Download BMT/PSC Transplant

HCT Transplantation: Version 6.0
Note: The term hematopoietic cell transplantation (HCT) will be used throughout this
section. This refers to all forms of hematopoietic stem cell therapy: autologous and
allogeneic, including bone marrow, peripheral blood stem cell, and cord blood
transplantation.
Sources of Hematopoetic Stem Cells from related or unrelated donors
•
Bone Marrow: (BM) the traditional source and still used in some cases.
o Primary advantages:
§
lower risk of acute and chronic Graft Versus Host Disease (GVHD)
§
generally good supply of stem cells
o Close matching required,
o usually slower engraftment than peripheral blood stem cells,
o average search time to find best match is about 2 months,
o potential source for re-transplant if necessary
•
Peripheral Blood: (PBSC) now much more common as stem cell source.
o Primary advantages:
§
faster engraftment than with either BMT or CBT, and
§
greater number of cells (measured by CD34+ counts) retrieved than
either.
o Close matching required
o GVHD risk is higher than BM, and the chronic form is often more difficult to
treat than the chronic forms arising from the other two sources
o as source for re-transplant is about the same as BM.
•
Cord Blood (CB):
o Primary advantages:
§
match doesn’t have to be as close as with the other sources,
§
donor blood may be available in half the time of PBSC or BM, and
§
there is lower risk for both acute and chronic GVHD.
o Disadvantages:
§
slower engraftment, thus longer hospital stays,
§
limited cell dose, and
§
no potential for re-transplant from same donor balanced, in part, by the
much more rapid availability of a second unit from a different donor.
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Types of Stem Cell Transplants (Definitions)
Autologous: Stem cell donor and recipient are the same individual. Is the safest type of
transplant whether given in setting of complete elimination of blood forming elements by
chemotherapy and/or radiation (myeloablative) or partial elimination through reducedintensity preparation which is reduced-dose chemotherapy with or without total lymphoid
irradiation (TLI). No GVHD risk. Used primarily for “rescue” therapy after undergoing
treatment for non-blood-borne conditions like solid tumors, and for conditions in which
the retrieved cells can be treated to remove most of the offending (cancerous) cells. It is
the primary form of HSCT used in transplant-eligible multiple myeloma patients.
Allogeneic: Stem cells retrieved from others and matched through human leukocyte
antigen (HLA) typing, either related to the patient (Matched Related Donor or MRD) or
not related (Matched Unrelated Donor or MUD). Cord blood transplants are a type of
MUD transplants. In the USA, all MUDs are managed through the National Marrow
Donor Program by law.
Subtypes of these two categories commonly encountered include:
• Haplo-identical transplants, where one parent (usually the mother, for
complex immunological reasons), although not a good match through
HLA typing, donates stem cells that contain a match for the part of their
offspring’s DNA that was inherited from that parent. High anti-tumor
effects are achieved at the cost of increased GVHD and severe infections.
Solutions for these problems are surfacing and in the right centers (there
are only a few of them) this investigational approach may be ideal for
some candidates.
•
Tandem transplants, where two stem cell transplants are a planned part of
the treatment regimen. Usually given as an autologous transplant first,
followed after some additional chemotherapy with another autologous or
occasionally an allogeneic transplant. Most common use is in the
treatment of Multiple Myeloma and some lymphomas in adults and for
treatment of neuroblastomas and other solid chemo-sensitive tumors in
children. As of this writing, the use of tandem transplants is diminishing
but no longer considered investigational for Multiple Myeloma by most
insurers. The bulk of the decline has been due to the increasing availability
of cord blood, haplo-identical transplants, and better pharmaceuticals (e.g.
bortezamib and thalidomide and its relatives for Multiple Myeloma).
Comment: The National Marrow Donor Program which facilitates the allogeneic
unrelated donor transplants in the US reports about 5500 of those in 2011, up from 4800
in 2009, which represents a 8.7% increase. The overall incidence of HCT is around
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6.6 per 100,000 population and rising. An estimated 16,790 patients underwent HCT at
200+ centers in the United States in 2009. Roughly 9,778 of these patients received highdose chemotherapy with autologous HCT, and about 7,012 patients underwent allogeneic
HCT. Using data from the Center for International Blood and Marrow Transplant
Research and the U.S. National Cancer Center, current estimates of the lifetime
probability of receiving a hematopoetic stem cell transplant is now hovering around 1 in
200 people.
