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Roundtable: Stem Cell Transplantation in Myeloproliferative Neoplasms

 

The prospect of a stem cell transplant (SCT) is never far from an MPN patient’s mind.  At first diagnosis the idea arises as a possibility to nip this disease in the bud, get a fresh start at producing healthy blood lines.

At the other extreme, SCT can appear to be our only option to stop progression once surging counts are brought under control.

There are  associated challenges, finding a compatible donor, arranging insurance coverage , preparing for the rigorous Induction procedure, housing, family support, etc. But the one overwhelming question is deciding whether or not to elect the procedure.

Should we elect a stem cell transplant in hope of a cure?  We hear many opinions, and recommendations, read case studies. Finally, however, it is up to each of us, alone, to make this life-altering decision.

As Dr. Ruben Mesa says in his introduction to this MPNclinic Roundtable discussion of MPN stem cell transplantation, “Anyone who tells you that the issue of whether or not to have a bone marrow transplant is a simple decision is an individual not facing that decision.”

Dr. Richard Silver puts the question of timing in stark perspective:  “We are very careful in making this decision, since it cannot be taken back once it is performed.”

We have had lengthy patient community discussions on SCT risks and benefits, one on-line discussion taking place over the course of days,  edited and published in full. With the participation of patients who have gone through the process as well as those just entering the first stages, those discussions helped frame the realities of this extraordinary procedure for all MPN patients.

Now, bringing the MPNclinic into the discussion adds the weight of deep professional and practical experience. The Clinic doctors and their colleagues address the issues of SCT timing, conditioning, isolation, means to measure outcomes. co-morbidities, age, emotional and psychological  In this Roundtable, these physicians, specialists all, have answered one or more questions compiled by MPNforum from submissions by SCT veteran patients and caregivers Marina Sampanes Peed,  Ann Haehn  and Kathy Dubin Flynn.

 

Will you continue to follow me post-transplantation?

*This varies by institution.  At some institutions the physician caring for the patient for myelofibrosis is the same as the physician who will take the patient through transplant.  At other centers (including mine), the transplant team is separate so there is a transfer of care as transplant approaches.  If problems arise post-transplant that are related to the MPN rather than a transplant complication like GVH, failed engraftment, or infection, then the MPN physician usually becomes involved again.

How can I improve my chances of a successful SCT?

*Following the recommendations of the treating team can be helpful (these protocols about diet, permitted and prohibited activities, and logistics such as follow-up schedule differ from center to center), but to a large extent success or failure of SCT is outside of the control of the patient.  This loss of control and uncertainty can be quite difficult.

On what factors would my estimated survival outcome be based?

*There are two types of factors that are the major drivers determining patient outcome with SCT: 1) patient factors such as age and the presence or absence of other medical problems (“comorbid conditions”), and 2) disease factors.  Patients who are younger, lack other medical problems besides the MPN, and are able to be active (“good performance score”) do best with stem cell transplant.  Those who have high WBC, high circulating blasts, high risk chromosome profile, and other negative disease factors tend to do more poorly.

When is it too late to consider transplantation?

*Usually the factors that prevent transplant are if the patient is too old or too sick or the disease is too poorly controlled (e.g., progression to leukemia and refractory to treatments attempted to try to reduce the leukemic blast cells).

How do I choose the right transplant team or institution?

*Many factors are involved.  The patient needs to have a comfort level with the treating team and institution.  In general outcomes are better at larger transplant centers, but geography needs to be taken into account and sometimes insurance (in the US) restricts where patients can have a transplant.

What are some of the emotional, social issues post-SCT I should expect?

*Isolation due to risk of infection, uncertainty about whether the MPN will relapse, feeling unwell and loss of control can take a heavy psychological toll on patients.  Having supportive family, friends, and treatment team can help but it is a long and difficult road.

Am I likely to require long-term drug therapy post-SCT?

