin's lymphoma (DLBCL) relapsed after an ASCT and treated with an

allogeneic stem-cell transplantation (allo-SCT). The European Group for Blood and

Marrow Transplantation database was scanned for a first allo-SCT in relapsed

DLBCL after a previous ASCT between 1997 and 2006. Other inclusion criteria



Page 19 of 39

were age at allo-SCT greater than or equal to 18 years and availability of an HLA-

identical sibling or a matched unrelated donor. A total of 101 patients (57 males;

median age of 46 years) were included. Median follow-up for survivors was 36

months. Myeloablative conditioning regimen was used in 37 patients and RIC was

used in 64 patients. Three-year NRM was 28.2 % (95 % CI: 20 % to 39 %), relapse

rate was 30.1 % (95 % CI: 22 % to 41 %), PFS was 41.7 % (95 % CI: 32 % to 52

%), and OS was 53.8 % (95 % CI: 44 % to 64 %). Non-relapse morality was

significantly increased in patients greater than or equal to 45 years (p = 0.01) and in

those with an early relapse (less than 12 months) after ASCT (p = 0.01). Relapse

rate was significantly higher in refractory patients (p = 0.03). A time interval to

relapse after ASCT of less than 12 months was associated with lower PFS (p =

0.03). The use of RIC regimens was followed by a trend to a lower NRM (p = 0.1)

and a trend to a higher relapse rate (p = 0.1), with no differences in PFS and OS.

No differences were seen between HLA-identical siblings and matched unrelated

donors. The authors concluded that allo-SCT in relapsed DLBCL after ASCT is a

promising therapeutic modality. Patients with a long remission after ASCT and with

sensitive disease at allo-SCT are the best candidates for this approach.

Maura and associates (2016) noted that follicular lymphoma (FL) is the 2nd most

common histotype of NHL, and it is generally characterized by a heterogeneous

clinical course. Despite recent therapeutic and diagnostic improvements, a

significant fraction of FL patients still relapsed. In younger and/or fit FL relapsed

patients, BMT has represented the main salvage therapy for many years. Thanks

to the ability of HDC to overcome the lymphoma resistance and refractoriness,

ASCT can achieve a high CR and favorable outcome regarding PFS and OS; allo-

SCT combines the HDC effect together with the immune reaction of the donor

immune system against lymphoma, the so-called “graft versus lymphoma” (GVL)

effect. Considering the generally higher TRM, allo-SCT is mostly indicated for FL

relapsed after ASCT.

Picleanu and colleagues (2017) stated that allo-SCT is a therapeutic option for

relapsed, advanced, and otherwise incurable NHL suggested by the existence of a

graft-versus-lymphoma effect. The main complications are GVHD and infections.

These investigators performed a retrospective analysis of patients with NHL, who

received an allo-SCT between January 1995 and December 2014. The parameters

that had an impact on OS were age less than or equal to 60 years old, chemo

sensitive disease pre-allo-SCT, and indolent NHL histology. The parameters that

had an impact on PFS were age less than or equal to 60 years old and chemo



Page 20 of 39

sensitive disease pre-allo-SCT. Only aggressive NHL histology and refractory

disease pre-allo-SCT showed an increased risk of death in the multivariate model.

The use of allo-SCT for young patients with multiple relapsed chemo-sensitive

indolent NHL is a suitable option. The authors concluded that despite poor

prognosis, young aggressive NHL patients can be considered for allo-SCT provided

they have chemo-sensitive disease.

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are

neoplasms of hematopoietic origin characterized by the accumulation of

lymphocytes with a mature, generally well-differentiated morphology. In CLL, these

cells accumulate in the blood, marrow, lymph nodes, and spleen, while in SLL they

are generally confined to the lymph nodes. CLL and SLL share many common

features and are often referred to as blood and tissue counterparts of each other.