General Features of Stem Cell Therapy
The field of stem cell therapy continues its rapid evolution. The indications for
autologous and allogeneic HCT are changing as more is known about the cytogenetics of
the leukemias and lymphomas and as newer methods of addressing the specific
intracellular metabolic defects associated with these illnesses are being developed. The
most well-known example of this kind of “targeted” therapy has been the development of
tyrosine kinase inhibitors (like Gleevec®) that interfere in the overproduction of an
enzyme (tyrosine kinase) that prolongs cell life in chronic myeloid leukemia.
In addition to changing indications for HCT, there continue to be major advances,
reported in the literature almost every week, in our understanding of the way in which
HCT benefits the patient. In the case of autologous HCT, as sometimes used in the
treatment of lymphomas and Multiple Myeloma, patients receive their own cells
following treatment with lethal doses of chemotherapy and total body irradiation (TBI).
This is more properly referred to as high-dose chemotherapy with stem cell rescue rather
than as a transplant. However for practical and insurance applications, it is common to
classify these as “transplants”.
Traditionally, the goal of therapy in an allogeneic HCT has been to ablate the tumor with
pre-transplant chemotherapy and TBI and then to rescue the patient with the donor stem
cells. Observations in identical twins who received different types of allogeneic
transplants led to questioning the basic assumptions behind this approach. Identical twins
who received marrow from the genetically identical sibling (syngeneic transplant) had a
much higher rate of tumor recurrence than identical twins who received marrow from
unrelated donors (allogeneic). In spite of the differences in disease recurrence, there was
no difference in overall mortality between the two groups. This has been attributed to
treatment toxicity in the twins receiving allogeneic transplants.
These observations led to the appreciation that the major desirable effect of the allogeneic
transplant is not that the patient’s leukemic or lymphoma cells are eliminated by lethal
doses of chemotherapy and TBI with marrow replacement by a healthy cell line from the
donor. Rather, the principal benefit appears to be that the donor cells are reacting against
residual tumor cells (graft versus tumor effect – GVT) in addition to repopulating the
patient’s marrow with healthy cells. Given this new understanding, much more attention
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is being paid by major transplant centers to balance this GVT effect with the concomitant
increase in graft versus host disease (GVHD) as described in more detail below.
One of the ways this new understanding is being put into practice is in the nonmyeloablative allogeneic HCT or “reduced intensity” transplant (sometimes called “minitransplant”). This technique is an attempt to induce a state of what is termed “mixed
chimerism” in the recipient where the marrow contains both lines of stem cells, the
recipient’s and the donor’s. The challenge here is to balance the competing effects of
treatment toxicity, graft versus tumor effect and graft versus host disease (GVHD).
In the case of a non-myeloablative HCT, the patient is given a reduced dose of the
conditioning regimen and may or may not have localized or full-body radiation
treatments. The goal is not to ablate the tumor with treatment as is the case with the
traditional allogeneic HCT, but to suppress the recipient’s immune system sufficiently to
allow engraftment of the donor stem cells which will then react against the residual
tumor. Obviously, immunosuppression in the post-transplant period must achieve a
delicate balance to minimize the severity of graft versus host disease (GVHD) and the
expected complications of an allogeneic transplant, while not suppressing the immune
system so much as to prevent the graft versus tumor effect and cause an increase in
severe infections. Frequently, these patients will receive boosts of donor cells to further
enhance the graft versus tumor effect. These are given in the form of donor lymphocyte
infusions (DLI). DLI does not constitute a separate transplant.
Because the non-myeloablative HCT is associated with less treatment toxicity, this
approach has opened up treatment possibilities for older patients with leukemia,
lymphoma and multiple myeloma who would not ordinarily be candidates for allogeneic
HCT. Protocols have been developed that are currently under investigation that utilizes
non-myeloablative HCT in older patients with refractory myeloma who may or may not
have previously undergone an autologous HCT (see Multiple Myeloma below). In many
centers, the age range has been increased to 70 years for suitable candidates.
Newer agents are being introduced, of which Gleevec has already been mentioned.
Prominent among these new agents that have gained widespread use are the monoclonal
antibodies (rituximab [Rituxan®], alemtuzumab [Campath®], for example) that are
directed at specific cell lines that are important in the body’s natural defenses against the
tumor or at those cell lines that help the body accept the new graft. Another novel
approach is to bind therapeutic agents including radioactive agents to a monoclonal
antibody so that they will be delivered selectively to a specific cell line. Ibritumomab
tiuxetan (Zevlin®) for example, is labeled with radioactive forms of indium or yttrium
that, when given to patients with B lymphocyte cancers like B-cell lymphoma, binds with
and kills normal and malignant B-cells, but not B-cell precursors which can then
repopulate the immune system with normal B-cells.
