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Outcomes of Bone Marrow Transplantation

  • Wilson Lam
  • Arijit Nag
  • Rajat KumarEmail author
Living reference work entry
  • 2 Downloads
Part of the Organ and Tissue Transplantation book series (OTT)

Abstract

Blood and marrow transplantation (BMT) has evolved over the years and is indicated when transplant offers better survival as compared to nontransplant therapy. Due to the risks of transplant related mortality, BMT is only undertaken after comprehensive risk assessment and after appropriate counseling with the patient.

The most common indications for allogeneic hematopoietic cell transplantation (HCT) are the hematological malignancies, like AML, ALL, MDS, myelofibrosis, and CLL, while for autologous HCT the commonest indications are multiple myeloma and lymphomas. Transplantation is offered to high-risk malignancies, and indications change as alternative therapies offer safer and better outcomes. CLL has seen major treatment changes as novel agents have been approved; however, transplant continues to remain the sole curative option. The use of autologous transplant in lymphomas has traditionally been used in the relapsed/refractory setting in patients with chemo-sensitive disease. In certain subtypes such as mantle cell lymphomas, autologous transplants are used upfront as consolidation therapy. Allogeneic transplants are generally reserved for lymphoma patients who experience relapse or have refractory disease.

For nonmalignant disorders like aplastic anemia, BMT is indicated in high risk disease or when there is no response to immune-modulation. In hemoglobin disorders (thalassemias and sickle cell disease), allogeneic BMT offers cure, at the cost of risk of early transplant related mortality. Certain indications are uncommon, such as autologous transplantation for autoimmune disorders like multiple sclerosis and Crohn’s disease and BMT for select solid tumors.

The results of HCT are improving, with better pretransplant conditioning and management of complications. The use of related haplo-identical donors has increased the options of BMT to patients who do not have a matched sibling or unrelated donor.

Keywords

Bone marrow transplantation (BMT) Hematopoietic cell transplantation (HCT) Graft-versus-host disease (GVHD) AML ALL MDS Hodgkin lymphoma NHL Aplastic anemia Hemoglobinopathies 

Introduction

This chapter deals with the outcomes of hematopoietic cell transplantation for the most common indications in clinical practice. The term “bone marrow transplantation” or BMT was used when the hematopoietic stem cells were collected by bone marrow harvest. Over time, these cells were more frequently mobilized by G-CSF and collected from blood by apheresis; these were termed as peripheral blood stem cells (PBSC). The term BMT was then used for “blood and marrow transplantation.” Over time, as there was use of cord blood or placental blood for transplant, a more inclusive term coined was “hematopoietic stem cell transplantation (HSCT)” or just simply “hematopoietic cell transplantation (HCT).”

Despite the differences in nomenclature, hematologists and transplant physicians understand the meaning being conveyed. In this chapter, the term hematopoietic cell transplantation (HCT) is primarily used for consistency in terminology. HCT is used in a variety of disorders and the outcomes vary according to disease characteristics, transplant related factors, and patient related factors. In general, the results are better in young fit patients, who have a fully matched sibling donor and a low risk disease amenable to be cured by transplant. Conversely, outcomes are worse as one or more factors pose a higher risk.

To comprehensively discuss all aspects of each disease and type of transplant is too extensive to cover in this chapter. Hence, the most common disorders in which transplants are performed are reviewed. Certain disorders, like hemoglobinopathies or aplastic anemia, are relatively more common in the developing countries and have been covered in some detail. While autologous transplants for autoimmune diseases are uncommon, those topics have been addressed due their novelty. Finally, allogeneic (allo) HCT has been emphasized over autologous, mainly because allogeneic transplants are more complex compared to autologous HCT.

Reporting Outcomes in Hematopoietic Cell Transplantation (HCT)

Most of the outcome data in hematopoietic stem cell transplant comes from the retrospective cohort analysis from major stem cell transplant databases. The two largest databases worldwide are the Center for International Blood & Marrow Transplant Research (CIBMTR) and the European society for Blood and Marrow Transplantation (EBMT). While CIBMTR is enriched in data from transplants and cellular therapy in North America and other participating centers worldwide, EBMT pools data from major centers in Europe and many other centers. These data are then analyzed and used for basic and clinical research, education, standardization, quality control, and accreditation for transplant procedures. There are other regional transplant registries (e.g., Japanese Data Center for Hematopoietic Cell Transplantation, Indian Stem Cell Transplant Registry) which may or may not be linked to one of the two major databases. Due to logistic and ethical constraints, prospective/randomized studies may not always be feasible in the realm of hematopoietic stem cell transplants. In such a scenario, retrospective analyses including pooled data from these large registries provide a means to formulate recommendations and guidelines thereof.

Establishing a common definition of outcomes is crucial for effective comparison of therapies across various hematopoietic cell transplantation (HCT) centers. Endpoints that are commonly reported by data collection centers include engraftment date, graft versus (vs) host disease (GVHD), graft failure, survival, and relapse. Other data that are commonly reported include infections and secondary malignancies.

Overall survival (OS) is often defined as the time from transplantation until death of the patient. Nonrelapse mortality (NRM) is defined as a death from any cause other than relapse. It is important to note that this is a competing event with relapse (return/progression of disease) as patients can potentially die before relapse can occur (Iacobelli and de Wreede 2019).

The use of graft-vs-host disease (GVHD) and relapse-free-survival (RFS) arose from a need to take patients’ quality of life outside of survival. Holtan et al. proposed a novel composite end point of GVHD-free/relapse-free survival (GRFS) in which events include grade 3–4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the first post-HCT year (Holtan et al. 2015).

Levels of Evidence in HCT Outcome Reporting

Evidence-based medicine is about finding the appropriate and relevant evidence and using that evidence to make clinical decisions. An essential component of this practice is the hierarchical system of classifying evidence. This hierarchy is known as levels of evidence. It is important that physicians find the highest levels of evidence while looking for an answer to their clinical questions.

The first system of categorizing evidence was developed by the Canadian Task Force on the Periodic Health Examination in 1979 (Canadian Task Force on the Periodic Health Examination 1979). The purpose of the report was to develop recommendations on the periodic examination of the population based on evidence available in medical literature.

Any hierarchical system usually ranks an evidence, based on the probability of bias. Randomized controlled trials (RCTs) are given the highest priority since they are designed to eliminate bias and have the least risk of systematic errors. A case series/report or expert opinion is often biased by the author’s experience/opinion and this intrinsic systematic error cannot be eliminated. Thus, this is usually given the lowest priority in grading the levels of evidence. It is also essential that the levels of evidence hierarchy take into consideration the quality of data. A poorly designed randomized control trial will have the same level of evidence as a good cohort study.

However, it must be recognized that each research question is unique and not all categories of evidence are uniformly applicable in answering these. A research question is divided into the following categories: diagnosis, treatment, prognosis, and economic/decision analysis (Burns et al. 2011). The Center for Evidence Based Medicine have periodically updated their guidelines on the categorization of the levels of evidence based on the specific research question of interest.

A review article from the steering committee for evidence-based reviews of the American Society for Blood and Marrow Transplantation (ASBMT) had categorized the levels of evidence used in reporting data in stem cell transplantation (Table 1) (Jones et al. 2005). This was based on the systems recommended by the Agency for Healthcare Research and Quality. The subsequent reports in BMT outcome reporting have been predominantly based on this classification.
Table 1

Levels of Evidence

1++

High-quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias.

1+

Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias.

1-

Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias.

2++

High-quality systematic reviews of case-control or cohort studies; high-quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal.

2+

Well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal.

2-

Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal.

3

Nonanalytic studies, e.g., case reports or case series.

4

Expert opinion.

Adapted from: The Evolution of the Evidence-Based Review: Evaluating the Science Enhances the Art of Medicine -Statement of the Steering Committee for Evidence-Based Reviews of the American Society for Blood and Marrow Transplantation. Biology of Blood and Marrow Transplantation. 2005 (Jones et al. 2005)

Acute Myeloid Leukemia (AML)

AML is a heterogeneous disease in terms of disease biology. The myriad pathways involved have made it very hard to devise a single drug or combination of drugs that could act as a blanket therapy to cure AML. Additionally, the treatment related mortality of intensive chemotherapy regimens has been very high, especially in the elderly population, necessitating use of less intense therapies (hypomethylating agents, kinase inhibitors). The rates of relapse have been very high and the best overall survival outcomes with chemotherapy alone have been around 60% at 5 years for the favorable-risk disease (Tamamyan et al. 2017). The risk classification systems are hence being used to tailor the optimum postremission treatment which may include allogeneic HCT (allo-HCT), autologous HCT (auto-HCT), and continued chemotherapy. Cytogenetics and molecular signatures have proven to be the most important factors in formulating these classification systems. The Medical Research Council, UK (MRC), European Leukemia Net (ELN), and Southwest Oncology Group (SWOG) have come up with similar models (Table 2). Allo-HCT exerts a potent graft-versus-leukemia (GVL) effect, which has been demonstrated across minimal residual disease (MRD) status as well as cytogenetic and molecular subcategories. However, the effect of transplant is somewhat ameliorated because of the high incidence of transplant-related mortality (TRM) (10–25%) in patients with poor performance status and major comorbidities. The decision on whether to transplant a patient with AML mainly relies on balancing the efficacy (GVL) and toxicity (TRM). Hence, risk-adapted approaches need to be incorporated in the decision-making process (Table 3).
Table 2

Comparison of the revised MRC, ELN, and SWOG risk classification systems of AML and outcomes with chemotherapy and Allo-HCT (based on ELN data)

Groups

MRC (2010)

ELN

SWOG

Relapse risk after chemo-therapy

Relapse risk after Allo-HCT

Favorable

t(15;17) (q22;q21)

t(8;21) (q22;q22)

inv(16) (p13;q22)/t(16;16) (p13;q22)

t(8;21) (q22;q22)

(inv(16)/t(16;16) (p12;q22)

NPM1+ and FLT3-ITD-WT (NK)

Mutated CEBPA (NK)

t(15;17), t(8;21)

inv(16)/t(16;16)/del(16q)

35–40%

15–20%

Intermediate

Those cytogenetic abnormalities not classified as favorable or adverse

Intermediate-1:

NPM1+ & FLT3-ITD + (NK)

NPM1-WT & FLT3-ITD + (NK)

NPM1-WT & FLT3-ITD-WT

Normal +8, +6, −Y, del(12p)

50–55%

20–25%

  

Intermediate-2:

t(9;11) (p22;q23) cytogenetic abn. Not classified as favorable or adverse

 

70–80%

30–40%

Adverse

abn(3q) (excluding t(3;5) (q21–25;q31–35], inv(3)/t(3;3) (q21;q26) add(5q), del(5q), −5, −7, add(7q)/del(7q)

t(6;11) (q27;q23), t(10;11) (p11–13;q23), t(11q23)[excl. t(9;11)

(p21–22;q23) and t(11;19) (q23;p13)], t(9;22) (q34;q11)

−17/abn(17p)

Complex (≥4 unrelated abnormalities)

Inv(3)/t(3;3) (q21;q23)

t(6;9) (p23;q34)

t(v;11) (v;23), MLL rearranged

−5 or del(5q)

−7

Abn(17p)