Both tend to occur in older individuals and present as asymptomatic enlargement of

the lymph nodes. Both tend to be indolent in nature but can undergo

transformation to a more aggressive form of disease. Treatment regimens used for

CLL are generally the same as those used for SLL and outcomes of treatment are

comparable for the 2 diseases. Both low- and intermediate-risk CLL and SLL

demonstrate relatively good prognoses with median survivals of 6 to 10 years, while

the median survival of high risk CLL or SLL may be only 2 years. Although typically

responsive to initial therapy, CLL and SLL are rarely cured by conventional therapy

and nearly all patients ultimately die of their disease. This natural history has

prompted the investigation of HDC as a possible curative regimen.

Compared to applications of HDC and transplant in other NHLs, there is less

literature regarding either autologous or allogeneic transplant for CLL. In general,

allogeneic transplant appears to be the preferred treatment due to the obvious

potential of marrow contamination with malignant cells associated with autologous

transplant, and due to the potential for a beneficial graft versus disease effect when

using allogeneic transplant. However, the lack of compatible donors and the older

age of most patients limit the applicability of allogeneic transplant. The European

Bone Marrow Transplantation Group (EBMTG) reported the results of allogeneic

transplant in 47 patients with B-cell CLL treated between 1984 and 1992 (Michallet

et al, 1993). All patients received HLA identical marrow donations. A total of 56 %

were in Rai stage III or IV at the time of transplant. A total of 33 (70 %) of patients

achieved a complete remission post-transplant and the projected probability of



Page 21 of 39

leukemia-free 5 year survival was 40 %. (It is unknown whether the diagnosis of

complete remission is based on histologic or more sensitive molecular criteria.)

The most important predictor of survival was stage at time of transplant. Those

transplanted in stage 0- to II had a leukemia-free survival of 60 % compared to only

20 % for those transplanted in stage IV. This study, presented in abstract form

only, provided no details regarding patient selection criteria or prior treatment. In

addition, treatment related mortality is not reported. In an earlier summary from the

EBMTG, 6 of 17 patients succumbed to treatment related mortality, primarily to

graft versus host disease (Michallet et al, 1991). In another 1991 review of

allogeneic transplant for CLL, Bandini et al estimated that the treatment related

mortality was as high as 50 %.

Rabinowe et al (1993) reported on 20 patients with poor prognosis B-cell CLL who

underwent either autologous (12 patients) or allogeneic (8 patients) bone marrow

transplantation. Poor prognosis was defined as International Workshop on CLL Rai

stage II-IV. Some patients had additional poor prognostic features such as diffuse

involvement of the bone marrow, abnormal bone marrow cytogenetics or a rapid

tumor growth rate. Additionally patients had to be less than 60 years old and had to

have a minimal disease state at the time of transplant. Minimal disease state was

defined as lymph nodes measuring less than 2 cm, absence of organomegaly and

less than 20 % involvement of the bone marrow. Nine patients had been treated

with chemotherapy prior to evaluation for transplant. The induction regimens varied

and included primarily cyclophosphamide based regimens or fludarabine. Only 3

patients were in complete remission prior to transplant. Of the 8 patients receiving

allogeneic transplants, 6 achieved a complete remission and remained in complete

remission at a median follow-up of 11.7 months. Of the 12 patients undergoing

autologous transplant, 10 achieved a complete remission and remained in complete

remission during a median follow-up of 5 months. There was only 1 treatment

related death in a patient undergoing autologous transplant. The authors

concluded that the above results were encouraging but that long-term follow-up is

necessary to determine whether the high complete response rate will translate into

increased patient survival.

Khouri et al (1994) also reported on a case-series study of 22 patients with CLL

who were treated either with autologous (11 patients) or allogeneic (11 patients)

transplant. Patient selection criteria for autologous transplant included marrow

lymphocytosis of less than 15 % at the time of transplant. The patient selection

criteria for allogeneic transplant are unclear, and it is unclear whether chemo



Page 22 of 39

sensitive disease was a requirement for either transplant option. All patients had

relapsed after fludarabine therapy and the median number of prior chemotherapy

regimens was 3. These patient selection criteria seem broader than those of

Rabinowe, described above. In Khouri's series there was not a requirement for a

minimal disease state, simply less than 15 % involvement of the bone marrow for

those undergoing autologous transplant. In fact, 8 and 4 patients had Rai stage IV

and stage III disease respectively. At the time of transplant, no patient was in

complete remission. Of the 11 patients who underwent autologous transplant, 6

achieved CR, 4 had only small foci of nodular lymphocytosis in the bone marrow

(termed a nodular CR or nCR), and 1 patient had a partial remission. Three

patients subsequently developed Richter's syndrome and died, and 2 others died in