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Distinct from tandem transplants, which are planned to be a series of HCTs as part of a
defined treatment protocol, there are many instances where a patient has suffered a
relapse following an initial autologous HCT as part of a definitive treatment plan. In this
instance, a second HCT may be offered. This will likely be an allogeneic HCT and may
be offered as part of a phase II or III investigational protocol. In the setting of failed
aggressive initial management, “standard” care may not have much to offer the patient,
thus it is reasonable to consider an IRB approved investigational protocol.
Donor stem cell harvesting is generally through apheresis, the process of separating blood
components, returning those not needed to the donor, and keeping those required for
treatment for possible cellular manipulation and later use. This has become the most
common source. As defined above, these are referred to as peripheral blood stem cells
(PBSC). This has the obvious advantage of being a much less invasive procedure for the
donor and much less uncomfortable than the process of harvesting bone marrow. The
donors are pre-treated with colony stimulating (CSF) and - in autologous stem cell
harvesting- mobilizing factors (plerixafor) to stimulate the production of immature cells.
Then, the cells are harvested. The harvesting is done in one or more sessions until a
sufficient number of cells have been obtained. There are differences in outcomes for
patients receiving cells collected through apheresis versus bone marrow. The principal
difference may be a somewhat better graft versus tumor effect accompanied by an
increased incidence of GVHD as mentioned above. For the donor, the long-term
consequences of receiving CSF are not known. The donors are being followed by the
NMDP to see what the long-term consequences, if any, will be. So far, none have
surfaced.
As you can see from the foregoing discussion, the field of stem cell therapy is a dynamic
and rapidly evolving one. As a result, there are many phase II and III clinical trials being
run by the major academic centers and cooperative groups in the US and abroad. The
best approach for many illnesses treated by HCT is no longer known with certainty. In
fact, in most of the major HCT programs, fewer than 50 percent of patients may be
offered treatment under standard care protocols. It is our opinion, and one shared by the
majority of major health plan medical directors, that our clients should be open to
considering coverage for their members when the physicians at an INTERLINK Health
Services Transplant Network center, or at other quality-based, reputable Center of
Excellence network propose HCT as part of an Insitutional-Review-Board approved
clinical trial. Most of the Blood and Marrow Transplantation centers in the INTERLINK
Health Services Transplant Network are major tertiary care centers that are well known
as leading centers in their field. They participate in multicenter trials sponsored by the
NIH, NCI and cooperative treatment groups. The results of these trials are published in
peer-reviewed journals that are considered to be authoritative journals in their field.
Because of the foregoing, when participation in a phase II or III clinical trial is suggested
by the treating physician, we feel that it is worth the time and effort to investigate the
proposed protocol and to have it reviewed by an independent reviewer if necessary.
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AUTOLOGOUS TRANSPLANTATION
The decline in the volume of autologous HCTs in the early 2000s with the release of the
generally negative results of clinical trials of high-dose chemotherapy (HDC) with
autologous stem cell therapy (ASCT or BMT) for breast cancer has pretty well been
reversed, due largely to the widespread use of Gleevec as well as related second and
third-generation drugs of its type as standard care in patients with chronic myelogenous
leukemia (CML). Transplants for this condition have declined substantially over the last
6 years. However, allogeneic transplants for Acute Myeloblastic Leukemia, Acute
Lymphocytic Leukemia, other Leukemias and Lymphomas, Myelodysplastic Syndromes,
and plasma cell disorders (e.g. multiple myeloma) have increased dramatically.
An additional factor in the increase has been a steady rise in the number of autologous
transplants performed in conjunction with solid tumor treatments – particularly for germ
cell cancers (testicular, ovarian and other related cancers).
What’s New in Blood and Marrow Transplantation?
1. Updated first year billed charges from Milliman:
See tables at the end of this Quick Reference Guide.
2. Guidelines for Timing of Referrals for HCT:
The NMDP and ASBMT have jointly published recommendations for the timing of
referrals for HCT. Patient outcomes can be significantly enhanced if these guidelines are
followed. The most current iteration of these guidelines may be found on the NMDP
website under “Recommended Timing for Transplant Consultation”
(http://www.marrow.org/PHYSICIAN/Tx_Indications_Timing_Referral/Recommended_
Timing_for_Tx_Cons/index.html). INTERLINK highly recommends these as being of
significant value to patients and to those involved in managing cases covered by these
guidelines. The largest complaint of the major blood and marrow transplant centers
around the country are late referrals for conditions very likely to be treatable only by
early transplantation, immediately upon clinical remission, or after relapse.
