Treatments > Allogeneic Stem cell Transplant

Last update: 12/23/2018

TOPICS: 
 
Background | About HLA Typing | Types of donors | Phases | Relapse after allogeneic transplant |  Donor Lymphocyte Infusions
| Q&A | Resources | Research News |  In the News

PubMed TOPIC SEARCH: Review | Therapy | Prognosis | GVHD  ... Scholar

Overview

Excellent videos explain the history of stem cell rescue, when it's needed, what it is, and how it's improved over time.

	MSKCC About transplants (stem cell rescue) - an excellent overview! MSKCC: Transplant (stem cell rescue) innovations
	NEW: Be the Match The Donor Selection & Transplant Process  marrow.org

A stem cell transplant* may sometimes be medically necessary for patients with lymphomas. 

With a stem cell transplant, the stem cells**  obtained from bone marrow, peripheral blood, or umbilical cord blood are given back to the patient following high dose treatment, which can damage or ablate (kill off) these vital cells. The engrafted stem cells can then restore bone marrow function**  impaired or destroyed by the high dose conditioning therapy.

A stem cell transplant is sometimes called a bone marrow transplant.

*The terms stem cell transplant, infusion, rescue, engraftment, or support may be used interchangeably and essentially have the same meaning. 

** Stem cells are "immature cells known as hematopoietic or blood-forming stem cells. Hematopoietic stem cells divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: white blood cells, which fight infection; red blood cells, which carry oxygen; and platelets, which help the blood to clot.

Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants" [in order to restore bone marrow function.]  Cancer.gov

The different types of stem cell transplants are named from the origin of the stem cells:

	autologous - stem cells harvested from self
	allogeneic - stem cells harvested from donor (following reduced for full intensity therapy)   syngeneic - stem cells harvested from identical twin cord blood  - stem cells from saved cord blood, from self or donor

Notes:  allogeneic and autologous are the two main types of stem cell transplantation (or rescue).  Allogeneic stem cells are derived from a matched donor (such as a sibling); in the autologous type, stem cells are derived from the patient.  Each type has unique risks and benefits, and which is preferred can depend on the clinical details.  See for example, Comparing SCT types 

About allogeneic stem cell transplant 

In this therapy stem cells from an HLA compatible donor are harvested, stored and then engrafted into the patient after the patient receives high doses of chemotherapy and/or radiotherapy conditioning therapy.   

The stem cells can be obtained from a related or unrelated donor.  The cells may be 'harvested" from the donor's bone marrow through a surgical procedure, or acquired from the donor's peripheral blood.*   

* The latter method of obtain stem cells has become more common. peripheral blood stem cell transplant, PBSCT

The goal of transplant therapy is to restore or rescue hematologic and immunologic function following high dose therapy. 

The stem cells are of a type that can develop into the full range of blood and immune cells. 

LymphoMom (on the Webmagic forum) describes the reduce-intensity allogeneic transplant nicely:

The mini-allo is sometimes also referred to as non-myeloablative, or reduced intensity. Just like Andy, it's what my son had as well. In fact it's becoming increasingly more common based on the type of lymphoma.

A traditional Bone Marrow Transplant (BMT) was myeloablative, meaning the conditioning chemo totally destroys the cells in the patient's bone marrow, and the new donor stem cells are infused (engrafted) in later.  The advantage of the myeloablative type is that it destroys the diseased bone marrow, and the chemo is typically strong enough to destroy any residual disease. The downside is that it has a high treatment related mortality (somewhere around 30-35%), and usually reserved for young, fit patients.

The mini (also called Reduced Intensity) doesn't completely destroy the bone marrow. It prepares it for the new stem cell graft, and then the patient goes through an extended period of time in what is called mixed chimerism. It means the bone marrow is part donor, part patient. It slowly converts over time to full donor....or at least that is the intent. Why it can work well is that the transplant works with what is called a Graft vs Lymphoma effect. That means transplant works not just from the chemo blowing away the old disease, but the new bone marrow actually fights the disease. The advantage of the mini is that it has less treatment related mortality (about 15% vs the 35%). The disadvantage is that it comes with a higher rate of relapse.