CR of infectious complications, leaving 3 patients alive in CR, 2 patients alive with

relapsed disease and 1 patient alive in partial remission at a median of 10 months

post-transplant. The autologous marrows were purged using an immunomagnetic

technique. Nevertheless 5 had residual disease after purging as detected by flow

cytometry. Although these patients received marrows contaminated with malignant

cells, all achieved either a CR or nCR after transplant.

Of the 11 patients undergoing allogeneic transplant, 8 had stage IV disease, and 1

had stage III disease. Seven were resistant to fludarabine. Nevertheless, 7

patients achieved a CR, and 2 had a nCR. (1 patient achieved a partial remission

after an initial transplant but subsequently achieved a nCR after a second

allogeneic transplant.) One patient achieved a partial response and 1 patient died

of infectious complications. Follow-up ranged from 2 to 36 months. The authors

were particularly encouraged with the results of allogeneic transplant in this group

of patients with advanced disease who, by their estimation, had a projected survival

of only a few weeks.

Khouri et al (1998) at MD Anderson Cancer Center reported the results of

allogeneic transplant in 10 patients with chemo-refractory and recurrent low-grade

lymphomas. Two of these patients had diffuse well-differentiated lymphoma, which

is the node-based equivalent to CLL. A total of 8 of the 10 patients achieved a CR

and none have relapsed at a median follow-up of 816 days. The authors

hypothesize that a beneficial graft versus leukemia effect may be partially

responsible for these surprising results. This hypothesis is supported by the

gradual disappearance of lymph node and bone marrow involvement, reminiscent

of the graft versus leukemia effect that has been documented post-allogeneic



Page 23 of 39

transplant inpatients with chronic myelogenous leukemia (CML). This article

challenges the general assumption that high dose marrow ablative therapy is only

effective in those patients who have chemosensitive disease.

In a review of the literature, van Besien et al (2001) concluded that randomized

studies are needed to establish whether autologous transplantation confers a

survival benefit over standard chemotherapy approaches. Allogeneic

transplantation has a considerable treatment-related mortality, but durable

remissions sometimes occur in patients with advanced disease. Further

refinements of transplant techniques and properly designed prospective studies are

necessary to establish the role of stem cell transplantation in the overall

management of CLL.

Rai et al (2001) reported on new and emerging therapies for CLL. Both matched

sibling and autologous stem cells transplants are far from proven as effective and

appropriate except in a setting of prospective and peer-reviewed research protocol.

Only when properly controlled clinical trials have been conducted can this treatment

be considered for general use.

Although there is less published literature regarding either HDC with autologous or

allogeneic transplant for CLL, HDC is regarded as a useful salvage treatment for

this otherwise incurable disease. Early estimates of treatment related mortality as

high as 50 %, have not been confirmed by more recent studies from the American

literature. Rabinowe et al (1993) and Khouri et al (1994) reported a 5 and 14 %

mortality rate among 20 and 22 patients respectively. These mortality rates are

similar to those reported for other applications of HDC.

As expected, in this early stage of evolution of HDC for CLL, most patients treated

had advanced disease. Even in this population of patients CR rates have generally

been above 60 % and the rates were not different between allogeneic and

autologous transplants. Despite this encouraging intermediate outcome, there is

limited data on long-term outcomes to determine whether HDC is curative or at the

very least provides a significant improvement in survival. Given the results in

patients with advanced disease, not unexpectedly there has been interest in

offering this therapy earlier in the course of disease when the tumor burden may be

lower and there is less chance of chemo-resistant disease. However, early in the



Page 24 of 39

course of disease the risk of HDC may become unacceptable when a prolonged

indolent course is anticipated or when the patient has achieved a CR with

fludarabine therapy.

