Mortality and morbidity both appear to be declining with the emergence of better antibiotics and growth factors, so hematologists are beginning to consider transplants for patients who were once considered too old or too sickly to endure anything as harsh as a stem cell transplant.
Kenneth C. Anderson, MD
Stem cell transplantation was rightly hailed as a breakthrough treatment for people with many blood-based cancers when pioneering hematologists began using them regularly in the 1970s. Their popularity grew slowly but steadily throughout the 1980s and then took off in the 1990s as multiple studies demonstrated their efficacy and new techniques made them safer. Total annual US transplantation figures grew from less than 2000 in 1990 to more than 19,000 in 2013, according to the Center for International Blood & Marrow Transplant Research (CIBMTR).1
The technique has undoubtedly saved or extended hundreds of thousands of lives, but even with steady improvements to the underlying technique, it is still dangerous. Treatment-related mortality may still approach 1%. Stem cell transplants are also expensive and agonizing. Total costs when patients receive their own stem cells can reach $100,000.2 Total costs when patients receive stem cells from others can reach $200,000.2
In both cases, the treatment and recovery rank among the more grueling of all cancer protocols. Many experts believe that new targeted therapies and new immunotherapies will eventually eliminate the need for most stem cell transplants.
They predict that such treatments will offer patients far easier ways to achieve better outcomes. So far, there are only a few instances where new treatment protocols have begun replacing transplants, but there are dozens of trials at various stages of completion that could significantly reduce the use of transplants for some cancers over the next few years.
At the same time, however, transplant techniques are improving. Mortality and morbidity both appear to be declining with the emergence of better antibiotics and growth factors, so hematologists are beginning to consider transplants for patients who were once considered too old or too sickly to endure anything as harsh as a stem cell transplant.“We have seen the numbers of patients transplanted for certin diseases move in both directions,” Martin S. Tallman, MD, chief of the Leukemia Service at Memorial Sloan Kettering Cancer Center (MSK), said in an interview. “Targeted therapies have greatly reduced our use of stem cell transplants in patients with chronic myeloid leukemia [CML] and begun to reduce them in patients with chronic lymphocytic leukemia [CLL]. On the other hand, patients historically felt to be too old to meet traditional transplantation guidelines may now undergo reduced-intensity transplantation.”
According to Tallman, the decline in transplants for patients with CML at MSK stems almost entirely from the introduction of tyrosine-kinase inhibitors (TKIs) such as imatinib (Gleevec).
ALL indicates acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; HL, Hodgkin lymphoma; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; NHL, non-Hodgkin lymphoma.
1. Center for International Blood and Marrow Transplant. Transplant Activity Report. US Department of Health and Human Services website http://goo.gl/lPydMP. Reported September 16, 2013. Updated May 18, 2015. Accessed January 4, 2016.
2. Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: 2014 CIBMTR Summary Slides. http://www.cibmtr.org. Accessed January 4, 2016.
Imatinib was first approved in 2001 for patients who relapsed after stem cell transplants, but it is now used for the treatment of newly diagnosed patients, as are several other TKIs. Stem cell transplants are now conducted after patients fail on TKIs, when they are performed at all.
A different class of novel medications has brought about a similar decline in the number of stem cell transplants that Tallman’s department performs on patients with CLL. The B-cell signaling pathway inhibitors ibrutinib (Imbruvica) and idelalisib (Zydelig), which are currently used as second-line treatments for the disease, can produce better outcomes and far less toxicity than protocols involving stem cell transplants.
Toxicity is a serious concern with stem cell transplants, which generally use doses of chemotherapy that would likely prove fatal but for the infusion of enough stem cells to restore the ability of patients to make their own blood cells. There are many different protocols. Some use bone marrow, while others use peripheral stem cells. Some harvest the stem cells directly from patients (autologous transplants), while others harvest them from compatible donors (allogeneic transplants). All of them use different chemotherapeutic agents, in different doses, for different periods of time. The same basic idea, however, still pervades all protocols: maximize the chance of curing each patient’s cancer by administering as about as much chemotherapy as possible.
Transplants are an ordeal for patients, but the techniques for making matches, performing transplants, and spurring recovery keep improving. As transplants have become slowly less taxing, eligibility requirements have slowly broadened, particularly in cases where transplants work significantly better than alternative treatments. Many cancer centers used to restrict transplants to patients who were under 50 years old. Tallman said that the unofficial age cap at MSK now hovers around 75 years for patients who are otherwise healthy.