*Yes.  Almost all patients require extended treatment with immunosuppressive medications to prevent GVH and prevent infection.  Whether other drugs such as ruxolitinib have a role post-transplant is currently being studied.

How do you measure outcome, “success’ or cure?

*Periodic monitoring with physical exam, blood tests and bone marrow biopsies allow serial assessment of response to transplant and monitoring for complications or relapse.  Long-term survival with full donor cell engraftment/chimerism and freedom from GVH enough to maintain a good quality of life is the measure of success.  “Cure” means living a long time and then dying of some unrelated cause with no evidence of MPN – remission is necessary for cure, but not the same as cure.

Is there anything a patient can do to help avoid serious GVHD?

*Adherence to the GVH medications and monitoring program is about the only thing that can be done.

How much of a factor is age?

*Age is a large factor in outcomes in transplant; in general, older patients do poorly, both due to decreased tolerance of treatment and the presence of comorbid conditions (e.g., kidney dysfunction, lung or heart impairment).  At my institution the upper age limit is 75 years old but whether an individual patient is eligible for transplant is not just a factor of chronological age, it is also a factor of ‘biological age’.   Some 50 year olds are too unhealthy to proceed to transplant whereas I have sent a number of 65-75 year olds to transplant with good outcomes.

What restrictions will an SCT place on my life

*For the first year after transplant the patient’s immune system is not fully recovered and numerous precautions about infection need to be followed.  This is often very difficult for patients since they spend much of the time at home or shuttling between doctors’ appointments and can easily get ‘cabin fever.’  In the short term after transplant quality of life is usually quite poor; the tradeoff is the hoped-for improvement later on.

 

 

“When should patients consider stem cell transplantation 

Ruben A. Mesa, M.D.

“Stem cell transplantation is a very complex therapy to understand; not only the logistics, but the risks involved….Getting a range of input and perspective is really quite helpful.”

When Zhen discussed with myself and my colleagues, the prospect of the MPNclinic Roundtable and colleagues tackling the concept and issues regarding stem cell transplantation (SCT), we shared with him that this was a very important and challenging topic.  Also, it is incredibly complex and very individualized.  Indeed, anyone who tells you that the issue of whether or not to have a bone marrow transplant is a simple decision is an individual not facing that decision.

SCT is truly a therapy that on one end of the spectrum can be miraculous.  Individuals can have curative therapy with a life-threatening disease such as myelofibrosis and go on to live many, many years, hopefully as long as they had been destined to live prior to their MPN.

Unfortunately, bone marrow transplant does not always produce miraculous results. There is a spectrum, both in terms of how well the transplant works (works meaning getting rid of the underlying disease), but too, how well the individual is able to heal up or tolerate the transplant process.  SCT introduces several types of risks to the individual; whether they be risks of infection, whether they be risks of graft vs. host disease, whether they be injury to their underlying body based on the effect of the chemotherapy one undergoes.

Indeed, the concept of transplantation is so complex that I find if individuals visit with me for a discussion around their MPN, I will frequently have them also visit with my colleague who focuses on bone marrow transplantation, Veena Fauble, M.D.  The reason for this is it is a very complex therapy to understand; not only the logistics, but the risks involved.  I do think getting a range of input and perspective is really quite helpful.

Indeed, for many, the issue of transplant, particularly for myelofibrosis can end up in three different categories: Transplantation in the near future;  transplantation in the more distant future if progression or worsening would occur; or finally transplantation is never a good future option.

Your medical team factors  many things into this decision making: (1) The underlying risk with your disease.  How likely is the disease to be a threat for you in the near future?  (2) Who would be potentially the donor?  The safety of bone marrow transplantation can vary depending upon the quality of the donor, whether that be a matched sibling, an unrelated donor, the age of that donor, etc.  (3) Finally your age and your overall health.  Indeed, transplantation is one of the most rigorous medical procedures an individual can undergo.  Your underlying health and age are both very important factors in terms of assessing the safety of the transplantation.  (4) The final component which is essential is really your input.  Simply put, for those for whom SCT is medically appropriate (between a combination of their risks and availability of the donor) transplantation is an individual decision.