Reljic et al (2015) stated that high-dose therapy (HDT) followed by auto-HCT is

offered to patients with chronic lymphocytic leukemia (CLL) both as front-line

consolidation and in the relapsed setting. The role of HDT in the front-line

consolidation setting in CLL is uncertain. These investigators performed a literature

search of PubMed and Cochrane until November 14, 2014 and the last 2 years of

abstracts from relevant conferences. End-points included benefits (OS; progression-

free survival [PFS]; event-free survival [EFS]) and harms (adverse events, secondary

malignancies, TRM). The search identified 495 references of which 4 studies met

inclusion criteria. Altogether, 301 patients were randomized to the HDT/auto-HCT

arm and 299 patients to the control arm. Offering front-line HDT/auto-HCT did not

result in statistically significant improvement in OS (HR = 0.91; 95 % CI: 0.62 to

1.33) or PFS (HR = 0.70; 95 % CI: 0.32 to 1.52). There was

a statistically significant advantage favoring HDT/auto-HCT for EFS (HR = 0.46; 95

% CI: 0.26 to 0.83). Moreover, HDT/auto-HCT did not result in higher rate of

secondary malignancy (risk ratio [RR] = 1.06; 95 % CI: 0.55 to 2.05) or TRM (RR =

1.32; 95 % CI: 0.43 to 4.06). The authors concluded that offering HDT/auto-HCT

as front-line consolidation in patients with CLL did not improve OS. Moreover, they

stated that at present this approach should not be offered outside the context of a

clinical trial.

An UpToDate review on “Treatment of relapsed or refractory chronic lymphocytic

leukemia” (Rai and Stilgenbauer, 2015) states that “Investigational therapies -

Many agents are under active investigation. These include novel agents (e.g.,

Bruton's tyrosine kinase inhibitors other than ibrutinib, PI3-kinase inhibitors other

than idelalisib, BCL-2 antagonists [ABT-199], and flavopiridol), combinations of

agents already used in CLL; agents approved for other diseases (e.g.,

lenalidomide, dasatinib); and new antibodies (e.g., anti-CD37 antibodies). The only

known curative therapy for CLL is allogeneic hematopoietic cell transplantation.

However, most patients are not candidates for this approach. Ongoing studies are

investigating the use of chimeric antigen receptor T cells (CAR-T cells) directed at

CD19. As an example, an intriguing report described three patients with relapsed

or refractory CLL who received autologous T cells modified with a lentiviral vector

expressing chimeric antigen receptor with specificity for CD19, coupled with CD137

and CD3-zeta signaling domains after a preparatory regimen. All three patients



Page 25 of 39

demonstrated a tumor response, which persisted in one for at least 10 months.

Toxicity included severe tumor lysis syndrome. Subsequent reports suggest that

the efficacy in a larger population may be lower. Further follow-up of these patients

and larger trials are needed to determine the efficacy of this approach”.

Primary Cutaneous T-Cell Lymphoma

Schlaak et al (2012) stated that primary cutaneous T-cell lymphomas (CTCL)

belong to the group of NHL and usually run an indolent course. However, some

patients progress to advanced tumor or leukemic stages. Up to now, no curative

treatment has been established for those cases. In the last few years, several

publications have reported durable responses in some patients following allogeneic

stem cell transplantation (alloSCT). Tin a Cochrane review, these researchers

compared the safety and effectiveness of conventional therapies with alloSCT in

patients with advanced primary cutaneous T-cell lymphomas. The search strategy

included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE

(1950 to May 2011), Internet-databases of ongoing trials, conference proceedings

of the American Society of Clinical Oncology (ASCO, 2009 to present) and the

American Society of Hematology (ASH, 2009 to present). These investigators also

contacted members of the European Organization for Research and Treatment of

Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study

activities. They hand-searched citations from identified trials and relevant review

articles. In addition, RCTs from the European Group for Blood and Marrow

Transplantation (EBMT) and International Conference on Cutaneous T-cell

Lymphoma, ASCO and ASH up to 2010 were hand-searched. Genetically RCT

comparing alloSCT plus conditioning therapy regardless of agents with

conventional therapy as treatment for advanced CTCL were eligible to be included.

