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What's New

                                                                                    HCT Transplantation: Version 7.0

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.  It is well known that patient outcomes can be significantly improved if these guidelines are followed, although studies have shown that there is much room for improvement in timing of referrals.  The most current iteration of these guidelines may be found on the NMDP website section for physicians located here. INTERLINK highly recommends these as they are 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 is delayed referral for conditions very likely to be treatable only by early transplantation, immediately upon clinical remission, or after relapse.


SPECIAL NOTE RELATING TO THE FOLLOWING INFORMATION: As mentioned above, INTERLINK, along with most of the major quality and outcome-based 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 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 continues to evolve.  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 high, 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 fully 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 no longer a common treatment choice given the switch to aggressive monitoring to detect lingering plasma cells (“minimal residual disease or MRD) and the variety of treatments available for the remaining clonal cell types that survive the conditioning regimen. Enrollment in clinical trials is nearly always appropriate and recommended.

Patients relapsing after treatment now have the FDA-approved proteosome inhibiter bortezomib available which has shown promise in significantly improving disease-free survival. Another drug in this class, ixazomib, was approved in November of 2015. These drugs are now used with the thalidomide-like drugs plus steroids, to treat MRD. 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. These centers have 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 present in a specific patient continues to evolve, it is also critically important to seek out a center capable of sophisticated cytogenetics and molecular analysis. In addition, next generation instruments capable of identifying very small numbers of residual cancer cells are usually found only in major centers.

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. 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 in some countries. The number of institutions performing UCBT has grown accordingly in the last several years, particularly apparent since the institution of congressionally mandated National Cancer and Blood Institute (part of the National Institutes of Health) banking of cord blood. Problems do remain, as there is limited 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 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, treatment-related 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 cure, but the disease is controlled.  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 treatment-related mortality is high, the incidence of acute and chronic graft-versus-host-disease (GHVD) is high, among other issues. This may change dramatically in the next year or two as world-wide studies with imatinib and its relative forms 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.

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 (Be the Match®)

        •    Transplants are increasing for non-malignant diseases:
                    Non-Malignant Disease Stem Cell Transplants (Children’s Hospital
                    of Philadelphia)

        •    Increasing use of cord blood and PBSC grafts:
                    Cell Sources (Be the Match®)

        •    Increasing use in older (>50) patients:
                    Changes over Time, Elderly (Be the Match®)