WHAT’S NEW FOR SPECIFIC CONDITIONS?
SPECIAL NOTE RELATING TO THE FOLLOWING INFORMATION: As
mentioned above, INTERLINK, along with most of the major quality and outcomebased transplant networks, supports active recruitment to these important trials when
conducted at participating centers under approved NIH or NIH sponsored cooperative
group protocols. The specifics of conditions, the rising ability to assess genotypes to
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shape therapies, and the rapid appearance of novel treatments showing great promise
cannot be effectively assessed without widespread, multicenter, high-quality trials to
gain the greatest improvement in outcomes.
Multiple Myeloma:
The treatment of multiple myeloma is evolving rapidly. High-dose chemotherapy
with autologous stem cell rescue has been standard care for the past few years for
those patients classified as high risk, but with the results of recent studies and the
arrival of novel therapies, the decisions for optimum treatment have become even
more complex. For example the risk of relapse with autologous transplant remains
continuous, but the transplant-related mortality is low. The opposite is true of
allogeneic transplantation – complete remission has been reported at up to 60%
with a 30 – 40% long-term survival, but transplant-related mortality is high.
Autologous transplant following high-dose-chemotherapy is a common approach
in appropriate low-risk patients, and two trials have shown that those attaining
complete remission don’t really benefit from a second (or “tandem”) transplant. A
treatment plan of a high-dose preparation regimen followed by an autologous
transplant then a non-myeloablative course of chemotherapy followed by a
matched related donor allograph, if available, is gaining acceptance based on
encouraging trial results. Although autologous transplants are no longer
considered experimental for this condition, allographs are as of the date of this
writing. Candidates for these should be entered into appropriate multi-center
trials.
Patients relapsing after treatment now have the FDA-approved proteosome
inhibiter bortezomib available which has shown promise in significantly
improving disease-free survival. There has also been important work in tailoring
the treatment plan to specific patient characteristics such as physiologic age, renal
function, and cytogenetics. As an example of the latter, patients who don’t have a
genetic translocation called t(4;14)(p16.3;q32) have much better outcomes from
high-dose chemotherapy than do patients with such a translocation, therefore,
those patients may have better outcomes by going directly to transplant.
The above paragraphs should alert the reader to the absolute necessity of getting
multiple myeloma (MM) patients to a center which treats significant numbers of
MM and has the capacity to do the special studies and tailored treatment plans
that give the lowest chance for complications and the best opportunity for good
outcomes for the individual patient. As treatment tailored to the individual genetic
abnormality involved in a specific patient continues to evolve, it is also critically
important that a center capable of sophisticated cytogenetics analysis be sought.
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Cord Blood Transplants:
The first unrelated cord blood transplant in the United States took place at Duke
University in 1993. Since then, an estimated 9,500 – 10,000 have been performed
worldwide and the use is growing as new opportunities and processes are
developed. There are several reasons for this. One is the markedly reduced
incidence of acute graft versus host disease (aGVHD) in those receiving an
unrelated cord blood transplant (UCBT) compared with a matched sibling donor.
Another is that among non-Caucasians, finding matched unrelated donors is often
a challenge. Overall, only about 30% of those needing HCT have a matched
sibling. A rough estimate is that an additional 25,000 patients needing, but not
getting, an HCT could be treated if donors were available and UCBT offers a
major opportunity to treat these patients.
It is estimated that there may be as many as 100,000 units of cord blood banked
worldwide (although of varying technical quality) and the number of institutions
performing UCBT has grown accordingly in the last several years. This has been
particularly apparent since the institution of congressionally mandated National
Cancer and Blood Institute banking of cord blood. Problems do remain, with wide
public access to stored cord blood because of the proliferation of private cord
blood banking services.
There are drawbacks of cord blood for HCT. These include relatively small cell
doses leading to a high rate of failure to engraft, prolonged hospitalizations
secondary to slow engraftment and graft failures. The advantages are that HLA
matching is less critical than with other stem cell sources and there is less graft
versus host disease (GVHD) as mentioned above. Various protocols have proven
to be quite successful in overcoming the problem of the small cell dose including:
1) in vitro expansion of the stem cell line, thus potentially increasing the number
of pluripotent stem cells available for engraftment and 2) using two cord samples
instead of one, e.g., “double cord” transplantation. In this case, even though two
genetically different cord bloods are introduced, only one will survive.