Complex (≥3 unrelated abnormalities)

abn(3q)

del(5q)/−5, −7/del(7q)

t(6;9), t(9;22), 9q, 11q, 20q,

21q

17p

Complex (≥3 unrelated abnormalities)

>90%

40–50%

Unknown

 

All other abnormalities

  
Table 3

Risk-adapted strategy for choosing Allo-HCT in AML

AML risk class

MRD status

Preferred postinduction therapy

Favorable

t(8;21) (q22;q22.1); RUNX1-RUNX1T1

inv(16) (p13.1q22) or t(16;16) (p13.1;q22); CBFB-MYH11

Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow

Biallelic mutated CEBPA

Negative

Chemotherapy/auto HSCT

Positive

Allo HCT

Intermediate

Mutated NPM1 and FLT3-ITDhigh

Wild-type NPM1 without FLT3-ITD or with FLT3-ITDlow

t(9;11) (p21.3;q23.3); MLLT3-KMT2A

Other cytogenetic abnormalities

Negative

Allo HCT (if TRM low)

Positive

Allo HCT

Poor risk

t(6;9) (p23;q34.1); DEK-NUP214

t(v;11q23.3); KMT2A rearranged

t(9;22) (q34.1;q11.2); BCR-ABL1

inv(3) (q21.3q26.2) or t(3;3) (q21.3;q26.2); GATA2, MECOM(EVI1)

−5 or del(5q); −7; −17/abn(17p)

Complex karyotype, monosomal karyotype

Wild-type NPM1 and FLT3-ITDhigh

Mutated RUNX1/ASXL1/TP53

Any

Allo HCT

Outcomes of Allo-HCT in AML in Adults

AML in CR1

AML patients in first complete remission (CR1) who have adverse cytogenetic features or are MRD positive after induction therapy should be considered for HCT, considering the high risk of relapse. Meta-analysis examining the benefit of allogeneic transplant over chemotherapy or autologous transplant has demonstrated an overall survival advantage for Allo-HSCT. The relapse incidence following Allo-HCT and consolidation chemotherapy are summarized in Table 2. In a subset of standard (good) risk AML who are in CR1 and MRD negative, the beneficial effect of Allo-HCT is counterbalanced by TRM. It would be wise to avoid Allo-HCT in this subset of patients. Whether to advocate Allo-HCT in elderly AML (>60 years) has been an intriguing question. A recent CIBMTR review comparing Allo-HCT and consolidation chemotherapy in patients aged 60–75 years in CR1 showed that despite higher early (<9 m) TRM, allo-HCT recipients had superior long-term OS [Allo-HCT 29% (24–34%) versus chemotherapy 13.8% (9–21%) at 5 years] (Ustun et al. 2019). Choosing the right patient and using reduced intensity conditioning can be the key to success in transplanting elderly patients with AML.

Advanced AML

Only a very small proportion of patients in CR2 achieve long-term cure if treated with salvage chemotherapy alone. Allo-HCT remains the preferred curative option for all patients beyond CR1. Long term survival rates have been 30–50% with Allo-HCT in advanced AML across studies (Gale et al. 1996; Tauro et al. 2005). About 10–40% patients with AML do not achieve a morphologic CR with 2 courses of induction chemotherapy. They are categorized as Primary Refractory AML. They do the worst in terms of overall survival. It has been shown that the long-term OS in this group of patients improves significantly with Allo-HCT (<10% with chemotherapy alone compared to 25–30% after Allo-HCT) (Ferguson et al. 2016). Allo-HCT continues to be the only available curative treatment option for this group of patients.

Acute Promyelocytic Leukemia

The treatment of acute promyelocytic leukemia (APL) has been revolutionized with the advent of differentiating agents and nonchemotherapy-based regimens that not only account for a high CR rate and low relapse, but also have significantly low treatment related toxicity/mortality. HCT is only indicated in those patients who do not achieve molecular remission at the end of consolidation (<1%). Indications of HCT and other recommendations in APL are summarized in Table 4.
Table 4

Indications of HCT in patients with APL

 

Allo HCT

Auto HCT

Indicated

≥CR2 with positive PML-RARA after salvage therapy

≥CR2 if an auto-HSCT has failed previously

≥CR2 in patients with high relapse risk and low TRM

≥CR2, but in molecular remission

Not indicated

CR 1 in molecular remission

CR 1 in molecular remission

Conditioning regimens in Allo-HCT.

There is still considerable difference on opinion regarding the optimal conditioning regimen in for patients with AML undergoing allogeneic transplantation. The choice is mainly driven by the performance status/frailty of the patient and the status of disease at transplantation (CR vs. less than CR). For younger patients (<45 years or <60 years depending the institutional preference) who are fit, the choice would be more inclined towards the myeloid-ablative conditioning (MAC) protocols given its better antileukemia activity, The BMT-CTN 0901 trial was a prospective, randomized phase III trial comparing the outcome of reduced intensity conditioning (RIC) versus MAC regimens in AML transplants. At 18 months, the rates of relapse were higher with RIC compared to MAC regimens (50% vs. 16.5%) leading to a lower RFS (47.3% vs. 68.8%) (Scott et al. 2017). This highlighted the survival advantage of MAC regimens compared to RIC.

GVHD Prophylaxis

Acute graft-versus-host disease (aGVHD) is a common complication of allogeneic transplantation and leads to significant posttransplant morbidity and mortality. Therefore, selection of the GVHD prophylaxis regimen is an integral part of the transplant planning. The most commonly used GVHD prophylaxis has been the use of a combination of a calcineurin inhibitor (CNI) (cyclosporine or tacrolimus) with methotrexate (MTX) or mycophenolate mofetil (MMF). The use of mTOR inhibitor sirolimus has also been tried and was shown to be acceptable alternative (combined with tacrolimus) to the conventional tacrolimus/MTX combination (Cutler et al. 2014). The duration of GVHD prophylaxis has been a matter of contention with few centers opting to use it for approximately 6 months (180 days) while others would prefer to taper and stop, starting at 2 months (60 days) to 3 months (90 days).

While acute GVHD prevention strategies have been quite successful in mitigating the risks, prevention of chronic GVHD is still a major challenge. T-cell depletion (TCD) strategies have been devised to address this problem and consists of ex vivo TCD (“positive” selection of CD34+ cells or “negative” selection eliminating specific T-cell subsets) (Table 5) or in vivo T-cell depletion using antithymocyte globulin (ATG) or alemtuzumab (Table 6). ATG has been shown to be beneficial in acute leukemias and hematological malignancies in recent Phase III trials.
Table 5

Outcomes with ex vivo T-cell depletion strategies

Year Study design

n

Graft source

aGVHD II-IV (%)

cGVHD

Relapse

Comments

2005 (Wagner et al. 2005)

Ph III RCT (TCD/CSA vs. CSA/MTX)

405

BM

39 vs. 63

No difference

20 vs. 7%

DFS (3y): 27% vs. 34%

CMV: 28% vs. 17%

2011 (Devine et al. 2011)

Ph II multi-center

44

PBSC

23

19% (2y)

Extensive: 7%

24

DFS (3y): 53%

2015 (Tamari et al. 2015)

Retrospective

102

PBSC

16

4

16

Graft failure: 4%

OS (5y): 49%

DFS (5y): 48%

BM Bone marrow graft, PBSC Peripheral Blood Stem Cells

Table 6

Outcomes with in vivo T-cell depletion strategies

Year

Study design

Drug

n

Graft source

aGVHD II-IV (%)

cGVHD (%)

Relapse (%)

Comments

2016 (Kroger et al. 2016)

Phase III RCT

ATG vs. standard

155

PBSC

21.3 vs. 34.7

32.2 vs. 68.7

Severe: 2.4 vs. 22.2

32.2 vs. 25.5 (p:0.17)

OS (2y): 74.1% vs. 77.9%

RFS (2y): 59.4% vs. 64.6%

2009 (Finke et al. 2009), 2016 (Socie et al. 2011):

Ph III RCT

Rabbit ATG vs. standard

201

PBSC

33 vs. 51

30 vs. 60

33 vs. 28 (p:0.5)

OS (3y): 55% vs. 43%

NRM: 19% vs. 34%

2001 (Bacigalupo et al. 2001):

Ph 3 RCT

Rabbit ATG vs. standard

55

PBSC

37 vs. 79

41 vs. 59

36 vs. 18 (p:0.8)

OS (1y): 43% vs. 43%

NRM (1y): 47% vs. 49%

2009 (Malladi et al. 2009)

Retrospective, Alemtuzumab vs. standard

88

 

14 vs. 22

Extensive: 4 vs. 47

35 vs. 19

OS (5y): 61 vs. 53%,

NRM (2y): 12 vs. 17%

BM Bone marrow graft, PBSC Peripheral Blood Stem Cells

Donor Source

The availability of high-resolution typing and more robust donor registries has allowed selection of more matched unrelated donors (MUD) who are matched for HLA-A, -B, -C, -DRB1, and -DQB1 at the molecular level (Gragert et al. 2014). Results with respect to OS and disease-free survival with MUDs currently compare well with those obtained with matched related donors (MRD) allo-HCT.

Related haploidentical HCTs (haplo-HCT) were first pioneered by the Perugia group using a myeloablative regimen with extensive ex vivo and in vivo T-cell depletion strategies. This seemed to be associated with impaired immune reconstitution, compromising both the graft vs. leukemia (GVL) effect and antiinfectious immunity (Aversa et al. 1998). Later, T-cell replete haploidentical HCT was developed, based on different immunosuppressive approaches varying from pretransplant ATG to posttransplant cyclophosphamide (PTCY). The use of PTCY has been the most significant progress in the field of haplo-HCT with reasonable rates of acute and chronic GVHD, without compromising on the GVL effect (Huang 2013; Lee et al. 2009; Luznik et al. 2008). Trials comparing outcomes of haploidentical HCT with MRD and MUD Allo-HCT in AML have shown comparable results, in terms of OS, relapse, and NRM with similar or lesser incidence of acute and chronic GVHD (Rashidi et al. 2019). Haploidentical HCTs have thus evolved as a viable alternative to matched sibling/donor HCTs in AML.

Autologous (Auto) Transplant in AML

Studies and meta-analyses comparing autologous transplant to intensive chemotherapy in AML patients in CR1 have shown benefit in leukemia free survival (LFS) (Nathan et al. 2004; Wang et al. 2010). However, there has been no demonstrated benefit in terms of overall survival, thus highlighting the high incidence of late relapse. Studies from the Japanese registry comparing autologous and allogeneic transplant in AML-CR1 have shown comparable efficacy in LFS (Mizutani et al. 2016, 2017). But overall survival continues to be superior for Allo-HCT probably accounting for the GVL effect and lower relapse incidence. Long-term survival has been approximately 40% in patients undergoing autologous HCT in CR2 with a reasonable disease-control after salvage chemotherapy. There have been no prospective trials comparing Allo-HCT with Auto-HCT in AML-CR2 and hence there is no objective data to guide the physician’s choice.

