Bone marrow (hematopoietic cell) transplantation in patients with non-malignant diseases and myelodysplastic syndromes

What every physician needs to know about bone marrow transplantation for non-malignant disease:

Indications for bone marrow (hematopoietic cell) transplantation in patients with non-malignant diseases and myelodysplastic syndromes

Hematopoietic cell transplantation (HCT) is a procedure by which a patient’s missing or diseased blood forming stem cells are replaced by cells from a healthy donor. The conditions considered here include:

Hematological Disorders

  • Aplastic anemia

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  • Paroxysmal nocturnal hemoglobinuria (PNH)

  • Pure red cell aplasia

Autoimmune Disorders

  • Multiple sclerosis

  • Systemic sclerosis

  • Systemic lupus erythematosus

  • Rheumatoid arthritis

  • Juvenile idiopathic arthritis

  • Crohn’s disease

  • Diabetes mellitus

HCT may serve as a rescue procedure in patients with malignant disorders treated with high-dose cytotoxic regimens or as replacement therapy in patients with missing, aberrant, or defective lymphohematopoietic cells, including marrow failure and autoimmune disorders. In both situations, however, HCT also has immunotherapeutic effects, which may provide important signals to eradicate the patient’s disease. In addition, HCT can serve as a vehicle for gene therapy and as a strategy to establish tolerance for solid organ transplantation. Finally, HCT is used in conjunction with cellular immunotherapy, such as CAR-T cells.

Rationale for transplant conditioning

In preparation for HCT, patients generally receive cytotoxic or immunosuppressive treatment, “conditioning”, with the following objectives.

  • To eradicate defective cells;

  • To suppress the patient’s immune system to allow for donor cell engraftment and prevent rejection

This applies to allogeneic but not to autologous cells (which basically constitute an “auto”plantation, rather than “trans”plantation) or to syngeneic cells, which should not encounter a histocompatibility barrier. However, immunosuppression is needed in preparation for syngeneic transplants in many patients with aplastic anemia, apparently to eliminate autoimmune reactivity, which may interfere with sustained hematopoietic reconstitution;

  • To progressively replace patient cells

In patients who are prepared for HCT with low/reduced-intensity conditioning (RIC) the damage inflicted upon the patient’s cells appears to provide sufficient advantage to donor cells to progressively replace patient cells.

Modalities of conditioning

Therapeutic modalities to prepare patients for HCT include:

  • Irradiation

Irradiation provides effective cytotoxicity and immunosuppression. However, there is a strong trend to avoid or reduce the radiation doses in patients who are transplanted for non-malignant disorders (to avoid potential long-term/delayed effects). In patients with aplastic anemia total body irradiation (TBI) doses as low as 200 cGy (2 Gy) and as high as 1,200 cGy (12 Gy) have been used, generally combined with chemotherapy.

  • Chemotherapy

Chemotherapy, particularly cyclophosphamide (Cy) and fludarabine (Flu), is included in many regimens. In patients with aplastic anemia, Cy has been used successfully as single agent for conditioning. Others have combined Cy or Flu with busulfan (Bu) ± antithymocyte globulin (ATG). Bu, when given orally, may show considerable variations in plasma levels, which may result in significant differences in toxicities and clinical responses. These variations can be minimized by monitoring of steady state plasma levels of Bu (BUss), and dose adjustments to target BUss plasma levels. More consistent levels are achieved with intravenous (IV) Bu, often given as a single daily dose, rather than every 6 hours as is standard with oral Bu. Cy has also been combined with Flu, ATG and low dose TBI in patients with aplastic anemia. Another recent addition is treosulfan given in combination with Flu, or melphalan combined with Flu.

  • Biologics

Biological reagents, such as ATG, a preparation of polyclonal horse or rabbit anti-human antibodies, or monoclonal antibodies directed at T-cell antigens or adhesion molecules, are employed primarily to suppress recipient immunity. Specific monoclonal antibodies targeting cancer cells, such as radiolabeled anti-CD45 or anti-CD20, are also used widely. Similarly, monoclonal antibodies (for example, anti-CD33) conjugated to chemotherapeutic agents have been tested in transplant conditioning regimens.