SCT is not like receiving antibiotics for strep throat, which is a clear and simple decision.  There are individuals who are bone marrow transplant candidates who fully understand the process and the risks and prefer not to undergo stem cell transplantation.  They hope for the best for the future, they are hopeful that medical therapies will continue to evolve. They are willing to understand and accept that to some degree there is a risk by not undergoing bone marrow transplantation that they will pass away from their disease.  But even with all those outcomes considered, they prefer not to undergo that therapy.

Conversely, there are individuals who are marginal transplant candidates, but their personal life experiences and philosophy lead them to be very aggressive regarding their healthcare and even if there is a small percentage of success, they would like to undergo transplantation.  It is important in this process if you are considering transplant that you fully understand the process, that you have an accurate sense of the risks and benefits, and that your input is essential.  It is key that your loved ones, your spouse, your support unit, is on board with your decision, but in the end it is you as an individual who will have to undergo this process and the consequences both good or bad that can occur.

The process of transplantation continues to be studied very acutely to improve its safety.  Indeed the safer a transplant becomes, the more beneficial a therapy it will be and the broader the group of individuals it may benefit.  So just as many of us who study medicines for MPNs continue to work to try to develop new medicines, the same is the case in transplantation.

Transplant specialists try to identify better ways of conditioning or the chemotherapy that goes along with transplant.  They try to identify whether transplant outcomes will be better if therapy occurs ahead of time with JAK2 inhibition, currently a subject of ongoing clinical studies.  New antibiotics are developed and tested and indeed have made the process safer.  Medications to suppress the immune system to decrease GVHD continue to be studied.

So, I can assure you that our colleagues who focus on transplantation are leaving no stone unturned and putting every effort into making this therapy as safe and beneficial as it can be and that regardless of where an individual undergoes a stem cell transplant, these are highly dedicated teams of very specialized individuals who will give you every effort to have that be as safe and effective a process as possible.

Ruben A. Mesa, M..D.  Professor and Chair Division of Hematology and Medical Oncology, Mayo Clinic.

“”We are very careful in making this decision, since it cannot be taken back once it is performed.”

Richard T. Silver, M.D.

Transplantation is never a sudden decision, rather one that relates to age, other morbidities, whether there is a match, the degree of splenomegaly or not,

and the physician’s belief whether or not splenectomy should be preformed prior to transplant or if JAK2 inhibitors should be used prior to transplant.

Many of these are research questions with no definite answer as yet, thus we must make sure we convey these uncertainties but in a positive way to our patient.  Of course, we always consider the issue whether an appropriate donor exists.  There is rarely a categorical answer to transplantation that can be given (a categorical answer, for example: all doctors would agree on the use of penicillin for the treatment of pneumococcal pneumonia).

After a referral to a transplant physician, it does not necessarily follow that a transplant automatically would take place.  The caring hematologist will always participate in that decision after thorough evaluation and discussion with the transplanter who obviously will deal with many of the technical factors involved with the patient prior to the decision whether or not a transplant will actually occur.

Marrow transplantation under all circumstances as we know is a very serious therapeutic decision and patients should know this as well (probably do).  Whereas we are very careful in making this decision, since it cannot be taken back once it is performed, we do have to elaborate upon the list of questions Zhen proposed both medically and legally but always maintaining an optimistic demeanor; since all of us experienced clinicians have seen wonderful results following this procedure.

— Richard T. Silver, M.D., Professor of Medicine and Director of the Leukemia and Myeloproliferative Center at New York Presbyterian -Weill Cornell Medical Center. 