Acute Lymphoblastic Leukemia (ALL)

ALL is a disease involving the proliferation of immature lymphocytes, with a bimodal distribution affecting childhood and above the age of 50. While chemotherapeutic treatment in children has been successful in long-term survival and cures, this has not similarly translated in the adult population. The adoption of pediatric inspired regimens in younger adults has been helpful in closing the gap; however, the increased toxicity limits its benefits particularly with older patients. The last decade has seen multiple new exciting therapeutic options including novel antibodies such as blinatumomab, bispecific T-cell engaging antibodies, and chimeric antigen receptor T-cells. Still, HCT remains the standard treatment to establish long term remissions in high risk ALL.

Indications for Transplant

Allogeneic hematopoietic stem cell transplant is used as a consolidative treatment following induction chemotherapy. Earlier studies supporting this included younger patients undergoing transplants with matched sibling donors as well as donor vs. no donor studies. However, these need to be balanced with the conventional chemotherapy of that era, as well as using mainly myeloablative and TBI based conditioning regimens. Subsequent studies have expanded the donor source, as well as introduced reduced intensity regimens. The clinical factors considered to be high risk included age of 35, cytogenetic changes, high white blood cell count, CD20 positivity, time to remission >4 weeks from induction, central nervous system involvement, and Philadelphia chromosome positivity. More recently, minimal residual disease was found to have a more predominant role in survival in comparison to previously described clinical factors (Leonard and Hayes-Lattin 2018).

Myeloablative Versus Reduced Intensity Conditioning

Myeloablative regimens have been restricted to younger populations due to significant toxicity. However, the introduction of reduced intensity regimens has allowed transplant to become a therapeutic option in less fit patients, particularly the older patient who is more likely to have less physiologic reserve. Prospective randomized trials are limited. In a recent review by Leonard and Hayes-Lattin, retrospective trials did not show a difference in overall survival, though some suggested decrease in nonrelapse mortality at the expense of relapse with reduced intensity conditioning, with the caveat of patient heterogeneity with regard to donor type and disease status at transplant (Leonard and Hayes-Lattin 2018).

A commonly used conditioning regimen which has been well-described is cyclophosphamide (Cy) and total-body-irradiation (TBI), known as CyTBI, due to disease sensitivity and penetrance to sanctuary sites. However, the concern with acute and late toxicities encouraged exploration of TBI-free regimens. A CIBMTR retrospective compared CyTBI to busulfan-cyclophosphamide (BuCy) and while relapse was increased in the BuCy group, there were no differences in overall survival (Kebriaei et al. 2018). In another retrospective, comparing CyTBI to a fludarabine-busulfan (FluBu) with a TBI of 400 cGy demonstrated no difference in survival, but suggested a decreased relapse in FluBu400 (Speziali et al. 2019). Other conditioning regimens that have been examined include fludarabine/melphalan (Leonard and Hayes-Lattin 2018) and etoposide-TBI (Czyz et al. 2018).

Role of Minimal Residual disease in ALL

Minimal-residual-disease describes malignancy that is on the submicroscopic cell. In ALL, multiple techniques are done such as immunoglobulin and T-cell receptor gene rearrangements, real-time PCR-based detection of fusion transcripts (e.g., BCR-ABL), and flow cytometry. Regardless of the method, the presence of minimal residual disease has been associated with poorer outcomes, including high rates of relapse in retrospective studies (Bassan et al. 2019). Multiple societies have recommended the use of minimal-residual-disease whenever possible including the European Society of Medical Oncology, National Comprehensive Cancer Network and the American Society of Transplantation and Cell Therapy (ASTCT). Controversy exists in the role of transplant for minimal-residual-disease negative in first remission for standard risk ALL. In an evidence-based review, the ASTCT recommends MAC conditioning in minimal-residual-disease positive ALL if possible and allogeneic transplant regardless of minimal-residual-disease status in high risk disease (Defilipp et al. 2019).

Role of TKI Use in Ph+ ALL

Philadelphia positive ALL has been previously identified a poor risk factor; however, with the advent of tyrosine kinase inhibitors (TKIs), significant improvements have been made on outcomes. This has enabled more patients to achieve remission and be considered for stem cell transplant, though questions have been raised on what whether this is still necessary (Ravandi 2017). The current recommendations from the ASTCT endorse allogeneic HCT from HLA-matched donor in CR1 (Defilipp et al. 2019).

Posttransplant tyrosine kinase use has been explored in Philadelphia positive ALL as a strategy to reduce relapse, though there is a paucity of prospective trials and retrospective reviews are inconclusive (Saini and Brandwein 2017). The EBMT recommends all patients with Philadelphia positive ALL should be considered for TKI post stem cell transplant, with patients having a history of CNS involvement to receive dasatinib (Giebel et al. 2016).

Donor Type

The use of an HLA-matched sibling is the first choice for a donor; however, availability is limited to only 25–30% of patients. Retrospective studies involving matched unrelated donors (MUDs) suggest equivalent overall survival (OS), relapse, and TRM to matched sibling donor, making it a viable alternative option should an HLA-matched sibling be unavailable (Hwang et al. 2015).

Haploidentical donors are also being increasingly used in those lacking a matched sibling donor. The EBMT has recently published a review comparing haploidentical donor HCT with MUD and mismatched unrelated donor (MMUD) transplants in ALL in first remission. The outcomes were similar in the three groups, suggesting that haploidentical donor HCT using PTCY was comparable to MUD and MMUD transplants using standard immunosuppression including ATG (Shem-Tov et al. 2020).

CIBMTR reports overall survival for ALL patients at approximately 60% at 3 years posttransplant (D’Souza and Fretham 2018). EBMT reports outcomes of overall survival ranging from 65 to 69% at 2 years, with a cumulative nonrelapse mortality rate of 14–22% and relapse of 19–26% (Giebel et al. 2017). Outcomes of HCT in ALL are shown in Table 7.
Table 7

Outcomes of HCT in ALL

Reference

MAC vs. RIC

Donor

OS

NRM

Relapse

Mohty et al. (2010)

78% MAC

22% RIC

100% MRD

45% MAC (2 y)

48% RIC

29% MACa (2 y)

21% RIC

31% MACa (2 y)

47% RIC

Segal et al. (2017)

87% MAC

11% RIC/NMA

2% missing

30% MRD

50% MUD

20% MMUD

35% MRDa

36% MUD

28% MMUD

27% MRDa

32% MUD

45% MMUD

43% MRDa

33% MUD

31% MMUD

Kebriaei et al. (2018)

100%

Cy-TBI vs. BuCy

51% MRD

49% other

53% vs. 57% (3 y)

25% vs. 19%a (3y)

28 vs. 37%a (3 y)

Rosko et al. (2017)

100% RIC

34% MRD

38% MUD

8% UCB

21% other

38% (3 y)

20–33%% (3 y)

45–57% (3 y)

Giebel et al. (2017)

100% MAC

45% MRD

34% MUD

14% MMUD

7% unknown

65–69% (2 y)

14–22 (3 y)

19–26% (2 y)

Shem-Tov et al. (2020)

80% MAC

20% RIC

11% Haplo

66% MUD

23% MMUD

54% Haplo (3 y)

62% MUD

62% MMUD

23% Haplo (3 y)

19% MUD

20% MMUD

28% Haplo (3 y)

28% MUD

25% MMUD

aDenotes significance

Future directions will need to address the role of minimal residual disease in transplant decision making, optimizing TKI use post stem cell transplant, and integrating novel therapies with transplant in the treatment of ALL.

Myelodysplastic Syndromes (MDS)

The only curative treatment for myelodysplastic syndromes (MDS) is Allo-HCT. As MDS is a disease of the elderly, Allo-HCT in MDS can have nonrelapse mortality ranging from 28% to 37% (Bartenstein and Deeg 2010). Hence, fitness, co-morbidities, frailty, and performance status are important consideration before transplant. Age alone should not be a criterion for withholding HCT from patients who are otherwise healthy. In a large study by Lim et al. in 1,333 MDS patients older than 50 years, the disease stage at the time of transplantation (but not recipient age or conditioning regimen intensity) was the most important factor influencing outcomes (Lim et al. 2010).

The timing of HCT in MDS is crucial to maximize length of life. Various studies have utilized Markov model based decision analysis and shown that delaying transplant till the disease is at higher risk, is the best strategy to maximize pretransplant survival, before exposing patients to the high early mortality risk of HCT, while not delaying transplant so long as to adversely affect outcomes (Saber and Horowitz 2016). The reason is that some patients in early phase of MDS may live for many years, but succumb to unpredictable factors soon after HCT (Cutler et al. 2004; Alessandrino et al. 2013; Koreth et al. 2013). As per the 2017 ELN recommendations, fit patients up to 65–70 years of age, who are IPSS intermediate-2 or high-risk, or IPSS-R high or very high risk should be candidates for HCT if otherwise fit, willing and with a suitable donor. For patients at intermediate or lower risk, those with “poor risk” features should be considered for HCT. The “poor risk” features were defined as: life-threatening cytopenias (neutrophils <0.3 × 109/L, platelet counts <30 × 109/L, high red cell transfusion requirements at ≥2 units per month for 6 months; poor-risk cytogenetics; persistent blast increase (>15% bone marrow blasts or >50% increase) (De Witte et al. 2017).

The type of pretransplant therapy is also controversial. There is general consensus that blasts in bone marrow should be <10% for best results. Both intensive chemo or hypomethylating agents are acceptable (Bartenstein and Deeg 2010; De Witte et al. 2017).

Introduction of RIC regimens has led to reductions in early TRM, leading to significant increase in transplant numbers in older patients. In addition, the availability of hypomethylating agents has increased Allo-HCT numbers in MDS by serving as an effective and well-tolerated means to reducing disease burden prior to transplant. There is conflicting published data in this regard, with some studies showing reduced relapse rates with MAC regimens, and others showing no difference compared to RIC approaches.

In a study of 257 patients with secondary MDS (including 103 whose disease had progressed to AML), the 5-year relapse free-survival was 29% overall, 25% for RAEB, and 41% for RA/RARS (Chang et al. 2007).

In another study, 836 patients with MDS who underwent HCT with HLA-identical sibling donors after RIC conditioning (n = 215) or conventional conditioning (n = 621) were analyzed. With RIC conditioning, the NRM was 22%, overall survival was 41%, and RFS was 33%. In contrast, with conventional conditioning, the NRM was 32%, OS 45%, and RFS 41% (Martino et al. 2006).

Saber et al. reported the outcomes of 701 adult MDS patients who underwent HCT between 2002 and 2006. With matched related donors, the 3-year TRM was 32%, relapse rates 30% and OS was 44% while with MUDs the corresponding figures were 40%, 25%, and 39%, respectively (Saber et al. 2013).

To risk stratify patients of MDS posttransplantation, various risk scores have been developed. The most recent, by the EBMT, has identified seven independent risk factors for poor survival: age ≥ 50 years, matched unrelated donors, Karnofsky performance status <90%, very poor cytogenetics or monosomal karyotype, positive cytomegalovirus status of the recipient, blood blasts >1%, and platelet counts ≤50 × 109/L prior to transplantation (Gagelmann et al. 2019). In conclusion, HCT should be offered to patients with MDS provided they are considered medically fit to undergo the procedure, and transplant offers better survival and quality of life compared to nontransplant options.