Source of stem cells

Several questions must be addressed when deciding upon the source of hematopoietic stem cells. First, is the patient and the patient’s disease a candidate for autologous or allogeneic HCT? Second, for allogeneic HCT, is the donor related or unrelated? Third, if an HLA (human leukocyte antigen) matched donor is not available, will cord blood cells or an HLA-haploidentical donor be the preferred stem cell source? Fourth, will stem cells be aspirated from the marrow or will G-CSF (granulocyte colony-stimulating factor) or plerixafor-stimulated PBPC (peripheral blood progenitor cells, dislodged from the marrow) be collected?

The development of graft-versus-host disease (GVHD) is an expression of the fact that transplantation of hematopoietic stem cells results not only in reconstitution of hematopoiesis, but also in the establishment of a new immune system derived from those donor stem cells, which can react against antigens that are present in the recipient (but not in the donor). A by-product of GVHD, primarily in its chronic form, is an enhanced graft versus tumor effect, which is desirable in patients transplanted for malignant disorders, but is of no known benefit in patients who undergo HCT for non-malignant diseases.

Allogeneic donor selection

Donors are selected firstly on the basis of matching for HLA-A, B, C (class I) and HLA-DR, -DQ (and -DP) (class II), with HLA matched siblings generally being the first choice. Based on inheritance patterns, theoretically 25% of persons will have genotypically HLA matched siblings. Phenotypically matched related donors are identified for about 1% of patients (for example, when parents share one HLA haplotype), and somewhat less than 1% of patients will have an identical (syngeneic) twin donor.

The typical second choice is an unrelated donor, HLA matched at high resolution (DNA level) typing for at least eight, ideally ten, and most recently even 12 HLA antigens. Due to the efforts of the Anthony Nolan Appeal in the UK, the National Marrow Donor Program in the United States of America (USA), the Deutsche Knochenmarkspenderdatei (DKMS, in Germany) and other organizations, more than 25 million volunteer donors have been HLA typed and entered in registries (easily accessed through the World Book) as potential stem cell donors. Confirming the eligibility and coordinating the timing of an unrelated donor transplant will take a few weeks (occasionally months), a delay that has gotten shorter over the years but that may be unacceptable for some patients with severe or aggressive disease. The probability of finding a fully HLA matched unrelated donor is currently 60-70% for North American Caucasian patients; the probabilities are lower for patients of different ethnic backgrounds.

Alternative donor options include cord blood (HLA mismatched in more than 95% of cases), generally obtained from cord blood banks, and HLA-haploidentical donors. Cord blood, due to its unique immunologic qualities, has less stringent matching requirements than unrelated donors, and an acceptably mismatched cord blood unit is therefore more easily attainable. HLA-haploidentical donors (related donors who share only one haplotype [the maternal or paternal chromosome 6] with the patient) are appealing, because nearly all patients will have a donor who is immediately available (at low search cost). However, the high degree of HLA mismatching inherent to haploidentical HCT creates significant immunologic challenges. In particular, graft rejection, GVHD, and poor immune reconstitution have been of concern. However, recent results are very encouraging, showing very few rejections and an unexpectedly low incidence, especially of chronic GVHD, apparently related to the post-transplant administration (days 3–4) of high-dose Cy, which does not affect stem cells but inactivates alloreactive donor T cells. Experience in patients with non-malignant disorders, including aplastic anemia, is limited. Some transplant centers favor the use of HLA haploidentical related donors over unrelated donors for certain diseases.

Once a donor (other than cord blood) is identified, a final consideration is whether to use stem cells collected from marrow or peripheral blood. While marrow from the donor is aspirated under anesthesia (general or spinal), PBPC are harvested via a leukapheresis procedure using peripheral venous access. Cord blood is, of course, drained from the umbilical cord and placenta immediately after delivery. While not without controversy, for patients with aplastic anemia, marrow is favored as the source of stem cells because of the lower probability of (chronic) GVHD.