 

Panelists

Dr. Donal McLornan, Consultant Haematologist, King’s College Hospital and Guy’s and St. Thomas’ Hospital NHS Foundation

Dr. Nicolaus Kroger,  Professor and Medical Director of the Department of Stem Cell Transplantationm University Hospital Hamburg-Eppendorf, Germany

Tsiporah Shore, M.D. FRCPC, FACP, Associate Director, Bone Marrow and Hematopoietic Stem Cell Transplant Program Service Chief,  Professor of Clinical Medicine, Weill-Cornell Medical College

Dr. Srdan Verstovsek,  Director of Clinical Research and Chief, Myeloproliferative Neoplasm Section, MD Anderson Cancer Center.

 

Dr. Veena Fauble, M.D., Hematologist/Oncologists, Stem Cell Transplant for Myelofibrosis Specialist, Mayo Clinic.

In a far ranging discussion, the full MPNclinic Roundtable addressed Ten Crucial Questions faced by MPN patients considering a stem cell transplant plus peripheral issues. Questions range from SCT timing and after-effects, means to improve odds of a successful transplant, the age factor, life restrictions post SCT, financial impacts.

 

The complete Roundtable will appear in the Summer issue of the  MPN Quarterly Journal.   Here is a slightly abridged discussion of the crucial  question of timing.   

“When should  patients consider stem cell transplantation?”

McLORNAN:

The question of the timing of transplant is an extremely important one. It is a matter of weighing the risks and benefits and determining when the appropriate time to intervene is. The answer to this question depends on not only the stage and characteristics of your myelofibrosis (MF) but also a lot of other factors about you that your transplant doctor has to consider.

Let’s consider the disease first…..

As many of you will know, the International Prognostic Scoring System (IPSS) has become the most commonly used risk stratification system at the time of MF diagnosis (Cervantes et al, 2009). This score is derived from five variables: anaemia (Haemoglobin <100), age >65 years, leukocytosis > 25 x 10⁹/L, peripheral blasts (early cells) ≥1% and the presence of so-called constitutional symptoms ( weight loss, drenching sweats etc).

Analysis revealed that 4 distinct groups could be determined: Low risk (0 risk factors), Intermediate-1 (1 risk factor), Intermediate-2 (2 risk factors) and high risk (3 or more risk factors). This scoring system has been further refined to the Dynamic IPSS (DIPSS), which can be applied to aid risk stratification at any stage in the disease, and with additional risk factors in the ‘DIPSS plus’ scoring system including low platelet counts ( thrombocytopaenia; platelets <100 x 10⁹/L), abnormal karyotype i.e. certain abnormal chromosome changes within the cell (including complex karyotypes, monosomal karyotypes, an extra copy of chromosome 8 and  certain chromosome 7 abnormalities (+many others)) and dependenCE on red blood cell transfusions (Passamonti et al, 2010, Gagnat et al, 2011).

In practice, I tend to favor use of the ‘DIPSS/ DIPPS-plus’ scoring systems when assessing patients for consideration of an Allogeneic Haematopoietic Stem Cell Transplant (AHSCT).

As suggested by the current European LeukaemiaNet consensus guidelines ‘ it is reasonable to justify the risk of alloSCT-related complications in otherwise transplantation eligible patients whose median survival is expected to be <5 years’ (Barbui et al, 2011). In practical terms, this would apply to ‘transplant eligible’ patients with IPSS Intermediate –II and high risk MF. It would also encompass those with red cell transfusion dependency and in those individuals who have a specific adverse ‘cytogenetic signatures’ such as a ‘monosomal karyotype’. When reading these figures it is important to remember that these are average (median) figures and that everyone is different.

Furthermore, as we are getting enhanced information from molecular testing etc (e.g.  looking for certain mutations in genes such as EZH2/AXL1 in patients with MF) we are identifying additional factors that may guide these discussions about likely disease outcome.In general, I do not routinely transplant those with either Low risk or Intermediate-1 risk  disease as classified by IPSS/ DIPSS and await a ‘trigger’ to move forward with AHSCT. In general, this is often the approach taken by a lot of transplant physicians but there will of course be exceptions to this.