Myelofibrosis (MF)

Myelofibrosis (MF) is the only myeloproliferative neoplasm where a HCT is indicated. Early reports on Allo-HCT in MF date back to the late 90s and early 2000s with the use of MAC regimens. Although there were reasonable 5-year survival rates (47–61%), the high NRM (27–34%) made it a challenge to proceed with transplant. The presence of a graft versus myelofibrosis effect was suggested by reports on the successful use of donor lymphocyte infusions (DLI) in myelofibrosis. Subsequently the use of RIC regimens was explored. There is ample evidence of the curative effect of allo-transplant in myelofibrosis. However, considering the treatment related toxicity and mortality, it is imperative to choose the right patient who would benefit from transplant.

Patients with primary MF or postpolycythemia vera (PV) myelofibrosis are quite heterogeneous in terms of disease biology and clinical behavior. Although the median OS in MF is approximately 6 years, it varies from less than 2 years to more than 15 years. Accordingly, it is imperative to divide the patients into appropriate risk-groups for prognostication and making the right treatment decisions. Risk scores such as IPSS (Cervantes et al. 2009), dynamic IPSS (DIPSS) (Passamonti et al. 2010), or DIPSS plus (Gangat et al. 2011) are currently used in clinical practice to determine the prognosis of patients with PMF. With greater understanding of the influence of molecular and cytogenetic factors influencing outcome in MF, subsequent studies have tried to build on the previous models with the incorporation of these data (MIPSS-70, MIPSS-70 Plus, MIPSS-70 Plus Version 2.0) (Guglielmelli et al. 2018; Tefferi et al. 2018). Prognostic models for post-PV or post-essential thrombocythemia (ET) MF have also been devised (MYSEC-PM) (Passamonti et al. 2017). Based on data comparing survival outcomes with transplant versus no transplant, the recommendations from the ELN/EBMT were to consider Allo-HCT for all patients with MF under the age of 70 years with an estimated median survival of less than 5 years (Kroger et al. 2015). This would include all patients falling in the intermediate-2 and high-risk categories as per DIPSS. Whether to consider transplant for patients in the intermediate-1 risk group has been a contentious issue considering the TRM with Allo-HCT and the natural history of the disease. Recommendations from the ELN/EBMT expert panel were to consider Allo-HCT in patients with intermediate-1 risk MF who also have other high-risk features like presence of peripheral blood blasts >2%, refractory transfusion-dependent anemia, and high-risk molecular signatures. However, the decision has to be highly individualized and should also take into consideration the patient’s wishes, symptom burden and objective quality of life. In the era of JAK-inhibitors (JAKi) where a significant control on disease-related symptoms and splenomegaly is possible, the availability of a well-matched donor may support the decision to proceed to an earlier HCT.

As patients with MF may have marked splenomegaly, a splenectomy is sometimes recommended, but this remains controversial. In theory, pretransplant splenectomy remains an option to consider as it could aid in faster engraftment and possibly better posttransplant outcomes. However, the procedure has its risks. Reports on the effect of splenectomy on posttransplant outcomes have had mixed conclusions with a few suggesting higher relapse rates, while others showing improved event free survival and OS (Kroger et al. 2009; McLornan et al. 2019). Given the potential effects of JAK-inhibitors on reducing splenomegaly, a trial of ruxolitinib would be indicated as an alternative strategy to splenectomy (Bacigalupo et al. 2010).

JAK inhibitors may improve performance status, reduce splenomegaly, potentially shorten time to engraftment and may dampen an inherently pro-inflammatory milieu (McLornan et al. 2019). Studies have not reported any major adverse events with the use of JAK 1/2 inhibitors prior to Allo-HCT (Gupta et al. 2019; Shanavas et al. 2016). Studies have reported a better survival outcome posttransplant in patients who respond to JAKi. While the use of JAKi in patients posttransplant has resulted in a significant reduction in terms of GVHD, there has been increase in CMV reactivation and other opportunistic infections as well as potential concerns of prolonged cytopenias. It is important to explore the use of JAKi peri-transplant and examine whether a balance can be struck between amelioration of the risk of GVHD without increasing the rate of posttransplant infections.

Donor Selection

Several retrospective studies failed to reveal significant differences in outcomes between MRD and MUD transplants (Kroger et al. 2009; Ballen et al. 2010; Rondelli et al. 2014). However, outcome of mismatched donor transplants has been poor, mainly on account of the high TRM. Use of umbilical cord blood transplant in MF poses some challenges in terms of the stem cell dose and a higher relapse rate reported in some initial studies (Takagi et al. 2010).

Conditioning Regimen

Retrospective studies have shown that RIC-regimens are noninferior when compared to MAC. Recently, a preliminary analysis from EBMT registry by McLornan et al. compared outcomes of transplants in MF using MAC and RIC regimens with no statistically significant differences in engraftment, GVHD, NRM, progression-free survival, and OS (McLornan et al. 2019). Due to significant MAC-associated toxicity, RIC protocols are recommended for patients older than 50 years.

Posttransplant Complications

Primary/secondary graft rejection has been a problem in patients with MF undergoing Allo-HCT with reported frequency of 2–24% with RIC regimens (Farhadfar et al. 2016; Kroger et al. 2015). Engraftment is influenced by the donor type, intensity of conditioning regimen, cell dose in the graft, degree of bone marrow fibrosis, and spleen size. Poor graft function is defined as cytopenia with full donor chimerism, in the absence of active GVHD. Studies have however failed to demonstrate differences in long-term survival outcomes in those with poor graft function (Alchalby et al. 2016). It has been demonstrated that MF patients have significantly more clearance of hematopoietic stem cells due to early splenic pooling (Hart et al. 2016). While treatment for graft rejection relies mainly on second transplant, poor graft function is usually treated with infusion of CD34-selected donor hematopoietic stem cells (‘CD34-boost’). Outcomes of HCT in MF are shown in Table 8.
Table 8

Outcome of HCT in myelofibrosis

Year

Study design

n

Conditioning regimen

aGVHD II-IV (%)

cGVHD

1. Limited

2. Extensive

OS (%)

Comments

2014 (Rondelli et al. 2014)

Prospective phase II

66

RIC

MSD: 38

MUD: 41

MSD: 36

MUD: 38

MSD: 75

MUD: 32

24% graft failure in MUD group

2010 (Ballen et al. 2010)

Retrospective

289

MAC

MSD: 43

MUD: 40

Other: 24%

MSD: 40

MUD: 32

Others: 23

5y:

MSD: 37

MUD:30

Other: 40%

Relapse (5y)

MSD: 32%

MUD: 23%, other: 40%

2007 (Kerbauy et al. 2007)

Retrospective

104

Predominantly MAC

64

1y: 84

7y: 61

 

2014 (Gupta et al. 2014)

Retrospective

233

RIC

37

1y: 42

MSD:56

MUD:37

Others:34

Donor type determinant on outcome

MSD Matched Sibling Donor, MUD Matched Unrelated Donor, RIC Reduced-Intensity Conditioning, MAC Myeloablative Conditioning

Chronic Lymphocytic Leukemia (CLL)

CLL is one of the most common types of leukemias in the Western Hemisphere. It is less prevalent in East Asian populations and potentially has a different disease biology (Yang et al. 2015). Previously allogeneic transplant was indicated for high risk features including chromosomal abnormalities (17p deletion) or short remission post purine analogs (Dreger et al. 2007). With significant advances in targeted therapies, such as the use of monoclonal antibodies and small molecule inhibitors, the indications for Allo-HCT have been revised to a later stage of disease (Kharfan-Dabaja et al. 2016). Performing Allo-HCT has been challenging given the average age of diagnosis about 70 (Hallek 2019).

In terms of choice of conditioning regimen, reduced intensity is recommended as previous (largely retrospective reviews) and showed an increased risk of nonrelapse mortality for myeloablative regimens (Kharfan-Dabaja et al. 2018).

Outcomes of HCT in CLL are shown in Table 9. Data from a CIBMTR report showed an overall survival at 3 years of 59% for related donors and 52% for unrelated donors (D’Souza and Zhu 2016). The EBMT has published retrospective studies that show a 5-year overall survival in 40–50% range, cumulative NRM of 30–40%, and relapse of 20–30% (Van Gelder et al. 2016, 2017). In the haploidentical donor setting, 5-year overall survival has been reported as 38%, cumulative relapse of 26%, and nonrelapse mortality 44% (Van Gorkom et al. 2018). Features that were associated with improved outcomes included younger age at transplant.
Table 9

Outcomes of Allo-HCT in CLL

Study

MAC vs. RIC

Donor

OS

NRM/TRM

Relapse

Sobecks et al. (2014)

55% MAC

45% RIC

100% MRD

36% MAC (5 y)a

48% RIC

54% MAC (5 y)

40% RIC

17% MAC (5 y)

35% RIC

Toze et al. (2012)

45% MAC

22% RIC

33% NMA

60% MRD

40% URD

55% (5 y)

36% (10 y)

22% (10 y)

van Gelder et al. (2016)

23% MAC

77% RIC

51% MRD

49% other

35% (10 y)

43% (10 y)

40% (10 y)

aHCT done after 2000

Challenges remain in integrating the use of novel therapies in the path to transplant, though evidence suggests that they can be an effective bridge (Dreger et al. 2019a). Another ongoing issue is improving the late/long term outcomes, where OS has been reported in 30% range (Van Gelder et al. 2016).

Lymphomas

Both autologous and allogeneic hematopoietic stem cell transplants have a role in lymphomas, although autologous transplants are generally preferred as first line treatment over allogeneic transplant.

Autologous HCT (Auto-HCT) is an established therapeutic modality in patients with lymphomas, either for relapsed/refractory (rel/ref) disease or for upfront therapy as a form of consolidation. In Hodgkin lymphoma (HL) and most of the non-Hodgkin lymphomas (NHL), Auto-HCT is used in relapse or refractory setting, provided there is chemo-sensitive disease. In mantle cell lymphoma and certain T-cell lymphomas, Auto-HCT is recommended as consolidation after achieving CR (Dahi et al. 2019).

Principle of Autologous Hematopoietic Cell Transplantation

Auto-HCT exploits the principle of steep dose-response relationship between chemotherapy and fractional cell kill, implying that a disproportionately high number of cancer cells are killed when drug doses are increased. The conditioning regimen delivers cytotoxic myeloablative chemotherapy to residual lymphoma cells and the infusion of previously collected hematopoietic stem cells restores hematopoiesis within a few weeks (Broccoli and Zinzani 2019). The most common regimen used for conditioning is BEAM (carmustine, etoposide, cytarabine, melphalan), followed by CBV (cyclophosphamide, carmustine, etoposide), BuCy (busulfan, cyclophosphamide), or TBI based regimens (Broccoli and Zinzani 2019). Other regimens are being explored, based on newer agents.

Hodgkin Lymphoma (HL)

Patients with Hodgkin lymphoma (HL) respond well to standard chemotherapy with or without radiation. For patients who fail induction or relapse, an Auto-HCT is standard therapy if patient is fit for transplantation (Broccoli and Zinzani 2019). In HL, two randomized clinical trials have demonstrated that Auto-HCT is superior over chemotherapy and that nearly 50% patients can be cured by this approach (Linch et al. 1993; Schmitz et al. 2002). The disease status at the time of transplant reflects the outcome, being much better if there is complete remission and PET scan is negative. Auto-HCT failures usually occur in the first 2–3 years posttransplant.

