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BMT/PSC Transplant


                                                                                    HCT Transplantation: Version 7.0

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 cell sources from bone marrow, peripheral blood, and cord blood.

Introduction

If, dear reader, you take away from this Guide just one message, it’s that anything we write here, anything at all, could be very different in a few weeks, a month, a year. The whole field of hematologic malignancies, genome anomalies, molecular transformations, and cellular therapies, is changing more rapidly than anything else in medicine. Those changes are driven by amazing discoveries in the lab, quick application to human studies, and fast translation to the bedside. Novel therapies for age-old clinical dilemmas, promises of therapies that may end the need for stem cell transplantation altogether, opportunities to use viruses to insert corrective genetic material into the right places in our genomes to correct inborn errors, halt errors in protein-building, and, through the rapidly evolving experience with CRISPR-Cas9 application, alter our genetic make-up altogether, all these raise huge ethical questions about which some believe we are ill-prepared. With that background, here is some basic knowledge to help guide you.

Basics

Hematopoietic Stem Cells: Cells that derive from embryonic stem cells and that have differentiated to the point where they are the precursors of our large collection of cells related to oxygen transplant, immune responses, natural cell death, and scavenging the remnants.

Here is a diagram of the hematopoietic stem cell differentiation process:



 

  • Sources of HSCs as used in blood and marrow transplantation are:

    • Bone Marrow: (BM) the traditional source and making a comeback due to distinct advantages in some situations

      • Primary advantages:     

        • lower risk of acute and chronic Graft Versus Host Disease (GVHD)

        • Single collection of cells usually sufficient

        • Not necessary to use drugs to mobilize stem cells.

      • Disadvantages

        • Need for procedure room, anesthesia, post-procedure donor discomfort

        • usually slightly slower time to engraftment than peripheral blood stem cells

        • average search time to find best match is about 2 months,

        • potential additional source for re-transplant if necessary

    • Peripheral Blood: (PBSC) now much more common as stem cell source.

      • Primary advantages:

        •  faster engraftment than with either BMT or CBT, and

        • greater number of stem cells (measured by CD34+ counts) retrieved than either.

      • Disadvantages:

        • Close matching required

        • 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

        • Donor exposed to mobilizing drugs with some side effects

    • Cord Blood (CB):

      • Primary advantages:

        • HLA 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.

      • Disadvantages:

        • slower engraftment, thus longer hospital stays,

        • limited cell dose so single unit adequate only for children

        • two units usually required for adults

        • no potential for re-transplant from same donor balanced, in part, by the much more rapid availability of an additional unit(s) from a different donor.

 

Types of Stem Cell Transplants (Definitions)

Autologous: Stem cell donor and stem cell 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 reduced-intensity preparation.  This approach involves a reduced-dose chemotherapy with or without total lymphoid irradiation (TLI). Essentially no GVHD risk, although some multiple myeloma patients treated under certain protocols may get an autoimmune response very like GVHD. 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 and for most lymphomas.

Allogeneic: Stem cells collected from other donors and matched through human leukocyte antigen (HLA) typing. May be 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 Be the Match (formally the National Marrow Donor Program) by law.


Important subtypes of these two categories are commonly encountered:

  • Haplo-identical transplants, where one parent (usually the mother, if possible, and for complex immunological reasons), 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 (these have grown in number dramatically over the last few years) this approach may be ideal for some candidates, particularly where a match is predicted to be difficult, or the need is critical. Some centers consider this cell source the first choice. This treatment is no long considered experimental, and the GVHD can be reasonably controlled in most settings.

  • Tandem transplants, where two stem cell transplants are a planned part of the treatment regimen. Although unusual now as treatment post-transplant has become so effective, it is carried out as an autologous transplant first, followed, after some additional chemotherapy, with another, planned, 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 planned 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., bortezomib and lenalidomide and its relatives for relapsed Multiple Myeloma).
     

Comment: Be the Match, which facilitates the allogeneic unrelated donor transplants in the US reports about 8,000 of those in 2014, up from 5500 in 2011, a 31% increase. This rise in volume has been driven by 1) increases in reduced intensity conditioning allowing older patients to undergo successful transplants, and 2) marked increases in numbers of transplants for myelodysplastic disease. The overall incidence of HCT is around 6.6 per 100,000 population and rising.  An estimated 20,000 patients underwent HCT at 200+ centers in the United States in 2014 a growth of about 20% since 2009. Roughly 12,000 of these patients received high-dose chemotherapy with autologous HCT, and about 8,000 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 hematopoietic 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 becomes 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 developed. The initial example was 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. This treatment and its second and third generation relatives has essentially eliminated transplant as a treatment for Chronic Myelogenous Leukemia (CML) see chart below).



 

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).  Despite 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 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 non-myeloablative allogeneic HCT or “reduced intensity” transplant. This technique is designed 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 have full-body radiation treatments or radiation limited to major locations of lymphoid tissues.  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 its complications in an allogeneic transplant recipient, while not suppressing the immune system so much as to prevent the graft versus tumor effect and/or causing an increase in the chance of 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 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 imatinib (Gleevec®) has already been mentioned.  Prominent among the initial 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. The number of these developed with specific targets in mind have expanded greatly. In 2015 along, the FDA approved 10 new monoclonal antibodies.

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.

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. As mentioned earlier, this has become the most common source.  As defined above, these are referred to as peripheral blood stem cells (PBSC).  This approach 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 before the cells are harvested.  The harvesting is done in one or more sessions until enough 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.  Thus, 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 most 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 Institutional-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 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.

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 imatinib and next generation tyrosine kinase inhibitors in 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 and Lymphoblastic 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).