Stem Cell Tandem Transplants Jun 17 1 National Medical Policy Subject: Tandem Stem Cell Transplants in the Adult Patient Policy Number: NMP331 Effective Date*: March 2007 Update: June 2017 This National Medical Policy is subject to the terms in the IMPORTANT NOTICE at the end of this document For Medicaid Plans: Please refer to the appropriate State’s Medicaid manual(s), publication(s), citation(s), and documented guidance for coverage criteria and benefit guidelines prior to applying Health Net Medical Policies The Centers for Medicare & Medicaid Services (CMS) For Medicare Advantage members please refer to the following for coverage guidelines first: Use Source Reference/Website Link X National Coverage Determination (NCD) Stem Cell Transplantation: http://www.cms.gov/medicare-coverage- database/search/advanced-search.aspx National Coverage Manual Citation Local Coverage Determination (LCD)* Article (Local)* Other None Use Health Net Policy Instructions Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL regions. Medicare LCDs and Articles apply to members in specific regions. To access your specific region, select the link provided under “Reference/Website” and follow the search instructions. Enter the topic and your specific state to find the coverage determinations for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare Administration Contractors (MACs) located outside their service area when those MACs have exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an LCD or article contains additional coverage information than contained in the NCD or National Coverage Manual.
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Stem Cell Tandem Transplants Jun 17 1
National Medical Policy Subject: Tandem Stem Cell Transplants in the Adult Patient
Policy Number: NMP331
Effective Date*: March 2007
Update: June 2017
This National Medical Policy is subject to the terms in the
IMPORTANT NOTICE
at the end of this document
For Medicaid Plans: Please refer to the appropriate State’s Medicaid manual(s),
publication(s), citation(s), and documented guidance for coverage criteria and
benefit guidelines prior to applying Health Net Medical Policies
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage guidelines first:
Use Source Reference/Website Link
X National Coverage Determination
(NCD) Stem Cell Transplantation:
http://www.cms.gov/medicare-coverage-
database/search/advanced-search.aspx
National Coverage Manual Citation
Local Coverage Determination (LCD)*
Article (Local)*
Other
None Use Health Net Policy
Instructions
Medicare NCDs and National Coverage Manuals apply to ALL Medicare members in ALL
regions.
Medicare LCDs and Articles apply to members in specific regions. To access your specific
region, select the link provided under “Reference/Website” and follow the search
instructions. Enter the topic and your specific state to find the coverage determinations
for your region. *Note: Health Net must follow local coverage determinations (LCDs) of Medicare
Administration Contractors (MACs) located outside their service area when those MACs have
exclusive coverage of an item or service. (CMS Manual Chapter 4 Section 90.2) If more than one source is checked, you need to access all sources as, on occasion, an
LCD or article contains additional coverage information than contained in the NCD or
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
Scientific Rationale – Update May 2016 The NCCN Guidelines (Version 3.2016) on Multiple Myeloma notes that “Potential
transplant candidates must undergo a stem cell harvest, collecting enough stem cells
for two transplants in anticipation of a tandem transplant or a second transplant,
within 6 months, as subsequent therapy. Alternatively, all patients may consider
continuation of primary therapy until the best response is reached. The optimal
duration of primary therapy after achieving maximal response is unknown; hence
maintenance therapy or observation can be considered beyond maximal response”.
The NCCN Guidelines (Version 2.2016) on Testicular Cancer notes: “Patients who do
not experience a durable complete response to first-line therapy or those who
experience a recurrence can be divided into those with a favorable or unfavorable
prognosis based on prognostic factors. These factors can be used in deciding whether
a patient is a candidate for conventional dose therapy or high-dose therapy with
stem cell support as a second line option”. Scientific Rationale – Update May 2015 Byrne et al (2015) reported on a prospective phase II clinical trial of multiple
myeloma (MM) patients who were randomized to receive a second (tandem)
autologous stem cell transplantation (ASCT) based on whether they achieved a
partial response or worse (≤PR) following initial ASCT (ASCT1). Patients who
achieved a very good partial response or better (≥VGPR) had salvage ASCT at
relapse. Seventy-five patients received conditioning therapy and ASCT1. A total of 44
patients (59%) achieved ≥VGPR, whereas 31 patients entered ≤PR and were offered
tandem ASCT. In all, 20 patients agreed to tandem ASCT. Demographic and clinical
characteristics were similar between the two cohorts except for median lactate
dehydrogenase (LDH) (P= 0.0141) and percentage of marrow plasma cells before
ASCT1 (P = 0.0047), both lower in the ≥VGPR group. Intent to treat analysis showed
that patients who achieved ≥VGPR to ASCT1 had a trend toward improved
progression-free survival (PFS) (37 vs. 26 months, P = 0.078) and superior overall
Stem Cell Tandem Transplants Jun 17 5
survival (OS) (not reached vs. 50 months, P = 0.0073). Patients with ≤PR who
declined tandem transplantation had shortened PFS (20 vs. 28 months, P = 0.05)
but similar OS (53 vs. 57.5 months, P = 0.29) compared to those who received it.