Nevertheless, the addition of the second cord seems to improve the time to
engraftment and reduce failures of engraftment. Cord blood transplants are
becoming standard care when applied to small children for whom the cell dose
is appropriate. However, when applied to older children and adults where the
cell dose is small for size and the above methods of enhancing graft efficacy are
used, cord blood transplants are best done within approved trials at large and
experienced centers.
Chronic Myelogenous Leukemia (CML) - Latest Thinking:
CML is a chronic blood cancer that has an incidence of about 15 per million
population and represents about 20% of all adult leukemias. The most common
environmental cause seems to be previous exposure to ionizing radiation. CML
has two distinct phases – the chronic phase which can last 4-6 years after first
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diagnosis, and the accelerated phase having two components: the accelerated
phase lasting up to a year, and the blast crisis which is usually fatal in a few
months.
As opposed to the earlier era when early transplant was the norm, treatmentrelated mortality was high, and successful donor matching was problematic,
Imatinib (Gleevec), along with other newer tyrosine kinase inhibitors are now
acknowledged to be standard care for virtually everyone with CML. Thus, the
number of stem cell transplants for CML has declined dramatically. However,
not all patients respond to Gleevec. Gleevec failure is about 4% per year with
50% of these presenting with molecular relapse only and 50% with accelerated
phase or blast crisis. Patients receiving tyrosine kinase inhibitors should be
followed closely at centers that are experienced with these patients and that have
the necessary monitoring procedures in place to identify non-responders and
relapses promptly so that rescue treatment can be initiated early. Once patients
have relapsed into blast crisis, it may be too late to salvage them. Early
identification of genetic subtypes and of primary non-responders and relapses
proceeding to early and effective alternative interventions is crucial to survival.
Patients treated with Gleevec and its relatives probably are not cured. Many, if
not all, will relapse. The best responders to drug therapy are those in the first
4 years of their diagnosis and those in the lowest risk categories (young age,
favorable cytogenetics). Most centers are recommending early allogeneic
transplants only for those in the highest risk categories since the treatmentrelated mortality is high, the incidence of acute and chronic graft-versushost-disease (GHVD) is high, among other issues. This may change
dramatically in the next year or two as world-wide studies with imatinib in
higher doses and for patients in the accelerated phase are showing promising
results.
With these options now available, state-of-the-art monitoring of patients
during treatment becomes critical. Monitoring with quantitative polymerase
chain reaction (PCR) tests to detect early primary failures or mutations in
the Brc-Able gene responsible for the bulk of the CML is now considered
standard.
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Other trends in allogeneic transplants as reported by the National Marrow Donor Program
(with associated web links)
•
Transplants are increasing for AML, ALL, MDS, and the lymphomas
Transplant by Patient Diagnosis
•
Transplants are increasing for non-malignant diseases
Transplants for Non-Malignant Diseases
•
Increasing use of cord blood and PBSC grafts
Cell Sources for Transplant
•
Increasing use in older (>50) patients
Recipient Age - Allographs
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Diseases Associated With HCT
Adults:
Condition