From eligible studies, data were extracted by 2 review authors and assessed for

quality. Primary outcome measures were OS; secondary criteria were time to

progression, response rate, TRM, adverse events and quality of life. These

researchers found 2,077 citations, but none was relevant genetically or non-

genetically RCTs. All 41 studies that were thought to be potentially suitable were

excluded after full text screening for being non-randomized, not including CTCL or

being review articles. The authors planned to report evidence from genetically or

non-genetically RCTs comparing conventional therapy and alloSCT. However, no

randomized trials addressing this question were identified. They stated that

prospective genetically RCTs need to be initiated to evaluate the precise role of

alloSCT in advanced CTCL.



Page 26 of 39

Bo and colleagues (2016) examined clinical characteristics, response, outcome,

and prognosis of peripheral blood stem cell transplantation (PBSCT) for patients

with peripheral T-cell lymphoma (PTCL). This study retrospectively analyzed the

effectiveness of PBSCT in 38 patients with PTCL. Kaplan-Meier methods were

used in survival analysis, and the Cox regression model was applied in multivariate

analysis; 10 clinical parameters were analyzed. The 2-year OS was 46 %, and the 5

year OS was 34 % after a median follow-up of 40 months. Patients who received

allogeneic PBSCT (allo-PBSCT) had a higher non-relapse mortality than

autologous PBSCT (auto-PBSCT), but they could achieve a longer-term disease-

free survival (DFS) in the former, which OS could achieve 40 %. Survival analysis

with Kaplan-Meier method showed the pre-transplant disease status, B symptoms

(systemic symptoms of fever, night sweats, and weight loss), serum lactate

dehydrogenase (LDH) in early (greater than 275 U/L), Eastern Cooperative

Oncology Group (ECOG) score (greater than 1), prognostic index for PTCL score

(greater than 2) were all prognostic factors for post-transplant OS. Pre-transplant

disease status was the only prognostic factor for allo-PBSCT. The authors

concluded that the key was to reducing transplant-related mortality of allo-PBSCT

by RIC. Factors such as level of early serum LDH, extra-nodal involvement, B

symptoms, ECOG score, Ann Arbor stage, and pre-transplant disease status were

all related to the prognosis of patients treated with PBSCT. They stated that allo-

PBSCT may be suggested as the first line therapy for late-stage PTCL patients who

could reach treatment remission before transplantation.

El-Asmar and co-workers (2016) noted that no prospective, randomized trials exist

comparing HDT followed by auto-HCT against conventional therapy for

management of PTCL either as upfront consolidation or in the relapsed/refractory

setting. Available data supporting this approach were limited to single-arm

prospective or retrospective studies only. These researchers performed a

systematic review/meta-analysis of the published literature; their search identified

1,586 publications, but only 27 (n = 1,368) met inclusion criteria. In the front-line

setting, pooled analysis of only prospective studies showed rates of PFS of 33 %

(95 % CI: 14 % to 56 %), OS of 54 % (95 % CI: 32 % to 75 %), relapse/progression

of 26 % (95 % CI: 20 % to 33 %), and TRM of 2 % (95 % CI: 0 % to 5 %); for

retrospective studies, rates of PFS, OS, relapse/progression, TRM, and secondary

malignancies were 55 % (95 % CI: 40 % to 69 %), 68 % (95 % CI: 56 % to 78 %),

36 % (95 % CI: 24 % to 48 %), 6 % (95 % CI: 2 % to 11 %), and 7 % (95 % CI: 2 %

to 14 %), respectively. On the other hand, pooled analysis of retrospective studies

evaluating HDT/auto-HCT in the relapsed/refractory setting showed pooled rates of