Allo-HCT is reserved for HL patients who relapse after auto-HCT. The role of allogeneic transplants in HL is controversial. Historically, patients with HL who underwent myeloablative conditioning had high NRM and relapse, with survival at 3 years reaching 20%. Using reduced intensity conditioning helped to reduce NRM but there was higher disease relapse, with overall survival less than 30% (Broccoli and Zinzani 2019). Results have improved with the use of haplo-identical donors and PTCY, as the GVHD and graft rejection rates are low, while the graft-versus-lymphoma effect is maintained. In a study of 62 consecutive HL patients who underwent haplo-HCT, the 3-year OS was 63%, relapse rate was 21%, and 1-year NRM was 20% (Castagna et al. 2017). With the newer agents available for use in HL, such as brentuximab vedotin and the antiprogrammed death 1 antibodies (PD-1 antibodies), the role and timing of HCT, as well as the pre- and posttransplant therapies are being reviewed as new data emerges.

Diffuse Large B-Cell Lymphomas (DLBCL)

DLBCL is the most common aggressive NHL, but is fairly responsive to chemotherapy. The adoption of Auto-HCT for DLBCL in first relapse came from the randomized PARMA trial in the 1990s, demonstrating its superiority to salvage chemotherapy with a 5-year overall survival of 53% vs. 32% (Philip et al. 1995). This effect was still sustained on follow-up studies in the rituximab era with survival maintained in the 50% range (Robinson et al. 2016). The use of upfront transplant DBLCL continues to be investigational.

In about 30–40% of patients with DLCBL, progression will occur post autologous stem cell transplant. Allogeneic transplant has been explored due to the potential for cure through graft vs. lymphoma effect; however, the benefits were offset due to treatment related toxicity. In a retrospective study by the EBMT Lymphoma Working Group (Robinson et al. 2016) evaluating Allo-HCT in first relapse, the use of MAC or RIC conditioning regimens did not carry a significant impact on relapse incidence, and there was decreased overall survival from NRM when compared to autologous transplant. However, the reasons for patients going to allogeneic HCT are not clear. In the setting of relapse post-Auto-HCT, Allo-HCT is the only option for sustained remission. OS rates can range from 30 to 50% at 3 years, with relapses ranging from 30 to 40% and nonrelapse mortality approximately 20–40% (Fenske et al. 2016; Epperla and Hamadani 2017).

The use of PTCY ignited interest in using haploidentical donors. Dreger et al. reported a CIBMTR retrospective study comparing haploidentical donors to matched related and unrelated donor group and the 3-year OS was 46% with haplo-identical donors (Dreger et al. 2019b). It was noted that there was a significant decrease in GVHD rates in the haplo donor setting, likely related to the use of posttransplant cyclophosphamide (Table 10). To conclude allogeneic transplant can establish long term remission in DBLCL; however, challenges remain in improving relapse rates and complications.
Table 10

Allo-HCT in DLBCL

Study

MAC vs. RIC

OS

NRM

Relapse

Robinson et al. (2016)

MAC 57%

RIC 43%

54% auto-HCT (4 y)a

30% MAC (4 y)

38% RIC

7%auto-HCT (4 y)a

25% MAC (4 y)

19%

50% auto-HCT (4y)

47% MAC (4 y)

53% RIC

Dreger et al. (2019b)

100% RIC

MSD 50% (at 3 y)

MUD (TCD+) 43%

MUD (TCD-) 46%

Haplo 46%

MSD 17% at 3ya

MUD (TCD+) 26%

MUD (TCD-) 30%

Haplo 26%

MSD 47%a

MUD (TCD+) 38%

MUD (TCD-) 34%

Haplo 41%

aDenotes significance; MSD matched sibling donor, TCD t cell depletion

Follicular Lymphomas

Follicular lymphoma is an indolent disease which can be managed with observation in a portion of patients. Inevitably due to progressive disease burden, many patients will eventually require multiple lines of therapy and cure is rare.

The use of autologous transplant is commonly done in first relapse, in particular when it occurs early (less than 24 months) as outcomes are reported to be better. Respective analysis by the German Low-Grade Lymphoma Study Groups (GLSG1996 and GLSF2000) as well the CIBMTR showed higher overall survivals at 5 years (73–75%) when compared to no transplant (Casulo et al. 2018; Jurinovic et al. 2018). Nonrelapse mortality is low at 5% (Smith et al. 2018), but there is concern regarding secondary malignancies such as myelodysplastic syndrome and acute myeloid leukemia.

Allogeneic HCT has demonstrated long term remission rates; however, the major limitation has been due to nonrelapse mortality (Klyuchnikov et al. 2015, 2016). The effects of conditioning regimen are conflicting, with some suggesting increased relapse with reduced intensity (Hari et al. 2008), while long term outcomes were worse with a myeloablative regimen (Sureda et al. 2018). Results are summarized in Table 11.
Table 11

Allo-HCT in follicular lymphoma

Study

MAC vs. RIC

Donor

OS

NRM

Relapse

Klyuchnikov et al. (2015)

100% RIC

MRD 53%

MUD 38%

MMUD 8%

74% auto (5 y)a

68% allo

5% auto (5 y)a

26% allo (5 y)

54% auto (5 y)a

20% allo

Klyuchnikov et al. (2016)b

100% RIC

MRD 59%

MUD 38%

MMUD 3%

59% auto (5y)a

54% allo

4% auto (5 y)a

27% allo

61% auto (5 y)a

20% allo

Smith et al. (2018)

MAC 31%

RIC 68.5%

Unknown 0.5%

MRD 53%

MUD 47%

73% autoa

73% MRD (5 y)

49% MUD

5% auto (5 y)a

17% MRD

33% MUD

58% auto (5 y)a

31% MRD

23% MUD

Sureda et al. (2018)

MAC 23%

RIC/NMA 77%

MRD 73%

MUD 27%

(well matched)

61% (5 y)

29% (5 y)

19% (5 y)

aDenotes significance

bGrade 3 lymphomas

A combined retrospective study from the CIBMTR and EBMT in relapsed follicular lymphomas showed a 61% OS at 5 years, cumulative incidence of relapse at 29% with nonrelapse mortality at 19% (Sureda et al. 2018).

Optimal choice between allogeneic versus autologous HCT at first relapse is still investigational. The prospective BMT CTN 0202 trial was to address this question. However, it closed early due to slow accrual. Of the patients participating (n = 30), the group reported a 3-year OS of 73% in autologous transplant versus 100% in allogeneic HCT, and 3-year PFS was 63% in autologous HCT versus 86% in allogeneic transplant (Tomblyn et al. 2011). Another CIBMTR retrospective study compared autologous, matched related, and matched unrelated allogeneic transplants in the rituximab era for early treatment failure (progression less than 2 years) for grade 1–2 follicular lymphoma (Smith et al. 2018). Nonrelapse mortality at 5 years significantly favored autologous over matched related or unrelated (5% vs. 17% vs. 33%), while relapse rates favored matched unrelated (23%) or matched related (31%) compared to autologous 58%. Overall survival was comparable between matched sibling (70%) and autologous (73%) compared to matched unrelated (49%). Given the ongoing issues, Hamadani and Horowitz suggest that the use of allogeneic transplant be individualized, taking into consideration medical fitness and donor availability in the relapsed setting (Hamadani and Horowitz 2017).

Mantle Cell Lymphomas

Mantle cell lymphomas (MCL) are an uncommon entity, comprising less than 10% of NHL. Initial therapy for fit patients includes induction therapy followed by autologous stem cell transplant, which can provide remission for several years (Fenske et al. 2016).

A number of studies have shown that in MCL, consolidation with Auto-HCT is superior to maintenance therapy (Falcone and Kuruvilla 2017). The optimal timing of transplant is early in the disease, with no more than two prior lines of therapy (Dahi et al. 2019). The outcome is inferior if HCT is done beyond CR1, as relapses are higher.

Allogeneic transplant has been typically reserved for the relapsed setting, based on a comparison of autologous with allogeneic transplant (Fenske et al. 2014). While the OS was no different between autologous and allogeneic in the early setting (first partial or complete remission), the NRM at 1 year was 25% in allogeneic vs. 3% in autologous. Thus, Allo-HCT was recommended as an option in the relapsed setting or after failure of at least two lines of therapy. Subsequent retrospective reviews showed a durable remission rate between 35 and 45% at 3 years (Fenske et al. 2016). It should be noted that even in the refractory disease durable responses can be seen in up to a quarter of patients post allogeneic transplant (Hamadani et al. 2013).

CIMBTR reports a 3-year overall survival of 53% (D’Souza and Fretham 2018). EBMT has reported a 5-year overall survival of 40%, nonrelapse mortality of 24%, and relapse of 40% (Robinson et al. 2018).

Future directions will examine the potential role of allogeneic transplant for high-risk disease, as it is still an unmet need in mantle cell lymphoma. Similar to CLL, novel therapies like ibrutinib are being investigated for their role as bridging therapy to transplant without adversely effecting outcomes (Dreger et al. 2019a).

T-Cell Lymphomas

T-cell lymphomas represent a variety of entities, including angio-immunoblastic T-cell lymphoma, peripheral T-cell lymphoma (not otherwise specified), anaplastic large cell lymphoma, and mycosis fungoides. Incidence is higher in Asia due to the increased prevalence of EBV driven T/NK lymphomas and increased prevalence of HTLV-1. T-cell lymphomas generally have a poor prognosis. Although there are no randomized trials in T-cell lymphomas, a number of retrospective studies have shown that Auto-HCT performed in CR1 has favorable outcomes compared to transplants in second remission or relapsed state (Dahi et al. 2019; Smith et al. 2013).

Allogeneic transplant is often utilized in the relapsed/refractory setting which often limits the number of patients eligible to undergo the procedure. A retrospective review (Schmitz et al. 2018) reported significant patient heterogeneity in donor type and conditioning intensity; however, overall response was demonstrated in approximately 50% and with a progressive free survival rate of 40% at 5 years. NRM remains a major concern with rates than can exceed 40% at 5 years, felt to be related to multiple lines of previous therapy (Modi et al. 2019).

Aplastic Anemia

Aplastic anemia (AA) is considered an immune mediated disorder, based on its responsiveness to immunosuppressive therapy (IST), and laboratory studies (Kumar et al. 2017). While IST is effective therapy, the response rates are around 60% and are often incomplete, relapses occur in 30%, and clonal evolution to AML or MDS occurs in 10–20%. In contrast to IST, Allo-HCT is considered curative, but with risk of transplant related toxicity. Various conditioning regimens have been used for HCT in AA, the most effective ones being Flu/Cy/ATG or Cy/ATG (Bejanyan et al. 2019). The outcomes are better for young patients, as compared to those older than 30 years.

HLA-Matched Sibling HCT

HLA matched sibling donor (MSD) transplants are recommended as first line treatment for SAA in young patients (up to 50 years age) who have a donor (Killick et al. 2016) with long term survival reaching 80% or more (Bacigalupo et al. 2015). Multiple studies on MSD HCTs have shown that bone marrow (BM) is better than G-CSF mobilized peripheral blood stem cells (PBSC) as a graft source due to increased chronic graft-versus host disease (cGVHD) and lower survival with PBSC (Schrezenmeier et al. 2007; Bacigalupo et al. 2012).