Thus, a favorable clinical response to ASCT1 identifies a low-risk group with superior
long-term prognosis despite similar PFS.
Iacobelli et al (2015) reported that previous studies have shown that obtaining
complete hematologic remission (CR) in multiple myeloma is an important predictor
of PFS and OS. This applies both to autologous and allogeneic transplantation.
However, the importance of CR obtained before vs after second transplant or
following allogeneic vs autologous transplantation is not clear. The author
investigated the role of CR analyzing data from the EBMT-NMAM2000 interventional
prospective study comparing tandem autologous/reduced intensity conditioning
allogeneic transplantation (auto/RICallo) to autologous transplantation-single or
double (auto/auto). Allocation to treatment was performed according to availability
of a matched sibling donor. Cox regression and multi-state models were applied. The
long-term probability of survival in CR was superior in auto/RICallo, both comparing
groups according to treatment allocated at start (28.8 vs 11.4% at 60 months,
P=0.0004) and according to actual administration of second transplant (25.6 vs
9.6% at 60 months, P=0.008). CR achieved before the second transplant was
predictive for PFS (hazard ratio (HR)=0.44, P= 0.003) and OS (HR 0.51, P=0.047)
irrespective of the type of second transplant. CR achieved after auto/RICallo was
more beneficial for PFS (HR=0.53, P=0.027) than CR after auto/auto (HR=0.81,
P=0.390), indicating a better durability of CR obtained after an allotransplant
procedure.
Scientific Rationale – Update May 2014 High-dose therapy with stem cell support is a critical component in the treatment
plan for eligible patients with newly diagnosed multiple myeloma (MM.) The types of
stem cell transplant (SCT) may be single autologous SCT, a tandem SCT (a planned
second course of high-dose therapy and SCT within 6 months of the first), or an
allogeneic SCT. An allogeneic SCT can either be performed after prior myeloablative
therapy or after nonmyeloablative therapy. A tandem transplant differs from a repeat
transplantation which is requested or performed more than 6 months after the first
transplant, and is used as salvage therapy after failure of initial transplantation or
relapsed disease. Nonmyeloablative therapy, also referred to as “mini transplant,”
is a technique to decrease toxicity of the allotransplant while preserving the
alloimmune graft-versus-myeloma effect. An allogeneic SCT may also follow an
autologous SCT.
Autologous SCT results in high response rates and remains the standard of care after
primary therapy for eligible patients with multiple myeloma. The NCCN Multiple
Myeloma panel recommends collecting enough stem cells for two eligible transplants
in ALL eligible patients. Per the Multiple myeloma panel, a tandem transplant with or
without maintenance therapy can be considered for all patients who are candidates
for SCT and is an option for patients who do not achieve at least a very good
partial response (VGPR) after the first autologous SCT. The benefit from the second
transplant in patients who are in complete response (CR), or VGPR and also in those
who achieve less than VGPR after the first SCT should preferably be answered in a
clinical trial. The other option for this group of patients includes maintenance
therapy or observation. NCCN notes that a randomized prospective NIH and
intergroup-supported trial is currently ongoing.
Stem Cell Tandem Transplants Jun 17 6
Imrie et al (2009) published guidelines on stem cell transplantation
recommendations in adults. Per the guidelines:
Autologous stem cell transplantation is the recommended treatment option for
eligible younger patients (under age 65-70 years) with newly diagnosed MM.
Tandem (double) autologous stem cell transplantation is an option for patients
who obtain less than a complete response to the first autologous transplant.
Repeat autologous transplantation is an option for patients with MM who relapse
after a long remission (> 2 years) to a single autologous transplant.
Allogeneic transplantation is an option for selected patients with MM including
those with high-risk cytogenetics and those whose disease is unresponsive to
primary therapy.
The guidelines states further that the evidence on the role of stem cell
transplantation in the management of multiple myeloma is rapidly emerging.
Kozelj et al (2013) reported that tandem autologous hematopoietic stem cell
transplantation (ta-HSCT) is a standard treatment for multiple myeloma (MM).
Patients receive a high-dose cyclophosphamide (CY), followed by two myeloablative
cycles of melphalan (MEL). There are scarce data about long term cardiotoxicity.