“If transplant techniques continue to improve and eligibility keeps expanding, you may see the total number of transplants increase for all leukemia patients despite the drop for patients with certain types of leukemia,” said Tallman, who noted there is also reason to think total transplants figures could fall rather than increase.
“A lot of ongoing trials are pairing targeted agents with older medications in hopes of creating synergistic effects that would eliminate the need for high-dose chemotherapy and transplants. There have already been successful trials of all-trans retinoic acid and arsenic trioxide that did well enough to eliminate not only the use of transplants in second-line therapy but also the use of chemotherapy in first-line therapy for patients with acute promyelocytic leukemia,” he said.New therapies have yet to make as much of an impact in the treatment of patients with multiple myeloma, which seems unusual for two reasons. First, stem cell transplants are more common for patients with multiple myeloma than patients with almost any other type of cancer. They generally are not used in conjunction with second-line therapies in patients who relapse after initial treatment. They are a standard part of treatment for patients who are newly diagnosed with active cancer.
Second, a steady flow of novel agents from several different drug classes has been approved to treat multiple myeloma in recent years. These new agents have led to significant changes to standards of care and significantly better outcomes for patients with myeloma, but they haven’t led to any reduction in transplant numbers—yet.
“Everyone definitely hopes that combinations of targeted therapies and immunotherapies will eventually eliminate the need for stem cell transplants entirely, but transplants remain the standard of care for most multiple myeloma patients. We’re using the many novel agents that have been approved for myeloma in the past few years in conjunction with transplants to achieve better outcomes—and those new drugs really have helped us achieve significantly better outcomes,” said Kenneth C. Anderson, MD, the Kraft Family Professor of Medicine at Harvard Medical School.
Those current standards, which were developed in part by the research team that Anderson leads at Dana-Farber Cancer Institute, typically start with a three-drug combination (which would likely include two novel agents and a corticosteroid). Next comes the harvesting of peripheral stem cells, a short sequence of very-high-dose melphalan, and then the return of the stem cells (which rebuild the bone marrow and blood cells destroyed by the melphalan). The last step is maintenance therapy with one or two targeted agents.
This standard of care has already changed greatly over the past decade. Options for multiple myeloma treatment now include the immunomodulating agents thalidomide (Thalomid), lenalidomide (Revlimid), and pomalidomide (Pomalyst); the proteasome inhibitors bortezomib (Velcade), carfilzomib (Kyprolis), and ixazomib (Ninlaro); and the histone deacetylase inhibitor panobinostat (Farydak). In November 2015, the FDA approved the first monoclonal antibodies for myeloma—daratumumab (Darzalex) and elotuzumab (Empliciti).
That list of options, moreover, may continue growing in the next several years. Experimental treatments at various stages of clinical trials include checkpoint inhibitors such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy).
Trials that have been completed to date have focused, for the most part, on showing that new compounds improve results when added to the existing standards of care. This has naturally meant testing the new compounds in conjunction with the melphalan- and-transplant protocol that has been at the heart of multiple myeloma care for several decades.
Many ongoing trials, on the other hand, are doing something significantly different: testing protocols that include the new medications but omit the transplants.
“There are already large, randomized trials under way that testing various combinations of targeted therapies with and without transplantation,” said Anderson, who is also the program director of Dana-Farber’s Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics.
“There are a lot of reasons to hope the results from those trials show that we no longer need transplantation as a first-line therapy, starting with the obvious fact that targeted therapies are dramatically less toxic than high-dose chemotherapy.
Additional advantages to a new standard of care would include everything from the ability to use transplantation as an effective second-line therapy to the elimination of the small-but-significant risk of secondary cancer that comes from the current protocol.”There are similar hopes that novel treatments may reduce the need for stem cell transplants among patients with several types of lymphoma, but, once again, transplant figures have yet to fall. That said, lymphoma treatment does not rely so heavily upon stem cell transplants. The procedure plays no role in the front-line treatment of many lymphomas, and, as with leukemia, it is generally used as a second-line treatment against those lymphomas that do respond to high-dose chemotherapy.