A CIBMTR analysis of 692 patients with severe aplastic anemia (SAA) who underwent MSD transplants showed that 5-year probabilities of OS after PBSC and BM transplantation for patients <20 years were 73% and 85%, and for older patients were 52% and 64%, respectively (Schrezenmeier et al. 2007).

An EBMT analysis of 1886 patients with acquired aplastic anemia who received a first transplant from 1999 to 2009 showed that the outcomes were better in younger patients <20 years than older patients and those who received bone marrow (BM) rather than PBSC, mainly due to a higher GVHD related complications. On univariate analysis, the actuarial survival of patients receiving BM or PBSC was 84% versus 68%, respectively (p < 0.00001). Under the age of 20 years, survival rates with BM vs. PBSC were 90% versus 76%, respectively (p < 0.00001). Over the age of 50, survival with BM was 69% while with PBSC it was 39% (p = 0.01) (Bacigalupo et al. 2012).

The outcomes also vary according to the resources of the country and region. To study these variations, patients who received HCT from MSD from 1995 to 2009 were studied according to the economic regions (Kumar et al. 2016). The study population (n = 2374) was categorized into those from high-income countries (HIC), further divided into USA-Canada (n = 486) and other HIC (n = 1264); upper middle income (UMIC) (n = 482); and combined lower-middle, low-income countries (LM-LIC) (n = 142). There were marked differences in overall survival across different countries (Table 12).
Table 12

Results of 5-year overall survival across countries classified to Gross National Income per capita on Univariate Analysis (Kumar et al. 2016)

Overall survival (5-year)

BM (N = 1927)

Possibility % (95% CI)

PBSC (No. = 447)

Possibility % (95% CI)

P value

USA-Canada

88 (84–91)

56 (45–67)

<0.001

Other HIC

87 (85–89)

77 (70–82)

0.001

UMIC

69 (64–73)

57 (43–72)

0.15

LM-LIC

46 (27–65)

61 (49–73)

0.19

This analysis shows that outcomes of 80% or higher survival may not be reproducible in countries with limited resources due to many factors, such as delay in transplants, complications due to prolonged cytopenias and limited supportive care. In the 1970s, the risk of graft failure with bone marrow transplantation was as high as 35% in the high-income countries (Storb et al. 1983), due to factors such as allo-immunization. In less affluent countries, many of those factors may still be applicable, prompting the use of PBSC as a graft source, even at the cost of higher GVHD. Chandy et al. reported 31% graft failure with BM as a graft source, which led to use of PBSC with survival rates of 82.8% and graft rejection of 2.9% (Chandy et al. 2001; George et al. 2007). In Iran, Ghavamzadeh et al. compared BM (n = 40) and PBSC (n = 145) as graft source in MSD transplants after cyclophosphamide/ATG conditioning and showed that the 5-year OS was similar but disease-free survival was better with PBSC compared to BM (73.5% and 52.3% P = 0.007), although cGVHD was lower with BM (25.7% vs. 52.2%, P = 0.014) (Ghavamzadeh et al. 2016).

This issue remains controversial. The Choosing Wisely campaign advocates that BM is the preferred graft source in aplastic anemia (Bhella et al. 2018) as there is lower risk of GVHD and better OS as shown in large registry-based studies, but PBSC may be acceptable in countries which experience poorer outcomes with BM as the graft source.

Unrelated Donor HCT

Results of unrelated donor HCT have improved remarkably. In children, the results of matched unrelated donor transplants are similar to those of matched sibling transplants (Dufour et al. 2015; Mackarel et al. 2017).

Bacigalupo et al. analyzed 1448 patients transplanted between 2005 and 2009 (Bacigalupo et al. 2015). The OS for 508 unrelated donor transplants was not statistically inferior to 940 MSD HCTs. Unrelated transplant recipients had significantly more acute grade II-IV (25% vs. 13%) and more cGVHD (26% vs. 14%). Use of PBSC grafts remained the strongest negative predictor of survival (p < 0.0001).

Hence, upfront matched unrelated donor bone marrow transplants may be considered as first line therapy for children with SAA who lack a MSD. In adults, results of 10/10 matched unrelated donors are approaching those of MSD HCT in young patients provided BM is used as a graft source.

Haplo-Identical HCT

There have been a number of recent studies on related haplo-identical HCT in SAA in patients who do not have a matched sibling or unrelated donor with very good results (Clay et al. 2014; Esteves et al. 2015; Dezern et al. 2017). DeZern et al. reported on a prospective phase 2 trial of PTCY based regimen for refractory SAA in which 16 patients (median age 30 years, range 11–69) underwent transplant from 13 haploidentical and 3 unrelated donors. The conditioning consisted of rabbit ATG, fludarabine, low-dose cyclophosphamide, and TBI 200 cGy. Graft source was BM. For GVHD prophylaxis, PTCY 50 mg/kg/day i.v. on days +3 and +4 was administered along with tacrolimus and mycophenolate mofetil (MMF). There was no graft failure and mild GVHD was seen in only two patients. This PTCY protocol is simple to adopt and if the results are reproducible, then it may become be the protocol of choice (Dezern et al. 2017). A more complex protocol has been described by centers in China, with overall survival of >80% but higher acute and chronic GVHD (Xu et al. 2017).

Haplo-HCT are attractive due to low cost and early availability of a donor, although issues of donor-specific antibodies are potentially problematic (Dezern and Brodsky 2018). Haplo-HCT with PTCY may have its maximum impact in developing countries, where economic resources are limited.

Conclusions

Allogeneic HCT is the most effective therapy in severe aplastic anemia, if there is a suitable donor and the transplant center has the necessary resources and experience. While a MSD is ideal, alternate donor transplant results are improving. The outcome remains poor in older patients and requires better protocols.

Thalassemia

Allogeneic HCT is the only approved curative modality for the treatment of transfusion-dependent thalassemia at present. Despite encouraging results of gene therapy, its use in thalassemia is currently limited to clinical trials. The greatest deterrent in making a decision to transplant a patient with a benign disease like thalassemia is the risk of transplant-related mortality. The lack of a suitable donor, access to a well-resourced facility with experience in performing transplants in thalassemia and above all, cost of therapy, are some of the other barriers to transplant, especially in developing countries. The heterogeneity of factors in thalassemia patients being taken for transplant makes it difficult to interpret available outcome data and formulate treatment algorithm or predictive models.

Risk Stratification in Thalassemia for HCT

The Pesaro risk stratification was based on transplants in beta-thalassemia major using a myeloablative conditioning regimen. The three risk groups (Pesaro classes I, II, and III) stratification was based on the liver size (>2 cm), presence of liver fibrosis, and inadequate iron chelation (adequate chelation was defined as initiation of chelation by 18 months from date of first transfusion and chelation with deferoxamine administered subcutaneously over 8–10 h/day for at least 5 days a week) (Lucarelli et al. 1990). Subsequently the group from CMC-Vellore was able to show that substratifying the Class III patients further into high and low risk subsets based on age greater than or equal to 7 years and liver size greater than or equal to 5 cm could lend more robust predictions of outcome (Mathews et al. 2007).

Conditioning Regimens

Individuals with thalassemia have an expanded hypercellular marrow (due to ineffective erythropoiesis) and an intact immune system. Therefore, the conditioning regimen for an allogeneic transplant needs to have adequate myeloablation and immunosuppression for sustained engraftment. Standard MAC regimens in thalassemia are mostly based on the use of alkylators (BuCy). Use of radiation is avoided due to the effect on growth and risk of secondary malignancies. The addition of fludarabine in the early 2000s has resulted in a reduced risk of graft rejection and to a certain extent chronic GVHD, without additional transplant-related toxicities (Li et al. 2012). Treosulfan is a more hydrophilic congener of busulfan with more linear pharmacokinetic profile. It has equipotent myeloablation with lesser toxicity, especially with regards to incidence of veno-occlusive disease (VOD). The regimen usually consists of a combination of treosulfan, thiotepa, and fludarabine (FTT) (Mathews et al. 2013). There has been anecdotal experience with the use of reduced-intensity and nonmyeloablative conditioning regimens in thalassemia transplants.

Donor Choice

As a general principle, matched sibling donor (MSD) transplants have been the preferred source of hematopoietic stem cells in thalassemia transplants. This reduces the risk of severe GVHD and increases the thalassemia free survival. However, the chance of having a HLA-identical nonthalassemic sibling is approximately 18.5%, thus making it imperative to look at alternate donors (Mathews et al. 2014). Studies using MUD have shown comparable outcomes to MSD transplants. It is important to stress that while selecting the donor in case of MUD transplants, a high resolution HLA typing of the donor and recipient pairs should be done and matched to select the best available 10/10 donor (Mathews et al. 2014). DPB1 matched or permissive mismatch significantly decreases the chances of graft rejection and hence should be taken into consideration, if possible (Fleischhauer et al. 2006).

Use of cord blood derived stem cells for allogeneic HCT has made substantive progress over the last two decades. Umbilical cord blood obtained at the time of delivery may be banked for future use for a related (sibling) recipient or donated to an umbilical cord blood bank for an unrelated recipient. The size of umbilical cord blood units (e.g., total nucleated cell count or CD34+ cell dose) must be sufficient to allow for reconstitution of the bone marrow (e.g., >3.5 × 107 nucleated cells per kg).

A large recently reported Eurocord and EBMT analysis showed comparative clinical outcomes with bone marrow and a fully HLA-matched related cord (Locatelli et al. 2013). Use of unrelated cord blood transplants in patients with thalassemia has not yielded very promising results (Ruggeri et al. 2011; Jaing et al. 2010). The use of this modality would still be considered investigational due to the risk of graft rejection.

Source of Stem Cells

A 2014 expert panel guideline has recommended bone marrow over peripheral blood stem cells as a graft source (Angelucci et al. 2014). Individuals may use PBSC in the setting of a clinical trial or if the donor refuses to or is unable to donate bone marrow.

GVHD Prophylaxis

The preferred GVHD prophylaxis in the majority of studies of HCT from MSD consisted of cyclosporine and methotrexate. Cyclosporine is usually continued for a longer duration posttransplant with gradual tapering and stoppage by 1 year in the absence of any GVHD. The addition of ATG to this regimen in nonsibling HCTs yielded promising results (Goussetis et al. 2012). Subsequently, its use in HLA-identical sibling HCT recipients and in those transplanted from a HLA-partially matched relative resulted in low rates of severe (grade III/IV) acute GVHD and chronic GVHD and minimal incidence of graft rejection (Goussetis et al. 2012; Sauer et al. 2005). With the increasing applicability of haplo-identical transplants in thalassemia, the use of PTCY in the GVHD prophylaxis regimen continues to evolve with encouraging results (Anurathapan et al. 2016; Yadav et al. 2018).