A Haploidentical (haplo) means half identical. When talked about donor matching, there are usually 8 or 10 factors the doctors look at in matching. For example my son had a 10/10 match. For people with less than a perfect match, a haplo takes a half identical match. It's a first degree relative, like parent, sibling or child. If the first degree relative isn't a perfect match (25% chance it will be), the next best thing is a half match. Haplos are becoming more safe and popular and are opening up transplants to people who wouldn't otherwise have a donor. I asked our doctor his opinion on Haplos and he said he would first prefer a 10/10 match, but he would prefer a haplo over a 9/10 match. So just to reiterate, a haplo isn't the same thing as a mini transplant. Haplo refers to the donor matching type, and mini or reduced refers to the type of conditioning used.

The doctors carefully choose which transplant is best for the patient. A lot depends on the underlying health of the patient, the disease status, and of course the disease itself. Some types of lymphoma have a better proven Graft vs Lymphoma (GVL) effect than others. For example with my son's PTCL, even though it has a poor rate of response to chemo in general, it does have an excellent GVL effect making a mini transplant a really good option.

Also, a mini isn't black and white - it's more of a spectrum of conditioning. The doctors can choose to make it more or less ablative depending on what they think is best.

I also want to emphasize that even though the transplant is called "mini", there's nothing mini about it. Having gone through it (and we are on day 88), it's the most difficult medical treatment I've seen. Manageable, doable, but serious stuff. I think the term mini sounds misleading, it's anything but, IMHO.

Types of donors:

HLA-matched sibling | HLA-matched unrelated donors (MUDs) | haploidentical allo-HCT (haplo-HCT)

"Allogeneic hematopoietic cell transplantation (allo-HCT) is a vital therapy for hematologic malignancies and often represents the only curative therapy for refractory disease.1

Historically, HLA-matched sibling donors provide the best clinical outcomes,2 whereas HLA-matched unrelated donors (MUDs) are considered the second-line option.2,3

However, matched sibling donors and MUDs are often limited by donor availability, especially for ethnic minorities.4,5 This limitation represents a major obstacle and restricts the number of patients who can receive potentially curative allo-HCT.

In contrast, the parents and children of a patient are all potential haploidentical donors by sharing at least 1 HLA haplotype, with each sibling having a 50% chance. Thus, haploidentical allo-HCT (haplo-HCT) represents an attractive alternative to MUD allo-HCT due to its increased donor availability. With the use of posttransplant cyclophosphamide (PTCy) to selectively deplete alloreactive T cells,6⇓⇓⇓-10 haplo-HCT has been shown to have similar outcomes when compared with MUD allo-HCT.8,"

Source:  HLA epitope mismatch in haploidentical transplantation is associated with decreased relapse and delayed engraftment | Blood Advances http://bit.ly/2EHbG6O

Typically allogeneic transplants have three phases:
donor matching, conditioning, and engraftment

Salvage therapy

1. Donor matching phase - in this phase the cells from potential donors are tested for compatibility.
   
   * MUD is- a common abbreviation used. It means Matched Unrelated Donor.
   
   The donor experience? 
   
   Potential donors are asked a series of questions to make sure they are healthy enough to donate and don’t pose an unacceptable risk of infection to the recipient.
   
   "Risks for donors are minimal, and serious complications are rare. Problems such as sore throat or nausea may be caused by anesthesia."  ASC
   
   See for details Harvesting Stem Cells
    

2. Conditioning phase - use of high dose therapies to eradicate the disease. Myeloablative means that the treatment kills (ablates) the myeloid stem cells in the bone marrow - the cells that produce new blood cells.
   
   "Once you are ready to begin the transplant protocol, you are admitted to the hospital for high doses of chemotherapy and/or radiation therapy for what is called “conditioning.” This conditioning phase can take five to 10 days and is completed a day or two before the infusion of the stem cell product.
   