The authors studied 12 patients (62.25 ± 8.55 years) six years after the completion
of MM treatment with ta-HCST. Late cardiotoxic effects were evaluated clinically and
echocardiographically. None of the patients developed clinical signs of heart failure,
all were in sinus rhythm and NT-pro BNP concentration was elevated (778 ± 902.76
pg/mL). The left ventricular (LV) size remained normal. The LV ejection fraction did
not decrease (73.75 ± 5.67%, 69.27 ± 6.13%, p = NS). The LV diastolic function
parameters (E, A, ratio E/A and A/a) did not change significantly. In tissue Doppler
parameters we observed a nonsignificant decrease in Em (10.26 ± 2.63 cm/s, 7.57
± 1.43 cm/s) and Sm velocities (8.7 ± 0.87 cm/s, 7.14 ± 1.17 cm/s, p = NS). The
E/Em values were in an abnormal range (8.66 ± 1.05, 10.55 ± 2.03). The authors
concluded the treatment of MM with ta-HSCT, during which patients receive a high
dose CY followed by two myeloablative cycles of MEL, causes mild, chronic, partially
reversible and clinically silent cardiotoxic side-effects. However, ta-HSCT in patients
with MM is a safe regarding cardiotoxic side effects, but, because of increasing life
expectancy needs long term attention.
Gahrton et al (2013) reported long-term follow-up of prospective studies comparing
allogeneic transplantation to autologous transplantation in multiple myeloma is few and
controversial. They reported an update at a median follow-up of 96 months of the European
Group for Blood and Marrow Transplantation Non-Myeloablative Allogeneic stem cell
transplantation in Multiple Myeloma (NMAM)2000 study that prospectively compares tandem
autologous/reduced intensity conditioning allogeneic transplantation (auto/RICallo) to
autologous transplantation alone (auto). There are 357 myeloma patients up to age 69
years enrolled. Patients with an HLA-identical sibling were allocated to auto/RICallo (n =
108) and those without to auto alone (n = 249). At 96 months progression-free survival
(PFS) and overall survival (OS) were 22% and 49% vs 12% (P = .027) and 36% (P = .030)
with auto/RICallo and auto respectively. The corresponding relapse/progression rate (RL)
was 60% vs 82% (P = .0002). Non-relapse mortality at 36 months was 13% vs 3% (P =
.0004). In patients with the del(13) abnormality corresponding PFS and OS were 21% and
47% vs 5% (P = .026), and 31% (P = .154). Long-term outcome in patients with multiple
myeloma was better with auto/RICallo as compared with auto only and the auto/RICallo
approach seemed to overcome the poor prognostic impact of del(13) observed after
Stem Cell Tandem Transplants Jun 17 7
autologous transplantation. Follow up longer than 5 years is necessary for correct
interpretation of the value of auto/RICallo in multiple myeloma.
Kharfan-Dabaja et al (2013) reported that despite advances in understanding of
clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of
more effective therapies, MM remains incurable. The autologous-allogeneic (auto-
allo) hematopoietic cell transplantation (HCT) strategy is based on combining
cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive
immunotherapy. However, conflicting results have been reported when an auto-allo
HCT approach is compared to tandem autologous (auto-auto) HCT. The authors
performed a systematic search that identified 152 publications, of which five studies
(enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion
utilized biologic randomization. Assessing response rates by achievement of at least
a very good partial response did not differ among the treatment arms [risk ratio (RR)
(95% CI)=0.97 (0.87-1.09), p=0.66]; but complete remission was higher in the
auto-allo HCT arm [RR=1.65 (1.25-2.19), p=0.0005]. Event-free survival did not
differ between auto-allo HCT group versus auto-auto HCT group using per-protocol
analysis [hazard ratio (HR)=0.78 (0.58-1.05)), p=0.11] or using intention-to-treat
analysis [HR=0.83 (0.60-1.15), p=0.26]. Overall survival (OS) did not differ among
these treatment arms whether analyzed on per-protocol [HR=0.88 (0.33-2.35),
p=0.79], or by intention-to-treat [HR=0.80 (0.48-1.32), p=0.39] analysis. Non-
relapse mortality (NRM) was significantly worse with auto-allo HCT [RR
(95%CI)=3.55 (2.17-5.80), p<0.00001]. The reviewers concluded despite higher
complete remission rates, there is no improvement in OS with auto-allo HCT; but this
approach results in higher NRM in patients with newly diagnosed MM. At present,
totality of evidence suggests that an auto-allo HCT approach for patients with newly
diagnosed myeloma should not be offered outside the setting of a clinical trial.
Armeson et al (2013) utilized meta-analysis to compare tandem autologous (TA)
hematopoietic SCT (auto-HSCT) or single auto-HSCT followed by reduced intensity
conditioning (RIC), allogeneic (AR) hematopoietic SCT in the upfront management of
patients with multiple myeloma (MM). A comprehensive search strategy of published and
unpublished reports utilized the following entry criteria: newly diagnosed patients, first
autologous transplantation in both arms, use of an RIC regimen and assignment to TA or AR
based exclusively on the availability of an HLA matched donor. Six trials were identified
yielding 1192 subjects in TA and 630 in AR. Patients in AR had higher likelihoods of TRM
34. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of
autologous bone marrow transplantation and chemotherapy in multiple
myeloma. NEJM. 1996;335(2):91-97.
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