The primary treatment for many lymphomas is still combination chemotherapy, without any targeted agents, and these treatments are generally administered at low enough doses that patients do not need stem cell transplants to restore their ability to make new blood cells. There is no need to administer higher doses as an initial treatment for patients with many lymphomas because relatively tolerable chemotherapy protocols are enough to produce significant cure rates for many tumor types.
For example, long-established first-line chemotherapy protocols cure about 55% of all patients who are diagnosed with large cell lymphoma and about 75% of all patients who are diagnosed with Hodgkin lymphoma. Subjecting all patients to the ardors of high-dose chemotherapy and stem cell transplants in an effort to improve those initial cure rates would make little sense, particularly given that chemotherapy plus transplant protocols still work on many patients who are not cured by first-line therapy.
“The widespread adoption of transplants as a second-line therapy for many lymphomas was a real treatment breakthrough,” said Anas Younes, MD, chief of the Lymphoma Service at MSK. “Essentially you had large numbers of patients who had stopped responding to chemotherapy, and you had nothing else to give them except more chemotherapy. Transplants allowed chemotherapy dosages to be increased to the point that this second-line chemotherapy followed by stem cell transplant, as a package, could cure more patients.”
Transplants also provided significant benefits for patients with incurable conditions such as mantle cell lymphoma; they bought many patients an extra remission and several extra years of life.
This story has remained largely unchanged for more than a decade now. A handful of combination chemotherapies led by R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone) have long served as the front-line treatment for most lymphomas. Initial cure rates have thus remained about the same, along with the percentage of patients who relapse and the percentage of relapsed patients who qualify for transplantation.
However, this period of relative stagnation may soon end. Researchers have completed (but not yet published) at least one large trial of a new first-line lymphoma treatment and several others are under way.
“The completed trial tested brentuximab [Adcetris] and AVD [adriamycin, vinblastine, dacarbazine] as a front-line therapy in about 1000 patients. It will be some time before the final results are out, but the early-phase trial results were excellent, so there’s some optimism about the phase III results,” said Younes. “At the same time, there are also a large number of trials that are trying to improve upon R-CHOP that are under way. They’re testing ibrutinib and R-CHOP. They’re testing lenalidomide and R-CHOP. They’re testing monoclonal antibodies and R-CHOP.
“There’s no data for any of them yet and no guarantee that they’ll all work. But as the frontline therapies improve, the number of patients who will be candidates for second-line therapy and stem cell transplant will decrease,” said Younes.Although it’s possible that the number of stem cell transfers has already started to fall, there are no signs of it in the latest data, which are from 2013. Autologous transplant totals dipped very slightly between 2012 and 2013—the first such decline since 2001—but a larger increase in allogeneic transplant procedures brought the total number of transplants performed in the United States to a record 19,316, CIBMTR statistics indicate.1 That figure represents an increase of nearly 3000 transplants over 2010, according to the US Department of Health and Human Services (HHS).3
Even drilling down to the transplant figures for individual tumor types, there’s little evidence that transplant figures had begun a decline by 2013. Indeed, the HHS data on patients with CML show 224 transfers in 2009 and 267 in 2013, while the data on CLL show 275 transplants in 2009 and 252 in 2013.3 Any decline in transplant figures for patients with those conditions would seem to be very recent, largely confined to academic cancer centers, or both.
Many experts do believe that significant declines in transplant figures are inevitable, if not in the next few years, then certainly in the next 10 to 20 years. The idea that one of the central tools of hematology will always be a technique for helping the body survive what should be a fatal dose of untargeted chemotherapy is impossible for them to believe in light of the rapid proliferation of targeted therapies.
If they’re right, the major beneficiaries will certainly be patients. Predicting other winners is somewhat more difficult. It would be natural to assume that bottle of pills would cost less than several weeks of daily (or near daily) treatments, along with a significant possibility of lengthy hospital stays (for patients who become too weak to stay at home). On the other hand, there are a number of cancer treatments that cost more than the $200,00 that is currently cited as the upper limit of transplant cost.
Other possible winners include independent oncologists. Stem cell transfers are complex procedures that generally take place at major cancer facilities. The need for them has forced many patients to abandon smaller practices. A move to replace transplants with targeted therapies with protocols that any oncologist could prescribe could keep more patients close to home, but only time will tell.