   The purpose of conditioning is to give high enough doses of chemotherapy and/or radiation to eliminate any cancerous cells that are present, to make room for the new cells, and to destroy your immune system. This is done to prevent rejection of the new donor cells. Please refer to the transplant section for further discussion of the conditioning regimen."  ⁷ Source: cancer.med.umich.edu
    
   NOTE: A  reduced intensity (or mini) transplant is also called a non-ablative or non-myeloablative transplant, because 
   the conditioning treatment is less intense and does not ablate all of the cells in the bone marrow.
   
   See also
   How to make stem cell transplantation less toxic http://bit.ly/8SL7qD 
   "In the protocol, published in the Lancet journal, TBI and standard chemotherapeutic doses were replaced by monoclonal antibodies"
   
   

3. Engraftment phase - the stem cells from a donor are given back to the patient to reconstitute the immune system. Sometimes purging techniques are used to clean the stem cells of residual tumor cells prior to engraftment, or shortly after.
   
   Approximately two to four weeks after your transplant you can expect to see signs of your bone marrow “engrafting” or beginning to grow. The first sign of this is the production of white blood cells. Platelets often take a little longer to begin developing. Once you have “engrafted” and your condition is stable, you will be discharged from the hospital. ⁷ Source: cancer.med.umich.edu

Potential Advantages of Allo Transplants

	Tumor free graft
	Undamaged Stem Cells
	Avoidance of MDS/secondary AML
	Graft versus lymphoma effect

Potential Problems with Allo Transplants

	Lack of suitable donors
	High Treatment Related Mortality   Regimen related toxicity Infection Graft versus Host Disease (See GVHD for details) (not a risk for auto SCT type)

Adapted from: Allogeneic Transplantation in Lymphoma
File Format: Microsoft Powerpoint 97  View as HTML

Relapse after allogeneic transplant

Therapeutic options for patients with lymphoma who relapse after allogeneic stem cell transplantation are expanding.  Delay in relapse and age can influence the opportunity to benefit from subsequent therapy.

Resources:

	Testing protocols after allogeneic transplant for relapsed lymphoma OR CLL  ClinicalTrials.gov http://1.usa.gov/1GbSAvb Testing immunotherapy - CART 19 in Chemotherapy relapsed/ refractory cd19 Lymphoma - prior transplant may be eligible http://1.usa.gov/1J2jzAm
	Barrett, 2010: Relapse after allogeneic stem cell transplantation http://1.usa.gov/1cYyuNx
	Wudhikam, 2011: Relapse of lymphoma after allogeneic hematopoietic cell transplantation: Management strategies and outcome http://1.usa.gov/1JS06T4 Novel treatments can control lymphoma with acceptable morbidity. Particularly for patients with later relapse, ongoing treatment after relapse can yield meaningful benefit and prolonged survival.

About Donor Lymphocyte Infusions

Patients with lymphoma in relapse after allogeneic stem cell transplantation can be treated by infusing leukocytes from the original stem cell donor with the goal of enhancing the graft versus lymphoma effect.

Resources:

	Barrett, 2010: Relapse after allogeneic stem cell transplantation http://1.usa.gov/1cYyuNx
	Wudhikam, 2011: Relapse of lymphoma after allogeneic hematopoietic cell transplantation: Management strategies and outcome http://1.usa.gov/1JS06T4
	JCO - Donor Lymphocyte Infusions: The Door Is Open
	Leo Luznik, MD, and Ephraim J. Fuchs, MD - Moffit.org: Donor lymphocyte infusions show promise as a treatment approach for patients with relapsed hematologic malignancies following allogeneic transplantation

About HLA Typing

TOPIC SEARCH: PubMed | Web 

HLA stands for Human Leukocyte Antigens.  These proteins are unique markers found on the surface of nearly every cell in the body, and are in especially high concentrations in white blood cells. 

Like a fingerprint, HLA proteins enable your immune system to distinguish between cells that belong in our body and cells that do not. 

HLA typing is important because finding a matched donor reduces the risk of developing graft rejection and acute Graft versus Host Disease or the graft could be rejected (Graft rejection) by the patient’s immune system.