Overall Long-Term outcomes of HCT in Thalassemia

The outcome of transplant in thalassemia has improved significantly over the years. A recent retrospective analysis from the EBMT included data from 1493 patients with beta thalassemia major transplanted after year 2000 (Baronciani et al. 2016) and reported an overall survival of 88% at 2 years. Factors contributing to better overall survival include: (a) younger age of recipient, (b) matched sibling donor, and (c) better iron chelation and lower liver iron concentration pretransplant. Summary of reports is given in Table 13.
Table 13

Outcomes of matched sibling donor Allo-HCT in thalassemia

Author

No of pts

Pt cohort/Pesaro category

OS

TFS

TRM

Comments

Galambrun et al. (2013)

108

All risk categories

15 y (86.8%)

15 y (69.4%)

15y (12%)

MSD

Regimen: Bu-Cy-ATG

Yesilipek et al. (2012)

245

Children

Low:41

Intermediate: 130

High: 63

1y

85%

1y

68%

1y

7.75%

88 BM, 137 PB, 20 CB

Regimen: Bu-Cy

Bernardo et al. (2012)

60

Children

Low: 27

Intermediate: 17

High: 4

Adults: 12

5y

93%

5y

84%

5y

7%

20 MSD, 40 MUD

Regimen: FTT

Sabloff et al. (2011)

179

Children

Low: 2%

Intermediate: 42%

High: 36%

5y

Intermediate: 91%

High: 64%

5y

Intermediate: 88%

High: 62%

5y

Intermediate: 5/75

High: 23/64

Bu-Cy-ATG: 77

Bu-Cy: 102

Ghavamzadeh et al. (2008)

183

Children

Low and intermediate

2 y

PBSC: 83%

BM: 89%

2 y

PBSC: 76%

BM: 76%

2 y

PBSC: 14%

BM: 9%

87 PB, 96 BM

Regimen: Bu-Cy

Locatelli et al. (2013)

259

Age: 1–24 (median:8)

Low:86

Intermediate: 122

High: 51

6y

95%

6y

86%

4%

Bu-Cy, Flu-Bu-Cy, Bu-Cy-Thiotepa+/− ATG

Di Bartolomeo et al. (2008)

115

All categories

20y

89.2%

20y

85.7%

1y

8.7%

Regimen: Bu-Cy

Mathews et al. (2013)

50

High risk

3y

86.6%

3y

77.8%

13%

Treosulfan based

MSD Matched sibling donor, MUD Matched unrelated donor, BM Bone marrow graft source, PB, Peripheral blood graft source, CB Cord Blood graft source, FTT Fludarabine, Treosulfan, Thiotepa, TFS transfusion free survival

Sickle Cell Disease (SCD)

Sickle cell disease (SCD) is the most common inherited hemoglobinopathy worldwide (Gluckman et al. 2017). Survival in children has improved with supportive measures, but in adults survival is lower. Over time, complications occur and quality of life is impaired. In the USA, the median life expectancy for homozygous SCD is less than 40 years (Galal and Asslan 2019). Allogeneic HCT is the only curative therapy. The results are better in children, before development of end-organ damage. Outcomes are worse in adults, who have more co-morbidities due to SCD. Results of allogeneic HCT in SCD in different age groups, using different regimes and donors, are presented. As SCD is a nonmalignant disorder, only patients with anticipated high risk for morbidity or mortality are offered HCT (Guilcher et al. 2018). (Table 14).
Table 14

Recommendations for indications for HCT in SCD (Guilcher et al. 2018)

Each indication below has been associated with increased mortality; in general, eligible for any type of HCT

Stroke or significant neurological defect lasting >24 h

Two or more episodes of acute chest syndrome (ACS) or vaso-occlusive crisis (VOC) in the 2-year period preceding HCT, despite supportive therapy

Tricuspid regurgitation jet velocity ≥2.7 m/s on echo

Regular red blood cell (RBC) transfusion therapy (≥8 transfusions per year for ≥1 year to prevent vaso-occlusive complications (i.e., ACS, VOC, abnormal transcranial doppler)

Each indication below has been associated with substantial morbidity, thus eligible for low-risk HCT. If 2 or more indications present, then eligible for moderate risk HCT in the context of clinical trials

Impaired neuropsychological function with abnormal cerebral MRI and angiography

Sickle nephropathy

Sickle liver disease

Osteonecrosis of multiple joints

Red-cell alloimmunization during long-term transfusion therapy

HCT in Children with SCD

The maximum experience of HCT in SCD is with children. HLA identical sibling transplants offer the best results. An international survey of 1000 HLA identical sibling transplants for SCD performed from 1986 to 2013 was recently published (Gluckman et al. 2017). All these cases were reported to either the EBMT, Eurocord, or CIBMTR. The median age at transplant was 9 years and median follow-up was more than 5 years. Myeloablative conditioning was used in 87% and reduced-intensity conditioning in 13% cases. The stem cell source was bone marrow in 839 (84%), peripheral blood in 73 (7%), and cord blood in 88 (9%) patients. The 5-year event-free survival and overall survival was 91.4% (95% CI, 89.6–93.3%) and 92.9% (95% CI, 91.1–94.6%), respectively. The event-free survival was lower with increasing age at HCT (hazard ratio (HR) 1.09; p < 0.001) and higher for HCT performed after 2006 (HR, 0.95; p = 0.013). Twenty-three patients experienced graft failure and 70 patients (7%) died. The most common cause of death was infection (Gluckman et al. 2017).

A more recent French study reported on 234 SCD patients less than 30 years age, who received myeloablative conditioning (busulphan+cyclophosphamide+ATG) with MSD HCT and a minimum follow-up of 5 years in surviving patients. Among the 190 patients transplanted after the year 2000, the 5-year EFS was 97.8% (95% CI; 95.6–100%), TRM was <2%. The risk of chronic GVHD was higher in patients older than 15 years (Bernaudin et al. 2019).

These studies suggest that results of HCT in children with myeloablative conditioning and a matched sibling donor are excellent. The low rates of TRM have to be seen in the context of mortality due to SCD itself, which ranges from 1% to 6.1% in different cohorts. Earlier criteria for eligibility for HCT included children who had severe or recurrent complications of SCD, but have now changed to include patients with early changes and before overt neurological or other organ damage. The results of myeloablative conditioning are not as good in adults, due to their higher co-morbidities.

HCT in Adult SCD with Myeloablative Conditioning

In adults with SCD, experience with MSD transplant using myeloablative conditioning is limited, as patients over the age of 16 years are either under-represented or excluded due to potential toxicity (Galal and Asslan 2019). The risk of infertility is also higher in adults, which is one reason that adults often decline the option.

A pilot study of 22 adolescent and young adult patients who were given myeloablative conditioning (busulfan-fludarabine-ATG) and received bone marrow from a matched sibling donor (17 patients) or matched unrelated donor (5 patients) was reported. The 1-year EFS was 86% (95% CI, 63–95%) and 1-year OS was 91% (95% CI, 68–98%). Acute GVHD grades II–III were seen in four patients (18%) and chronic GVHD in six patients (27%) (Krishnamurti et al. 2019).

Unrelated Donor HCT in Children

There is limited experience of matched unrelated donor transplantation in SCD. A Blood and Marrow Transplant Clinical trials network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4–19 years; 29 were eligible for evaluation. Conditioning regimen included alemtuzumab, fludarabine, and melphalan. Transplant indications included stroke (n = 12), or transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12) or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. The 1-year and 2-year EFS rates were 76% and 69%, respectively, and the corresponding OS rates were 86% and 79%, respectively. The day 100 incidence of grade II-IV acute GVHD was 28% and 1-year incidence rate of chronic GVHD was 62% (with 38% classified as extensive). There were seven GVHD-related deaths. Authors concluded that this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis (Shenoy et al. 2016).

Nonmyeloablative Matched Sibling Donor HCT in Adults

To reduce the toxicity of myeloablative conditioning in adults patients with SCD, nonmyeloablative (NMA) regimens have been introduced. The best results have been reported by the use of a protocol developed by the National Institute of Health (NIH). This NIH protocol consists of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (TBI) 3 Gy, sirolimus, and infusion of G-CSF mobilized peripheral blood stem cells from matched sibling donors (Hsieh et al. 2014). From July 2004 to October 2013, 30 patients underwent HCT using this protocol. The disease-free survival was 87%, with only one death in a patient with secondary graft failure (Hsieh et al. 2014). The University of Illinois, Chicago, used the same protocol and reported similar outcomes in 13 high-risk SCD patients. There was only one graft failure in a noncompliant patient, with no mortality and stable mixed chimerism in 12 patients (92%) (Saraf et al. 2016). In both these studies, there was no acute or chronic GVHD. The same regimen has been used with similar results in children and adolescents in Calgary (Guilcher et al. 2019). Using this regimen, mixed donor chimerism is adequate to alleviate the symptoms and phenotype of SCD. The regimen does require long term administration of sirolimus for 1–2 years, with weaning after donor chimerism of 50% or more. There are reports of fertility preservation with this protocol.

Related Haploidentical HCT

As many eligible patients do not have a matched sibling donor, related haplo-identical donor transplants have been reported from a few centers. A phase II trial of a nonmyeloablative haploidentical bone marrow transplant with posttransplant cyclophosphamide has reported encouraging results (De La Fuente et al. 2019). The original Hopkin’s protocol use resulted in two graft failures in their first three patients. The protocol was therefore modified by adding thiotepa. With this modification, there was 93% EFS and 100% overall survival (De La Fuente et al. 2019). Saraf et al. modified the original Hopkin’s protocol by increasing the dose of TBI to 3Gy and used PBSC instead of bone marrow. Of their 8 reported cases, all engrafted initially, but one lost the graft. Seven patients (87.5%) maintained >95% donor chimerism at 1-year posttransplant. One patient who had chronic GVHD died more than 1 year after transplantation of unknown causes (Saraf et al. 2018). These two studies show that in selected cases, haplo-HCT is feasible using two different regimens.

Conclusions

HCT is feasible in selected cases of SCD. Best results are in children, where a MAC can be used. The role of NMA conditioning is being explored. In adults the NMA regimen for MSD is safe, with very low mortality and almost no GVHD. Related haplo-HCT results are also encouraging. MUD transplants results need to be improved. Patients must be willing for the immediate, unpredictable risks of transplants for the long-term benefits and should be compliant with the needs of regular appointments and need to continue medication as per protocol.

Multiple Myeloma

Multiple myeloma (MM) is a clonal disorder of plasma cells with an annual incidence is 4 per 100,000. The median age at diagnosis is between 65 and 70 years. Myeloma cells are usually sensitive to high dose melphalan (Mel). Considering this, high-dose therapy (HDT) followed by autologous HCT, performed either at the time of initial diagnosis or at relapse, is considered the standard of care for younger patients (less than 70 years of age) with newly diagnosed multiple myeloma (MM). Although high-dose therapy with autologous HCT is not curative, event-free survival and overall survival are prolonged compared to treatment with standard-dose myeloma treatments alone (Giralt et al. 2009). With some documented evidence for a graft-versus-myeloma effect, allogeneic HCT has the potential for cure but has high TRM, especially considering that patients with myeloma have multiple organ related complications and are usually elderly.

Initial Induction Prior to Autologous Transplant

In patients who are candidates for Auto-HCT, induction chemotherapy is commenced prior to stem cell collection in order to reduce the tumor load in the bone marrow. Melphalan-containing regimens should be avoided prior to the collection of stem cells, since their use has been associated with damage to the hematopoietic stem cells as well as with an increased risk of myelodysplasia following transplantation (Kumar et al. 2009). Hematopoietic stem cells are usually collected within the first four cycles of initial therapy even in patients in whom a delayed autologous HCT is contemplated.