From a practical point of view, it is important to discuss the transplant option with your hematologist if this is a current or potential future treatment avenue for you and also to start the process of looking for a potential donor. The Human Leucocyte Antigen (HLA) system plays a prime role in immunity and recognition of ‘self’ versus ‘non-self’. In brief, if you have a brother or sister, each has a 1 in 4 chance of being a ‘tissue-type’ match to you. It is important to remember that no-one is fully HLA-identical apart from identical twins! Even if you have a brother or sister who is a match, and if they agree to be a potential donor, they will have to be fully – and independently – medically assessed to ensure they are fit to proceed.  Potential volunteer unrelated donor (VUD) matches will also be looked for through the Stem Cell Transplant registries such as Anthony Nolan and the National Marrow Donor Program (NMDP). These donors can be ‘matched’ or ‘mismatched’ and your transplant doctor will try and find the most suitable match or minor mismatch for you. It is important to remember that sometimes it can be very difficult to find a suitable donor. An excellent article on the importance of the HLA-system for AHSCT can be found on the NMDP site. 

The intention to perform allogeneic stem cell transplantation is to cure the malignant disease. However, not all patients can be cured from allogeneic stem cell transplantation. There is ….a risk of therapy related complications inclusive therapy-related mortality and the risk of relapse.

KROGER:

In the more recent years several risk scores have be introduced, which allows to roughly estimate the survival of patients with newly diagnosed myelofibrosis or during the course of the disease. The most important factors for survival age: age, constitutional symptoms, circulating blast, high white blood cell counts and anemia.

Regarding timing of transplantation 3 major factors have to be taken into consideration:

 (1)  Disease-specific factor

(How advanced is the disease? What is the life expectancy without transplantation?)

(2) Transplant-specific factor?

(Do I have a fully matched donor?)

(3) Patient-specific factor?

(What is my age? Do I have a co-morbidity?)

These factors should be always taken into consideration for balancing the risk and the benefit of transplantation.

SHORE:

The window for successful transplants is not well defined. Often we use the DIPPS Plus scoring system (see Tefferi, Blood 2011) to guide us on when to offer transplant. But sometimes the patient’s age, frequency of transfusions, donor availability, and other comorbidities lead us to offer transplant earlier or later. Transplant is still the only curative approach and should be offered when it has the best chance of success. For patients who have transformed to AML, it is important to get them back into remission before proceeding with transplant.

FAUBLE:

The question of the timing of transplant is an extremely important one. It is a matter of weighing the risks and benefits and determining when the appropriate time to intervene is. We use the Dynamic International Prognostic Scoring System to help guide our decision making. This is a classification system that allows us to assign a score to a patients disease. It takes into account various characteristics that affect prognosis for example age, hemoglobin, platelet count, white blood cell count, constitutional symptoms (fevers, night sweats, bone pain, itching…) and  cytogenetics. This classification stratifies patient into 4 main catergories based on the score accumulated: low(median survival 15 years),  intermediate-1 (median survival 8-10 years), intermediate-2 (median survival 3-5 years), and high risk (median survival 16 months). In general we suggest ASCT for those with intermediate-2 and high risk disease with certain exceptions for those with intermediate-1 risk.

Age is an important timing factor in determining eligibility for ASCT but it is important to keep in mind that functional age (how healthy an individual is) is just as important as the numeric age. The average age of diagnosis of Myelofibrosis is 67 years. Therefore many patients we consider for ASCT are considered to be older. A study done in 2011 looking at patients age 60-78 years showed that selected older patients with advanced myelofibrosis can be treated successfully with ASCT.

 

 

And a Reflection on SCT:   GVHD, Antigens, Stinkbugs and the workings of our immune system
Take me back to the Contents

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