Diagnoses
Autologous HCT
ICD9: 201.xx through
205.xx, 238.7, 174.x,
186.x, 183.x, 194.0,
170.9, 171.9, 277.3,.0, ,
189V42.81, V42.82
Acute myelogenous leukemia (AML)
Acute lymphoblastic leukemia (ALL)
Chronic myelogenous leukemia (CML)
Chronic lymphocytic leukemia (CLL)
Myelodysplastic syndromes (MDS)
Hodgkin’s disease (HD)
Non-Hodgkin’s lymphoma (NHL)
Multiple myeloma (MM)
Solid tumors including:
• Breast cancer
• Germ cell/testicular tumors
• Ovarian cancer
• Neuroblastoma
• Ewing’s sarcoma
• Rhabdomyosarcoma
• Renal cell carcinoma
Primary amyloidosis
S/P bone marrow or peripheral stem cell transplant
Allogeneic HCT
ICD9: 201.xx through
205.xx, 238.7, 284.x,
283.2, 174.x, 186.x,
183.x, 194.0, 170.9,
171.9, 172.x, 277.3,
996.85, V42.81, V42.82
Acute myelogenous leukemia (AML)
Acute lymphoblastic leukemia (ALL)
Chronic myelogenous leukemia (CML)
Chronic lymphocytic leukemia (CLL)
Myelodysplastic syndromes (MDS) including:
• Aplastic anemia
• Paroxysmal nocturnal hemoglobinuria
Hodgkin’s disease (HD)
Non-Hodgkin’s lymphoma (NHL)
Multiple myeloma (MM)
Solid tumors including:
• Breast cancer
• Germ cell/testicular tumors
• Ovarian cancer
• Neuroblastoma
• Ewing’s sarcoma
• Rhabdomyosarcoma
• Renal Cell
• Metastatic melanoma
Amyloidosis
Graft failure
S/P bone marrow or peripheral stem cell transplant
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Pediatrics:
Condition
Diagnoses
Autologous
ICD9: 201.xx through
205.xx, 194.0, 191.6,
170.9, 186.x, 189.0,
V42.81, V42.82
Acute myelogenous leukemia (AML)
Acute lymphoblastic leukemia (ALL)
Allogeneic
ICD9: 201.xx through
205.xx, 191.6, 170.9,
186.x, 189.0, 279.xx,
277.5, 284.x, 282.4,
282.6x, 756.52, 996.85,
V42.81, V42.82
Acute myelogenous leukemia (AML)
Acute lymphoblastic leukemia (ALL)
Juvenile chronic myeloid leukemia (JCML)
Juvenile myelomonocytic leukemia (JMML)
Myelodysplastic syndromes (MDS)
Hodgkin’s disease (HD)
Non-Hodgkin’s lymphoma (NHL)
Solid tumors including:
• Medulloblastoma
• Ewing’s sarcoma
• Germ cell tumors
• Wilm’s tumor
Non-malignant disorders including:
• Histiocytic disorders
• Immunodeficiency
• Inborn errors of metabolism
• Congenital bone marrow failure
• Acquired aplastic anemia
• Thalassemia major
• Sickle cell anemia
Osteopetrosis
Graft failure
S/P bone marrow or peripheral stem cell transplant
Hodgkin’s disease (HD)
Non-Hodgkin’s lymphoma (NHL)
Neuroblastoma
Solid tumors including:
• Medulloblastoma
• Ewing’s sarcoma
• Germ cell tumors
• Wilm’s tumor
S/P bone marrow or peripheral stem cell transplant
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Indications for HCT1
Indications for Hematopoietic Stem Cell
Transplants for Age ≤ 20yrs
in the United States, 2009
700
Allogeneic (Total N=1,815)
Autologous (Total N=787)
Number of Transplants
600
500
400
300
200
100
0
Other
Cancer
ALL
AML
Aplastic MDS/MPS
Anemia
HD
NHL
CML
Other
Leuk
NonMalig
Disease
Slide 9
SUM-WW11_9.ppt
Indications for Hematopoietic Stem Cell
Transplants in the United States, 2009
5,500
Allogeneic (Total N=7,012)
5,000
Autologous (Total N=9,778)
Number of Transplants
4,500
4,000
3,500
3,000
2,500
2,000
1,500
1,000
500
0
Multiple
Myeloma
NHL
AML
HD
ALL
MDS/MPD Aplastic
Anemia
CML
Other
Leuk
NonOther
Malig Cancer
Disease
Slide 8
SUM-WW11_8.ppt
1
Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIMBTR
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Summary Slides, 2011. Available at: http://www.cibmtr.org.
Recommended Timing of Referral for HCT Evaluation
The following recommendations have been published jointly by the NMDP and ASBMT
in 2009 and represent the consensus of an expert panel of nationally recognized bone
marrow transplant physicians.
Source: Evidence-based Reviews, American Society of Blood and Marrow Transplantation, 2009.