Autologous versus allogeneic HCT

Patients often ask “Why can’t we use my own stem cells?” As discussed above, autologous HCT is generally not an option for patients with non-malignant disorders other than autoimmune diseases, either because stem cells are lacking or they are defective. Some studies have been carried out with genetically modified autologous stem cells in patients with congenital disorders, such as Fanconi anemia, and further studies are underway.

The source of hematopoietic stem cells

For the purpose of marrow harvest, the donor (or, in the autologous setting, the patient) receives anesthesia, and under sterile conditions, multiple small volume aspirates (approximately 3–5 ml) of marrow are obtained from both posterior iliac crests. About 10–15 ml/kg donor weight is collected, usually yielding 1 to 4 × 108 cells/kg recipient weight. The concentration of stem cells tends to be higher in children than in adults. The harvested cells are passed through filters, using one of several available systems, and placed in a plastic bag. If there is no ABO incompatibility and no in vitro manipulation is planned, the cell suspension is infused IV, generally via an indwelling intravenous catheter.


Hematopoietic stem cells circulate at low concentrations in blood. The numbers are increased during recovery from chemotherapy or by intentional mobilization with G-CSF or plerixafor, which interferes with CXCR4 (C-X-C chemokine receptor type 4)/CXCL12 (chemokine [C-X-C motif] ligand 12) interactions. This allows for “harvesting” of stem cells from peripheral veins by leukapheresis.

The best current marker of cells required for a successful HCT (stem cells are long-term repopulating cells) is the surface glycoprotein, CD34. For autologous procedures, the goal is to harvest at least 3 to 5 × 106 CD34+ cells/kg recipient weight. Higher cell numbers are targeted if the cells are to be processed in vitro or if cells for a “back-up” infusion or second transplant are desired. The yield of CD34+ cells per apheresis (usually 10-16 liters over 2-4 hours) for autologous transplants varies widely, largely dependent upon prior therapy given to the patients.

The most reliable indicator of the success of cell mobilization for apheresis is the concentration of CD34+ cells in the blood. In many patients, one single leukapheresis (carried out over 4-5 hours) will suffice; in others (particularly heavily pre-treated individuals undergoing autologous HCT), several sessions are required. Autologous cells typically are cryopreserved until later use.

In healthy (allogeneic) donors, rather consistently 2 to 20 × 106 CD34+ cells/kg are obtained with a single harvest (with increasing donor age, the likelihood of requiring more than one leukapheresis increases). As the harvest can be timed such that it coincides with completion of the conditioning regimen in the patient, allogeneic PBPCs are usually transplanted fresh. Cryopreservation is possible, however, and has been used, for example, to accommodate donor scheduling preferences for the procedure.

HLA haploidentical transplants were initially carried out exclusively with marrow, because of concern about severe GVHD. However, recent studies show that PBPCs can be used as well, possibly without an increase in GVHD incidence or severity.

Cord blood

Cord blood has emerged as an important source of hematopoietic stem cells. The fact that cord blood units are cryopreserved and stored offers a major advantage, since they are almost instantaneously available. The low numbers of available cells may lead to delayed engraftment, particularly in (large) adults. There is also a high rate of Cytomegalovirus (CMV) reactivation as cord blood cells typically will not convey anti-CMV-immunity. However, the use of two cord blood units (double cord) or the use of one unit that has been “expanded” in vitro combined with an unmodified unit can substantially shorten the interval until count recovery, thereby reducing the risk of bleeding or infections associated with prolonged pancytopenia.

There are numerous public cord blood banks in the U.S. and worldwide, with different levels of accreditation, with an inventory of greater than 600,000 units. A significant private cord blood banking industry has also developed. For a collection and storage fee, parents may bank their child’s cord blood for future personal use. However, given current indications for cord blood transplantation, uses of privately banked cord blood are extremely limited. Additionally, private cord blood banks are not currently regulated, and the quality of units collected is not guaranteed. Though the future use of privately banked cord blood, particularly for regenerative medicine, cannot be predicted, expert opinion does not currently encourage private cord blood banking.