Page 27 of 39

PFS, OS, relapse/progression, and TRM of 36 % (95 % CI: 32 % to 40 %), 47 %

(95 % CI: 43 % to 51 %), 51 % (95 % CI: 39 % to 62 %), and 10 % (95 % CI: 5 % to

17 %), respectively. Among the various histologic subtypes, PFS and OS rates

appeared to be higher in anaplastic large cell lymphoma, regardless of disease

stage. The authors concluded that in the absence of a multi-center, RCT

comparing HDT/auto-HCT to a non-transplantation strategy, the findings of this

systematic review/meta-analysis may represent the best evidence supporting the

role of HDT/auto-HCT for treatment of PTCL as front-line consolidation or in the

relapsed/refractory setting.

Kitahara and associates (2017) stated that cyclophosphamide, doxorubicin,

vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy has been mostly

applied to patients with untreated PTCL. Because the long-term outcome of

patients with PTCL, especially those achieving CR, has not been fully elucidated,

these investigators retrospectively analyzed 78 consecutive patients initially treated

with CHOP/CHOP-like chemotherapy, without HDC followed by autologous stem

cell transplantation (HDC/auto-SCT). Median OS and PFS in all 78 patients were

44 and 17 months, respectively, with a median follow-up of 62 months. In the 53

patients achieving CR, the median relapse-free survival (RFS) was 21 months, and

2-, 3-, and 5-year RFSs were 46, 45, and 36 %, respectively. The authors

concluded that although these findings showed an unfavorable outcome for PTCL

as a whole, those who achieved CR following CHOP/CHOP-like chemotherapy did

not always have a poor outcome without the consolidation of HDC/auto-SCT; in

particular, 45 % of the 65 years or younger patients were alive without disease at 5

years.

CPT Codes / HCPCS Codes / ICD-10 Codes

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

CPT codes covered if selection criteria are met:

38205 Blood-derived hematopoietic progenitor cell harvesting for

transplantation, per collection; allogenic

38206 autologous

38230 Bone marrow harvesting for transplantation



Code Code Description

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 (MLC)

Other CPT codes related to the CPB:

38204 - 38215 Bone Marrow or Stem Cell Services/Procedures

96401 - 96450 Chemotherapy administration

Modifiers 4A -

4Z

Histocompatibility/Blood Typing/Identity/Microsatellite

HCPCS codes covered if selection criteria are met:

S2150 Bone marrow or blood-derived 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 n umber of days of pre-and post-transplant care in the global

definition

Other HCPCS codes related to the CPB:

Q0083 - Q0085 Chemotherapy administration

ICD-10 codes covered if selection criteria are met:

C82.00 - C96.9 Malignant neoplasm of lymphoid, hematopoietic and related tissue

[except Hodgkin's disease]

Page 28 of 39

The above policy is based on the following references:

1. Takvorian T, Canellos GP, Ritz J, et al. Prolonged disease free survival after

autologous bone marrow transplantation in patients with non-Hodgkin's

lymphoma with a poor prognosis. N Engl J Med. 1987;316(24):1499-1505.



Page 29 of 39

2. Raubitschek A, Goffman T, Glatstein E. A staging of lymphomas: Practical

thoughts on impractical practices. J Natl Cancer Inst Monograph.

1990;10:13-17.

3. Chopra R, Goldstone AH, Pearce R, et al. Autologous versus allogeneic

bone marrow transplantation for non-Hodgkin's lymphoma: A case-

controlled analysis of the European Bone Marrow Transplant Group

Registry Data. J Clin Oncol. 1992;10:1690-1695.

4. Williams CD, Pearce R, Taghipour G, et al. Autologous bone marrow

transplantation for patients with non-Hodgkin's lymphoma and CNS

involvement: Those transplanted with active CNS disease have a poor

outcome -- a report by the European Bone Marrow Transplant Lymphoma

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Copyright © 2001-2019 Aetna Inc.



AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0494 Hematopoietic

Cell Transplantation for Non-Hodgkin's Lymphoma

For the Pennsylvania Medical Assistance plan, if the transplant institution’s criteria are met, then the transplant will be covered.

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

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