Stem Cell Dose

The minimum CD34+ stem cell dose considered sufficient for successful engraftment is 2 × 106 CD34+ cells/kg, but the optimal target is usually set at 5 × 106 CD34+ cells/kg (Al Hamed et al. 2019). Collection of upward of 5 × 106 CD34+ cells/kg allows for cryopreservation of stem cells for a second transplant, if that is a potential option. For those who achieve complete or near complete response with the first transplant, the cryopreserved stem cells may be reserved for transplantation at relapse (Hari et al. 2006; Kyle and Rajkumar 2004).

Conditioning Regimen

Based on in vitro studies showing the sensitivity of myeloma cells to high dose melphalan, the current accepted standard conditioning regimen is intravenous high dose melphalan (200 mg/m2).

HCT in patients with renal failure must be approached with caution. For patients with serum creatinine >2.0 mg/dL, the dose of melphalan is reduced to 140 mg/m2. In patients >70 years of age, it is recommended to reduce the dose of melphalan to 140 mg/m2 with data showing comparable outcomes to patients <65 years with myeloma (Kumar et al. 2008). Trials using higher doses of melphalan, addition of busulfan or bortezomib have not translated into increase in OS (Bashir et al. 2019; Bensinger et al. 1996; Roussel 2017). As such, high dose melphalan (200 mg/m2) remains the standard conditioning regimen prior to Auto-HCT. Table 15 shows the outcomes of various studies.
Table 15

Comparison of conditioning regimens used in Auto-HCT in myeloma

Year, study design

n

Conditioning

TRM (%)

OS

Median EFS (months)

Comments

2002 (Moreau et al. 2002), Ph II, RCT

282

(Mel 200) vs. Mel (140 + TBI 8Gy)

45 m:

65.8 vs. 45.5

21 vs. 20.5

Mel 200 noninferior to Mel 140 + TBI 8Gy

2010 (Palumbo et al. 2010), Ph III RCT

298

Mel 200 vs. Mel 100

3.1 vs. 2.9

Median OS:

31.4 vs. 26.2

34.4 vs. 27

Mel 200 longer remission duration

2019 (Bashir et al. 2019), Ph III RCT

205

Mel 200 vs. Bu + Mel140

0 (both groups)

43.5 vs. 64.7

Higher toxicity, greater PFS with Bu Mel 140

2016 (Bensinger et al. 2016), Phase III RCT

131

Mel 200 vs. Mel 280

0 (both groups)

 

(3y):

46% vs. 54%

nCR 22 vs. 39%

Higher toxicity. Better CR rates posttransplant with Mel 280

Timing of Autologous HCT

Stem cells are harvested after 3–4 cycles of initial induction treatment. Subsequently there are 2 options in terms of timing of the transplant: (a) Early transplant: Proceed with transplantation after initial stem cell collection or (b) Delayed transplant: Cryopreserve the stem cells and continue induction therapy with plan to transplant at the time of relapse.

The optimum timing of transplant has been a matter of debate, especially with the addition of newer drug molecules in the basket. There has been evidence to support both strategies (Table 16). In randomized trials, early transplantation results in deeper responses and improved progression-free survival (PFS), but no clear overall survival (OS) benefit.
Table 16

Early vs. delayed/salvage transplant in myeloma with the use of novel agents

Year

Study design

N (early vs. delayed)

Induction

Consolidation

CR (%) (early vs. late)

PFS (%) (early vs. late)

ORR (%) (early vs. late)

OS

2013 (Dunavin et al. 2013)

Retrospective

102 vs. 65

Novel agent based

Early (within 12 m) vs. delayed with Mel 200

50 vs. 28

3y: 32 vs. 28

99 vs. 97

Median: NR vs. 75 m, 3y: 90 vs. 82%

2012 (Kumar et al. 2012)

Retrospective

173 vs. 112

Thalidomide/lenalidomide based

Early (within 12 m) vs. delayed with Mel 200

35 vs. 37

25.4 m vs. 26 m

92 vs. 87

4y: 73% in both groups

Tandem Transplant

Given the survival benefits observed with autologous HCT, trials have studied double (tandem) autologous HCT. However, this approach has not been shown to have a survival benefit, predominantly because of increased TRM. Double transplant may be considered for selected patients with high-risk cytogenetics, although this is based on low levels of evidence (Al Hamed et al. 2019).

Outcomes and Treatment of Relapse after Auto-HCT

The prognosis of patients who relapse after Auto-HCT appears to differ based on the time to relapse after the initial transplant. In general, a second autologous HCT is not recommended for patients who relapse within 12–18 months of the first, since the PFS following the second HCT will most likely be even shorter than seen with the first transplant (Shah et al. 2012). In patients who received lenalidomide maintenance, a second Auto-HCT is not recommended if the relapse occurs within 36 months of the first HCT.

Maintenance Therapy After Transplant

Almost all patients who received autologous HCT for MM eventually relapse. Therefore, trials have investigated the use of consolidation or maintenance therapy following HCT. Maintenance therapy can prolong PFS in MM and may improve OS. For all patients, it is recommended to continue at least 2 years of maintenance rather than observation after transplant. For standard-risk patients, maintenance with lenalidomide and for high-risk patients, maintenance with a proteasome inhibitor based regimen has been found to be most effective.

Allogeneic Transplant in Myeloma

Allo-HCT has been limited predominantly because of higher TRM and when compared to Auto- HCT, there has been no demonstrated benefit in overall survival.

Scleroderma and Autoimmune Diseases

Scleroderma or systemic sclerosis is a multiorgan disease with significant morbidity and mortality with overall survival of approximately 55% at 10 years (Mayes et al. 2003). It has been classically described as due to an autoimmune process with fibrotic deposition; however, the model has been evolving to a process of dysregulated or dysfunctional tissue repair (Denton and Khanna 2017). Clinical manifestations include pulmonary fibrosis, pulmonary hypertension, skin tightening or contractures, scleroderma renal crisis, vasculopathies, and GI dysfunction.

Autologous stem cell transplantation was explored in the early 2000s using either cyclophosphamide or melphalan as the conditioning regimen in patients with severe systemic sclerosis. The procedure was relatively well tolerated with a 9% mortality rate. While there was an initial response based on functional and skin assessment in 8 of 10 patients assessed at 3 months, five subsequently had disease progression (Farge et al. 2002).

Later trials further established its efficacy. In the ASTIS trial, for early diffuse cutaneous systemic sclerosis, there was a long-term benefit from disease progression or death (4-year event free survival of 81% vs. 74%) with auto-HCT, despite a higher mortality risk of approximately 10% in the first-year post transplant (van Laar et al. 2014). The SCOT trial, which involved patients with pulmonary or renal involvement, demonstrated an overall survival benefit compared to monthly cyclophosphamide (86% vs. 51% at 72 months, p = 0.02) (Sullivan et al. 2018).

Crohn’s Disease

Crohn’s disease is another progressive autoimmune condition in which autologous transplant has been explored. Remissions with conventional therapy are in the 40% range with unfortunately only about half of them being sustained (Snowden et al. 2018). In a trial by Lopez-Garcia et al. involving higher risk patients (active disease, nonresponsive, nonoperative), 37 patients underwent a cyclophosphamide based conditioning regimen with autologous rescue. Drug free remission was reported in 61% in the first year posttransplant which decreased to 15% at 5 years posttransplant. However, patients had regained drug responsiveness and 80% regained clinical remission (Lopez-Garcia et al. 2017). Although Auto-HCT could not be a seen as a permanent treatment of the disease, there is potential benefit to be gained in allowing for retreatment with previously used medications.

Multiple Sclerosis

Autologous HCT has been used in the aggressive forms of the disease, including relapsing remitting multiple sclerosis (MS), aggressive MS, treatment-refractory MS, or progressive MS. Early studies were without direct control groups; however, the response rates have been promising compared to other treatments, with up to 70–80% of patients showing no evidence of disease activity in 2 years (Atkins et al. 2016; Nash et al. 2017; Muraro et al. 2017).

A randomized trial comparing standard drug modifying therapy to a nonmyeloablative Auto-HCT suggested a significant benefit to transplant (Burt et al. 2019). At median follow-up of 2 years the time to disease progression was significantly lower in the transplanted group at 5.2% at 3 years, compared to disease modifying treatment (62.5%). The median time of progression could not be calculated as there were too few events in the transplant group. No deaths have been reported in either treatment arm, and the most common transplant reported toxicity was febrile neutropenia. Thus, while autologous transplant demonstrated promise in the more aggressive forms of multiple sclerosis, the duration of response remains an open question.

Transplant in Solid Organ Malignancies

Breast

Autologous treatment had previously gained favor as a treatment option for high risk breast cancer during the 1990s, as studies suggested a 5-year event free survival of up to approximately 30% in patients with metastatic breast cancer who had a complete response to high dose chemotherapy (Laport et al. 1998; Tallman et al. 2003). However, subsequent negative studies were published and questions were raised with regards to selection bias (Stadtmauer et al. 2000). From the 2000s onwards, the number of autologous transplants done for this indication has fallen drastically (Appelbaum 2007). A recent systematic review (Farquhar et al. 2016) revealed little to no benefit, and increased risk of mortality. However, there is some evidence suggesting that selected high-risk populations (e.g., BRCA+ metastatic disease) may still benefit from this modality (Boudin et al. 2016).

Male Germ Cell Tumors

Outcomes in male germ cell tumors have been steadily improving over time with 3-year overall survivals reaching 54% in the last decade (Kilari et al. 2019). This is felt to be related to increased adoption of tandem transplants as well as performing transplant earlier in the course of the disease. Relapse rates have decreased from 68% at 3 years in the early 1990s to 42% in the last decade. The 100-day nonrelapse mortality has remained less than 10%. Remaining areas of controversy relate to the optimal timing of transplantation and the number of cycles of high dose chemotherapy.

Conclusion

The outcomes of BMT vary according to the underlying disease, type of transplant, and the fitness of the patient. The best outcomes of transplantation are achieved with full cooperation and participation of the patients (and appropriate caregivers), as the course of transplant and recovery is often prolonged, requiring compliance with appointments, medications and seeking early medical attention in case of any deterioration. The resources available to support the therapy also influence the outcomes.

As expected, results are better in high-income countries with better health care services. As BMT is expensive and resource intensive, majority of HCTs are performed in high-income countries and consequently literature reflects the outcomes from institutions located in the more affluent nations. The results of transplantation may be different in other countries, due to limitations in supportive care such as blood component availability, infection control and salvage therapy for relapse, GVHD, or graft failure. It is important that all centers performing transplants should share their experience and results with national and international registries and contribute to the global effort to improve BMT outcomes.

Cross-References

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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Medical Oncology and HematologyPrincess Margaret Cancer CentreTorontoCanada
  2. 2.Faculty of Medicine, University of TorontoTorontoCanada

Section editors and affiliations

  • Vivek Radhakrishnan
    • 1
  1. 1.Tata Medical CenterKolkataIndia

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