Modification of hematopoietic stem cells for gene therapy

Initial attempts at treating primary immune deficiencies with gene-corrected hematopoietic stem cells failed to yield long-term engraftment in patients who were not conditioned. Conditioning of patients before infusion of the gene-corrected cells allowed multilineage reconstitution of the immunohematopoietic system with corrected cells to result in clinical benefit. Setbacks have been related to insertional mutagenesis, leading to clonal expansion of transplanted cells and the development of clonal T cell disorders or myelodysplasia. Recent research has improved safety by developing vectors with a reduced risk of insertional mutagenesis. Several limited trials have reported correction of adenosine deaminase (ADA) deficient SCID (severe combined immunodeficiency) without evidence of clonal proliferation. Trials are ongoing for various congenital disorders.

Bone marrow versus PBPC

Marrow harvesting requires anesthesia of the donor; this is not required for leukapheresis. Unless T cell depleted, PBPCs contain significantly greater numbers of T cells than marrow, and result in a higher incidence of chronic GVHD. Given the ease of collecting PBPC relative to marrow, PBPCs are currently the preferred source of stem cells used for HCT. One advantage of PBPCs is more rapid hematologic recovery. However, because of the higher incidence of chronic GVHD, they should not be used routinely in HCT for aplastic anemia and other non-malignant diseases. On the other hand, the prophylactic use of ATG, while not without controversy, or administration of Cy after donor stem cell infusion have substantially reduced the incidence of chronic GVHD, even with the use of PBPCs.

Regardless of what cells are transplanted, the current transplant approach is with IV infusion, typically through an indwelling catheter (double lumen Hickman line or equivalent device) placed in the subclavian vein. Via the circulation the infused cells will be delivered to their appropriate niches in the marrow cavity.

Historically, because of major ABO mismatches between donor and patient, and the patient having high isoagglutinin titers directed at the donor’s ABO blood group, plasmapheresis was carried out to reduce the titer and prevent severe hemolysis. Vice versa, plasma was removed from the donor marrow to eliminate isoagglutinins directed at recipient cells. With the use of PBPCs or cord blood the volume of donor plasma that is infused is low, and no such manipulations are necessary. In cases where marrow is used and hemolysis remains a concern red blood cells are removed.

The severity of marrow failure that characterizes aplastic anemia, with anemia, thrombocytopenia, and neutropenia, and the need for frequent red blood cell transfusions or the attendant risk of hemorrhage or infection, generally determines the patient management.

If such a patient has an HLA-identical sibling who could serve as a hematopoietic stem cell donor, HCT is typically offered as first-line therapy, certainly in patients up to 50 (or even 60) years of age. As many as 80-90% of these patients are transplanted successfully using Cy plus ATG or Flu-based conditioning regimens. The rejection rate is less than 5%. Incorporation of TBI (total body irradiation) in the conditioning regimen probably does not offer an advantage in the setting of HLA-identical sibling transplants. The transplant success rate is highest in the youngest patients and declines with age.

Older patients, and those who do not have HLA identical siblings, generally will receive first-line therapy with IST (immunosuppressive therapy) using ATG, preferentially with horse ATG, typically combined with the calcineurin inhibitor cyclosporin (CSP), and will come to HCT only if they do not respond to IST, or have recurrent marrow failure after an initial response. Recent results indicate that with regimens that combine Cy and Flu with ATG and low dose TBI (200 cGy), survival rates of 80-90% are achieved even with (HLA-matched) unrelated donors in patients up to 65 years of age, but with the best outcome observed in younger patients. On that basis it has been proposed to offer HCT from HLA-matched unrelated donors to young patients with aplastic anemia.

Pure red cell aplasia can be associated with various disorders, for example, with parvovirus B19 infection, chronic lymphocytic leukemia, other malignancies, and immune disorders. It usually responds to steroids and IST. Some patients with red cell aplasia of undetermined etiology who do not respond to steroids or other non-transplant strategies aimed at the underlying disorder have been referred for HCT. These patients are transplanted with conditioning regimens as used for aplastic anemia, using, for example, a combination of Cy, 4 × 50 mg/kg, with ATG. No large series has been reported.