So the goal is to obtain as close a donor-recipient match of HLA as possible, without undue delay.  The ideal candidates for a match are siblings, perhaps of the same sex and blood type. Blood is drawn and white blood cells are isolated from the sample.  

"The odds of finding “matches” between siblings greatly increases compared to the general population because we have a 1-in-4 chance of being identical to each sibling."⁶

Two tests are available to determine a person's HLA type: serological typing and molecular (DNA) typing. Although serological typing is usually sufficient to determine if a patient and a sibling have the same HLA type, molecular typing gives more detailed results. Thus, when searching for an unrelated donor, molecular typing is recommended. Molecular typing enables the NMDP to more quickly and accurately identify matches. 

Note: transplants can be successful with a less than perfect match. If there is no perfect match, the doctor may want to do a mismatched donor transplant, depending on the patient's age, disease and other factors. ¹

Six HLA-factors (alleles)

Alleles are variant forms of the same gene that determine our characteristics. 

A,   B,   C,  
DRB1,   DRB3-5,   DQB1 

Five most important: A, B, C, DRB1, and HLA-DQB1

The minimum acceptable match was originally required at least 5 matches, ie, a 5 of 6 match. Although the required level of resolution has evolved over the years,  the basic minimum requirement for a 5 of 6 match has not changed. This is because there are abundant data to show that HLA matching at this minimum level can lead to successful transplantation outcomes. However, it is also clear that transplantation outcomes can be improved by matching strategies that increase the degree of HLA compatibility above the minimum. ¹

Non-HLA Factors 

These factors may be considered when donors are selected

	cytomegalovirus (CMV)—negative serology (for patients with CMV-negative serology)
	male sex
	younger age
	ABO (blood type) compatibility
	larger body weight
	matched race 1

Bone Marrow Transplantation (BMT) and Peripheral Blood Stem Cell (PBS) Transplantation Questions and Answers  cancer.gov 

 1)  What are bone marrow and hematopoietic stem cells? Cancer.gov
 
 2)  What are bone marrow transplantation and peripheral blood stem cell transplantation? Cancer.gov
 
 3)  Why are transplants used in cancer treatment? Cancer.gov 
 
 4)  What types of cancer are treated? Cancer.gov 
 
 5)  How are the donor’s stem cells matched to the patient’s stem cells in allogeneic or syngeneic transplantation? Cancer.gov
 
 6)  How is bone marrow obtained for transplantation? Cancer.gov  
 
 7)  How are peripheral blood stem cells (PBSCs) obtained for transplantation? Cancer.gov 
 
 8)  How are umbilical cord stem cells obtained for transplantation? Cancer.gov 
 
 9) Are any risks associated with donating bone marrow? Cancer.gov 
 
10) Are any risks associated with donating PBSCs? Cancer.gov
 
11) How does the patient receive the stem cells during the transplant? Cancer.gov 
 
12) Are any special measures taken when the cancer patient is also the donor (autologous transplant)? Cancer.gov 
 
13) What happens after the stem cells have been transplanted to the patient? Cancer.gov 
 
14) What are the possible side effects of BMT and PBSCT? Cancer.gov 
 
15) What is a “mini-transplant”? Cancer.gov 
 
16) What is a “tandem transplant”? Cancer.gov
 
17) How do patients cover the cost of BMT or PBSCT? Cancer.gov 
 
18) What are the costs of donating bone marrow, PBSCs, or umbilical cord blood? Cancer.gov 
 
19) Where can people get more information about potential donors and transplant centers? Cancer.gov

Resources

1. Bone Marrow Transplant (BMT)  makna.org 

2. National marrow donor program HLA-matching guidelines for unrelated marrow transplants  bbmt.org 

3. Advances in HLA Typing  (for physicians)  marrow.org

4. Searching for a Donor Through the NMDP  bmtinfonet.org 

5. Finding the Perfect Donor  bmtinfonet.org

6. BMTinfoNet: www.bmtinfonet.org 

7. Low grade Lymphoma  asheducationbook.org /2004 full text

8. The donor experience  ASC

9. Re-immunization after SC

10. Infections Post-Transplant: Antibiotic prophylaxis with meropenem after allogeneic stem cell transplantation nature.com (2003)