Published in Biology of Blood and Marrow Transplantation and available online at:
http://www.marrow.org/PHYSICIAN/Tx_Indications_Timing_Referral/Recommended_Timing_for_Tx_C
ons/PDF/recommended_timing.pdf
Adult Leukemias and Myelodysplasia
1. Acute Myelogenous Leukemia
High-risk AML including:
• Antecedent hematologic disease (e.g., myelodysplasia (MDS))
• Treatment related leukemia
• Induction failure
CR1 with poor-risk cytogenetics
CR2 and beyond
2. Acute Lymphoblastic Leukemia
CR1 up to age 35
High-risk over age 35 including:
• Poor-risk cytogenetics (e.g., Philadelphia chromosome (t(9:22)) or
11q23 rearrangements)
• High WBC (> 30,000 – 50,000) at diagnosis
• CNS or testicular leukemia
• No CR within 4 weeks of initial treatment
• Induction failure
CR2 and beyond
3. Myelodysplastic Syndromes (MDS)
Intermediate-1 (INT-1, internmediate-2 (INT-2) or high IPSS score which
includes either:
• > 5% marrow blasts
• Other than good risk cytogenetics (good risk includes 5q- or
normal)
• > 1 lineage cytopenia
4. Chronic Myelogenous Leukemia (CML)
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•
•
•
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No hematologic or minor cytogenetic response 3 months postimatinib (Gleevec) initiation
No complete cytogenetic response 6 to 12 months post-imatinib
initiation
Disease progression
Accelerated phase
Blast crisis (myeloid or lymphoid)
Pediatric Acute Leukemias
1. Acute Myelogenous Leukemia (AML)
• Monsomy 5 or 7
• Age < 2 years at diagnosis
• Induction failure
CR1 with HLA matched sibling donor
CR2 and beyond
2. High-Risk Acute Lymphoblastic Leukemia (ALL)
• Induction failure
• Philadelphia chromosome positive
• WBC > 100,000 at diagnosis
• 11q23 rearrangement
• Mature B-cell phenotype (Burkitt’s lymphoma)
• Infant at diagnosis
CR1 Duration < 18 months
CR3 and beyond
Lymphomas
1. Non-Hodgkin’s Lymphoma
Follicular
• Poor response to initial treatment
• Initial remission duration < 12 months
• Second relapse
• Transformation to diffuse large B-cell lymphoma
Diffuse Large B-Cell
• At first or subsequent relapse
• CR1 for patients with high or high-intermediate IPI risk
• No CR with initial treatment
Mantle Cell
• Following initial therapy
2. Hodgkin’s Lymphoma (Hodgkin’s Disease)
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No initial CR
First or subsequent relapse
Multiple Myeloma
• After initiation of therapy
• At first progression
Patient Selection Criteria
Patient selection criteria will vary by center. The following criteria are representative.
For specific patient selection criteria, INTERLINK Health Services Transplant Network
encourages the referring case managers and physicians to contact the center directly to
discuss the proposed referral candidate.
Source: National Marrow Donor Program
http://www.marrow.org/PHYSICIAN/Tx_Indications_Timing_Referral/Evaluating_Adult_Patient
s_Prio/index.html
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Good performance status (ECOG 01 or KPS > 70 percent)
No serious neurologic or psychiatric condition
Serum creatinine < 1.5 mg/dl or creatinine clearance > 60cc/minute
Cardiac left ventricular ejection fraction, non-cardiac MUGA scan > 50 percent
Pulmonary diffusion capacity (DLCO) and an FEV1 on pulmonary function
testing must be > 60 percent
Bilirubin < 2 mg/dl, SGOT and SGPT < 2x upper limit of normal and stable
Patients must be HIV negative and have no active infections
Patients must be willing to sign informed consents and cooperate with extensive
follow-up examinations
Patients must have evidence of source of financial support (insurance) for the
transplant
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Contraindications
Source: multiple programs
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Significant systemic or multi-system disease
Severe noncorrectable cardiac, vascular or lung disease
Active or extrapulmonary infection
Significant hepatic disease
Significant renal disease
Cachexia or morbid obesity
Current cigarette smoking
Drug or alcohol abuse
Psychiatric illness
Severe osteoporosis
For allogeneic transplants, generally age > 55 years is a contraindication. With
the newer, non-myeloablative techniques older patients tolerate the procedure
better. This opens treatment possibilities to patients older than 55 years.
Survival Following HCT
Patient survival is highly dependent on the underlying disease, its stage, prior treatment,
the patient’s age and co-morbidities. In general, patients undergoing autologous HCT
tolerate the procedure fairly well and, following engraftment, their prognosis is that of the
underlying disease that has been modified (hopefully) by the treatment. In contrast,
patients undergoing an allogeneic HCT face a whole host of problems related to the
toxicities of the procedure, the sequel of receiving stem cells from another donor and the
long-term effects of immunosuppression, GVHD, fungal infections, viral infections, posttransplant tumors, etc. These are in addition to the effects of the natural history of the
underlying illness that may not have responded to treatment. The overall one-year
mortality varies tremendously with diagnosis, stage of the disease, etc. and can vary from
as low as 10 percent survival to as high as 90 percent survival. Overall, one-year
mortality for patients undergoing allogeneic HCT is approximately 50 percent.