Registry data suggest that problems with sustained engraftment may be more common than with other marrow failure states, and TBI may be required to achieve sustained donor cell engraftment. It is important to recall that pure red cell aplasia may also develop after HCT for other indications, particularly with the use of ABO-incompatible donors and after low-intensity conditioning regimens. Therapy in that situation may again involve IST.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of hematopoiesis resulting from the expansion of a clone that arises by somatic mutations in the X-linked PIG-A gene in pluripotent hematopoietic stem cells. This gene encodes a protein that affects the synthesis of glycosylphosphatidyl-inositol (GPI), an anchor for numerous cell surface antigens, for example, CD55 and CD59. Patients with PNH classically present with hemolytic anemia, venous thrombosis, and defective hematopoiesis, associated either with marrow aplasia or with a cellular marrow. The definitive classic test is a flow cytometric analysis of peripheral blood cells, to show the absence of GPI anchored surface proteins. Greater sensitivity is offered by the FLAER (fluorescein-labeled proaerolysin) test. Some patients show evolution into myelodysplastic syndromes (MDS) or acute leukemia. PNH clones may also be found in patients who present with the classic features of aplastic anemia or MDS.

For patients with prominent hemolysis, the current treatment of choice is with the monoclonal antibody eculizumab (directed at complement component C5). However, for patients who are unresponsive or patients who present with marrow failure, allogeneic HCT is effective therapy. HCT corrects hematopoiesis and resolves thrombotic complications. HCT from syngeneic donors without preceding conditioning of the patient has failed to correct the underlying disease, supporting the concept that the PNH clone has a survival and proliferative advantage. In at least one syngeneic transplant recipient with PNH “recurrence”, molecular analysis revealed that a new PNH clone had arisen.

Patients with PNH are generally prepared for HCT with regimens similar to those used for aplastic anemia (for example, Cy plus ATG), although in patients with hypercellular marrows in whom hemolysis may be the most prominent finding, a more intensive regimen, including for example, Bu, to “ablate” the marrow may offer an advantage. For HCT from HLA-identical siblings, survival rates of 60-70% have been reported, with outcomes being superior in patients with marrow failure compared to those with hemolytic/thrombotic complications. Success rates in patients transplanted from unrelated donors have been inferior, but with the use of RIC regimens, such as Flu + 200cGy of TBI, more encouraging results with survival in the range of 70% have been reported.

Disease characteristics, pathophysiology, non-HCT therapy, and prognosis are discussed in the disease-specific chapters. These diseases involve a reaction of the person’s own immune system against one or multiple organs. Proof that HCT may offer effective treatment for severe autoimmune disorders came from observations in patients who received HCT for other indications, for example, leukemia, and were found to be cured of concurrent autoimmune disorders such as rheumatoid arthritis. However, since various IST or cytotoxic therapies are available, patients with autoimmune diseases have generally come to HCT only with rather advanced and refractory disease late in their course.

The observation of flares of autoimmune disorders after autologous HCT for various malignancies, led to trials specifically aimed at autoimmune diseases. One strategy involved the depletion of T cells from the autologous transplant inoculum. Alternatively, non-cytotoxic immunosuppressive agents were added to the conditioning regimen for in vivo T-cell depletion. Conditioning regimens have been of varying intensities. High-dose Cy provides low-intensity conditioning not requiring stem cell support (Cy does not affect stem cells). High-dose regimens requiring stem cell support include TBI or high-dose Bu.

Systemic depletion of autoreactive T cells resulted in high initial response rates, and a significant proportion of patients achieved sustained remissions, 70-80% after high-intensity, and 30% with low-intensity regimens.

In patients with rheumatoid arthritis, remissions were longer with higher doses of Cy (200 mg versus 100 mg/kg). However, all patients eventually relapsed. Experience was similar in systemic sclerosis (SSc). The addition of ATG to Cy may improve response rates and duration. Since Cy, as indicated, does not ablate marrow function, its use without autologous HCT has also been investigated. This approach proved feasible, but in one study only 36% of the patients had durable complete remissions. Treatment-related mortality ranged from 3-14%.