Resources on Allogeneic Transplantation

	Comprehensive Checklist: Before, During, After Allo SCT: uwhealth.org
	Common Questions  nbmtlink.org
	Allogeneic vs Autologous Transplantation for Indolent Non Hodgkin's Lymphoma, Bruce Cheson, MD National Cancer Institute John G. Gribben, MD Harvard Medical School   PAL/Healthology
	Allogeneic Bone Marrow Transplantation in Patients With Sensitive Low-Grade Lymphoma or  Mantle Cell Lymphoma Biology of Blood and Marrow Transplantation 7:561-567 (2001) Abstract-WEB | Full-PDF | PDF-Help
	Highly recommended: Search for Stem cell Transplant Centers BMTinfoNet Also provides: background, Number of Transplants done,  Minimum Donor Match Criteria, Contacts, Support Groups Available
	Support group for SCT: ACOR BMT-Talk  Support Groups
	Patient SCT Stories - Cyberfamily  | What to take to Hospital  Cyberfamily
	Also see Questions to Ask about Allogeneic Transplant

Return to top

Research News

Scholar Search

	* BMT 2014: “Allogeneic hematopoietic cell transplantation for diffuse large B cell lymphoma: who, when and how?” http://bit.ly/1eyiWiF  Speaks to an urgent unmet need and novel approaches.  Encouraging that pd-1 antibody was noted as a possible advance - as I wasn't sure if I was overestimating the significance of the recent report by Leo Gordon's group on pd1 consolidation after transplant.  No mention of CART 19 ... which is another very promising approach for patients with lymphoma refractory to chemo. (Karl)
	An allo SCT (from a donor) is thought to have very good curative potential, even for indolent lymphoma – but sometimes the lymphoma returns.  A discovery provides a potential way to improve the result  http://bit.ly/9gYdMq
	Allogeneic stem cell transplantation in follicular lymphoma: recent progress and controversy http://bit.ly/9QY8aa "Allogeneic stem cell transplantation (allo HCT) is a curative treatment for follicular lymphoma, but is hampered by a relatively high treatment-related mortality and by difficulties in identifying high-risk groups for whom transplant is warranted."
	Mini-allo SCT for relapsed DLBC Lymphoma: a multicentre experience http://bit.ly/a8hDdq
	How to make stem cell transplantation less toxic http://bit.ly/8SL7qD  "In the protocol, published in the Lancet journal, TBI and standard chemotherapeutic doses were replaced by monoclonal antibodies"
	GVHD: Prochymal, no better than a placebo in two final trials. http://bit.ly/BkDo9  Osiris said Tuesday preliminary results for two Phase III trials evaluating Prochymal for the treatment of acute graft versus host disease showed no statistical difference between the drug and a placebo in either trial. Osiris said Prochymal did show significant improvements in response rates in difficult-to-treat liver and gastrointestinal graft versus host disease even as it failed to meet its primary endpoint in both trials.
	Outcome report: 8-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide and rituximab. Blood. 2008 Apr 14; PMID: 18411419  Forty-seven patients were included. All patients experienced complete remission, with only 2 relapses. With a median follow-up time of 60 months (range, 19-94), the estimated survival and progression-free survival rates were 85% and 83%, respectively.
	Outcome report:  Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007 May;92(5):627-34  PMID: 17488686  In patients in CR, PR and chemoresistant disease, the 3-year overall survival rates were 66%, 64% and 32%, respectively, while the 3-year event-free survival rates were 66%, 52% and 32%, respectively. The 3-year cumulative incidences of TRM were 32%, 28% and 63%, respectively. The incidence of relapse was 9.6%. INTERPRETATION AND CONCLUSIONS: Although associated with significant TRM, RIC allogeneic SCT in advanced chemosensitive disease leads to long-term survival.
	Review: T cell therapies following hematopoietic stem cell transplantation: surely there must be a better way than Donor Lymphocyte Infusion (DLI) ?  nature.com pdf  Advances in the past few years have significantly improved adoptive immunotherapy strategies available following autologous and allogeneic hematopoietic stem cell transplantation (HSCT).
	Chimera: from bane to blessing  bloodjournal.org   "New data suggest that a mild preparative regimen of antibodies that block CD40 ligand and deplete host NK cells may make allogeneic hematopoietic stem cell transplants safe, establish long-term immunologic tolerance, and broaden the applicability of cord blood as a source of stem cells by making engraftment more efficient."
	Safer Allos?  The Immune "Character" of Allogeneic Hematopoietic Transplants CME   Medscape (free login req.)
	New marrow transplant method developed at Stanford may eliminate fatal side effects [of GVHD] eurekalert.org Dec 2004    By increasing the relative amount of these cells [regulatory t-cells], he found that he could retain the desired effect of killing cancerous cells following bone marrow transplantation, but eliminate the attack on host tissues. "It allows you to throw out the one effect but not the other," he said.
	Long-term disease-free survival of patients with advanced follicular lymphoma after allogeneic bone marrow transplantation. Br J Haematol. 2004 Nov;127(3):311-21  PMID: 15491292 | Related articles
	The allogeneic effect in non-Hodgkin's lymphoma. Leuk Lymphoma. 2003;44 Suppl 3:S91-7. Review  PMID: 15202531 | Related articles
	Allo SCT & GVHD: Impact of transplanted CD34+ cell dose in allogeneic unmanipulated peripheral blood stem cell transplantation. Bone Marrow Transplant. 2003 Jun; 31(11): 967-72  PMID: 12774046 | Related articles
	Treatment of advanced mycosis fungoides by allogeneic stem-cell transplantation with a nonmyeloablative regimen. Bone Marrow Transplant. 2003 Apr;31(8):663-6. PMID: 12692606  PubMed
	Outcome report: Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma.  Bone Marrow Transplant. 2002 Jun;29(12):973-8. PMID: 12098065  PubMed
	Outcome report: Allogeneic stem-cell transplantation for lymphoproliferative disorders using BEAM-CAMPATH (+/- fludarabine) conditioning combined with post-transplant donor-lymphocyte infusion. Cytotherapy. 2001;3(3):203-10.  PMID: 12171727  PubMed
	OPTIMIZING: The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002 Jun 1;99(11):4200-6. PMID: 12010826  PubMed