Unfortunately, unlike solid organ transplantations, the number of variables is so large and
the number of centers performing HCT is so large that it has been nearly impossible to
perform center specific, transplant specific outcomes analyses that have statistical
credibility. For this reason, the INTERLINK Health Services Transplant Network does
not report comparable center specific outcome results as we do with solid organ
programs. The NMDP reports self-reported outcomes by disease for those centers
submitting voluntary data, but in the very near future, by congressional mandate,
outcomes by center by specific disease will be reported. In the meantime, it is most
important to evaluate each program individually and understand the relative strengths and
weaknesses of each program when making the best selection for your members. The
factors that we feel are important when evaluating HCT programs are:
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Tertiary care center recognized as a leading transplant center with a regional
and/or national reputation. The center will receive referrals from other major
medical centers in the area because of that expertise.
The center offers autologous, related donor allogeneic and unrelated donor
allogeneic transplants to adults and children.
The program has been in existence for at least three years with substantially the
same professional team.
The program director has had at least two years experience as a stem cell
transplanter and is engaged in HCT full-time.
The center meets ASBMT standards.
The center is FACT accredited.
The center is a member of the NMDP.
The center participates in clinical trials of substantial merit sponsored by multicenter organizations such as ECOG, COG, SWOG, NIH, NCI, etc. and the results
of these trials are published in peer reviewed journals that are recognized as
authoritative journals in their field.
The center is affiliated with a university and, if it has a post-graduate training
program, that program meets ASBMT standards.
One or more of the following: participation in NCCN, the NCI Clinical Trials
Network and designation as a NCI Comprehensive Cancer Center or NCI Clinical
Cancer Center.
All care is performed under institutionally approved protocols; either standard
care or an IRB approved clinical trial.
All patients are evaluated within the program and patient selection is performed
using institutionally approved protocols administered by an institutionally based
patient selection committee.
The transplant takes place and all subsequent care is rendered within the
institution where the patient was evaluated.
All pre and post-transplant care is coordinated by full-time employees of the
institution.
There is close communication with the referring physician and health plan.
Housing in the immediate vicinity of the center is available for families and
patients and the center staff assists the families with these arrangements.
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Risk Factors Associated with Decreased Survival Following HCT
Patient survival can be looked at over two time intervals: the first 100 days following
initiation of ablative therapy or the conditioning regimen in the case of nonmyeloablative transplants and one-year following the transplant. The factors that
influence the outcome are different in these two phases of recovery.
First 100 Days:
• Age. Younger patients do better than older patients. The basic cohorts are < 20
years, 20-55 years and > 55 years.
• Condition of the patient at the time of transplant
• Underlying diagnosis
• Treatment toxicity
• Consequences of pancytopenia and profound immunosuppression, such as
infection, hemorrhage, impaired nutrition, etc.
• Failure to engraft
• Severe acute GVHD
• Center specific issues: knowledge and experience of the team, facility factors,
consultants who are knowledgeable about transplant patients, etc.
First Year:
• Acute and chronic GVHD
• Complications of immunosuppression
• Failure of engraftment or incomplete marrow recovery
• Post-transplant lymphoproliferative disease (PTLD)
• Disease recurrence
• Compliance
• Lack of psychosocial support
In general, if patients survive the first one to two years following allogeneic HCT, they
tend to have a favorable outlook. We suggest that clients familiarize themselves with
these outcomes which can be found at:
http://www.marrow.org/PHYSICIAN/Outcomes_Data/index.html. The most current
available survival information is presented here.
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Average Billed Charges
Estimated US average billed charges per HCT projected for 2011: 1
Autologous
30 Days Pre-Transplant
Procurement
Hospital Transplant Admit
Physician Transplant Admit
180 days Post Transplant Admit
OP Immunosuppressant & RX
Total
$44,600
18,200
198,200
10,800
84,900
7,100
$363,800
Allogeneic – Related & Unrelated Donor
30 Days Pre-Transplant
Procurement
Hospital Transplant Admit
Physician Transplant Admit
180 days Post Transplant Admit
OP Immunosuppressant & RX
Total
$41,400
38,900
419,600
22,400
259,800
23,300
$805,400
1
2011 US Organ and Tissue Transplant Cost Estimates and Discussion.
http://www.milliman.com/Milliman. April 2011. Accessed 24 January 2013.
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