Patients with multiple sclerosis (MS) and rheumatoid arthritis had lower treatment-related mortality than patients with SSc and systemic lupus erythematosus (SLE) who suffered from significant internal organ dysfunction related to their disease. More careful patient selection (without severe organ dysfunction) and modifications to the treatment regimen, have reduced treatment-related mortality. In a recent randomized trial in patients with SSc (high-dose immunosuppression, followed by autologous HCT or pulse Cy), only one patient died from treatment-related complications.

Multiple sclerosis

Most multiple sclerosis (MS) patients (85%) present with relapsing-remitting disease, and about 50% will evolve to the secondary progressive type of MS over 10 years. Some 15% of patients have primary progressive disease.

All reported trials included patients with advanced and progressive MS. All patients received high-dose combination chemotherapy or TBI plus Cy. Most patients were transplanted with PBPC, often involving T-cell depletion by way of CD34-selection. Treatment-related mortality was less than 3%, and progression-free survival/neurological stability ranged from 36-95% at 2-3 years. A proportion of patients showed a marked reduction of gadolinium-enhancing lesions in the brain, sustained up to 5 years.

However, a substantial loss of brain volume over 2 years has been noted. The brains of patients with progressive MS who had died after HCT, showed ongoing active demyelination and acute axonal damage in MS lesions, without lymphocytic infiltration. Studies in a murine model indicate that inflammation after HCT may be sustained by endogenous microglia/macrophages and suggest that HCT earlier in the course should be more effective.

Reports on 80 patients since 2008 show no treatment-related mortality. Two more recent clinical trials observed 100% progression-free survival among patients transplanted earlier in their course. Disease activity-free survival was 62% in one study.

A National Institutes of Health (NIH)-sponsored High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT MS) clinical trial for relapsing-remitting MS has had very slow accrual, and results are not expected until 2017. Randomized clinical trials have been difficult to conduct because of poor accrual. Updates on two prospective studies are expected to be published in the near future.

Systemic sclerosis

Systemic sclerosis (SSc) is an uncommon disabling autoimmune disease that is characterized by small vessel vasculopathy and fibrosis. Diffuse cutaneous SSc has a higher mortality rate than limited cutaneous SSc, related to interstitial lung disease, hypertensive renal crisis, diffuse gastrointestinal disease, and myocardial involvement. The modified Rodnan skin score (MRSS) and the modified SHAQ (Health Assessment Questionnaire Disability Index for SSc) are two validated tools for evaluating the degree of scleroderma and measuring the effect of disease on overall function.

A few clinical trials of autologous HCT for SSc have been conducted. High-dose Cy or melphalan, followed by autologous HCT, resulted in some responses, but most patients quickly relapsed or did not achieve responses. In one study, survival was 96% and event-free survival was 64% at 5 years. However, about half of those patients did not have internal organ involvement. In a trial using TBI and Cy in patients with diffuse cutaneous disease and internal organ involvement, 63% of evaluable patients (n = 27) who survived at least 1 year had sustained responses at a median follow-up of 4 years.

There was a major improvement in the degree of scleroderma as measured by MRSS and in overall function. There was increased capillary density in the skin, and cytokine levels were normal. Treatment-related mortality was 23%, and progression-free survival was 64% at 5 years. Other studies observed disease progression at 5 years in 48% of patients, and 5-year survival of 72%. Randomized clinical trials are currently ongoing. Please see the scleroderma reference below.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterized by the presence of anti-nuclear antibodies and immune complexes. Disease severity may vary from mild to life-threatening, and numerous organ systems may be involved. Standard treatment options are not curative and complete sustained remissions are rare. Antimalarials, such as hydroxychloroquine, and immunosuppressants such as Cy, azathioprine, rituximab, and mycophenolate mofetil (MMF) can control disease activity.