In the News

	ASCO 2014: Allo SCT in a cohort of 314 advanced lymphoma patients. Abstracts http://bit.ly/1hncCrl
	Cancer Biol Med. Mar 2013 Reduced-intensity conditioning allogeneic stem cell transplantation in malignant lymphoma: current status http://1.usa.gov/1ffQkH8
	The Oncologist, Moskowitz, Controversies in the Treatment of Lymphoma with Autologous Transplantation
	DLBCL - ASCO 2012:  High-dose chemotherapy followed by allogeneic stem cell transplantation in high-risk relapsed and refractory aggressive NHL: Results of a prospective study of the German high-grade non-Hodgkin lymphoma study group. Patients with primary refractory disease, early relapse (<12 months) or relapse after autologous SCT of aggressive B-cell (n=61) or T-cell (n=23) NHL were enrolled ...
	Biol Blood Marrow Transplant. 2011 - HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. HLA-C antigen-mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA-matched donors.
	DLBL, relapsed - BjH, 2007: Non-myeloablative (mini) allogeneic stem cell transplantation for relapsed diffuse large B-cell lymphoma: a multicentre experience "Patients with DLBCL who relapse after, or are ineligible for, autologous HCT have a poor prognosis with conventional therapy. This study provides evidence that non-myeloablative allogeneic HCT is an effective salvage therapy which can produce long-term disease-free survival in a subset of these patients. Given that virtually none of these patients would be expected to achieve durable disease-free survival with conventional therapy, the rate of PFS seen after non-myeloablative allogeneic HCT is encouraging and provides proof of the principle that immunological GVL effects alone can control DLBCL in some cases."
	Be The Match - Patients Connect Facebook Page People can join the Be The Match Registry® – the world’s largest listing of potential marrow donors and donated cord blood units – contribute financially and volunteer.