The SLE Disease Activity Index (SLEDAI) is a validated tool for following disease activity. Clinical trials of HCT have been conducted in patients who were refractory to standard therapies. Conditioning with Cy (200 mg/kg) and ATG followed by T cell-depleted CD34-selected autologous cells, showed significant improvement in the SLEDAI score, and clinical and laboratory parameters. Overall survival at 5 years was 84%, and 50% of patients were “disease-free”. In comparison, a study of 14 patients given high-dose Cy (200 mg/kg) without HCT, yielded durable responses in only five patients (36%), although the relapse rates were comparable. Thus, while experience is limited, available data indicate that high-dose immunosuppression can induce responses in many patients with SLE refractory to standard therapy.

Rheumatoid arthritis

The pathological hallmark of rheumatoid arthritis is synovial inflammation with proliferation of macrophages and fibroblasts, which may destroy cartilage and bone. Other complications are vasculitis, pulmonary, and cardiac disease. Prognosis depends upon the extent of the disease and the intensity of inflammation. Mortality increases with extra-articular manifestations to as high as 30% at 5 years. Many agents such as methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, infliximab, adalimumab, etanercept, abatacept, anakinra, and rituximab have shown efficacy. None of these treatments are curative. The criteria for determining response to treatment have been defined by the American College of Rheumatology.

High-dose Cy with or without ATG has led to major early responses, but all patients eventually relapsed. No mortality was observed. Registry data on autologous HCT were comparable to the experience reported from clinical trials, with major responses in 67% of patients, but most patients required additional treatment by 6 months.

Juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of chronic inflammatory diseases involving the joints and extra-articular tissues, beginning before age 16 years. A macrophage and T cell activation syndrome develops in 5-8% of patients, and may be life-threatening (mortality less than 1%). One clinical trial of autologous HCT used TBI (400cGy) plus Cy plus ATG to treat 22 patients with treatment-refractory JIA. With a median follow-up of more than 6 years, overall and disease-free survival rates were 82% and 36%, respectively. There was significant sustained improvement in disease activity. Similar data have been presented by others. Thus, in JIA patients who fail to respond to standard treatment, autologous HCT may be of benefit.

Crohn’s disease

Data are limited, but at least two reports showed sustained remissions for 1-3 years in patients refractory to conventional therapy. Longer follow-up is required to assess response durability.

Diabetes mellitus

The data are very preliminary, but one study showed independence from insulin therapy for 2-3 years in patients with recent onset diabetes mellitus after high-dose Cy and HCT. C-peptide levels were significantly increased after transplant compared to baseline. Further follow-up is required.

Allogeneic HCT for other diseases in patients with concurrent autoimmune disorders

As indicated above, initial evidence that allogeneic HCT may be beneficial came from patients transplanted for other diseases, for example, aplastic anemia or leukemia. However, relapses were observed. In at least one instance, the HLA-identical donor was serologically positive for rheumatoid factor. One patient who relapsed with Crohn’s disease showed mixed hematopoietic chimerism at 3 months after HCT. Overall the data suggest, however, that responses were durable. There is some evidence for an association of the development of GVHD and recurrence of the autoimmune disease. The risk for relapse of the autoimmune disease was lower after allogeneic, than after autologous HCT.

Autoimmune disease as primary indication for allogeneic HCT

The major risks associated with allogeneic HCT are morbidity and mortality related to GVHD, and delayed immune reconstitution, providing the basis for the reluctance to consider allogeneic HCT for autoimmune diseases. However, there may be a greater potential for sustained remissions than after autologous HCT, and, as a result, improved overall outcome. So far no clinical trials of allogeneic HCT for autoimmune diseases as the primary indication have been reported. A prospective trial for Crohn’s disease is currently ongoing.

The answer to this question will depend upon the clinical presentation and the differential diagnosis that is being considered.

Marrow failure conditions are typically diagnosed on the basis of a complete blood cell count, including reticulocytes. It is often helpful to also test for hemolysis and check lactate dehydrogenase (LDH) and haptoglobin levels. Immunophenotypic analysis by flow cytometry is an essential test to establish the diagnosis of PNH, by showing the absence of PIG-anchored surface markers. Small PNH clones may also be present in patients with aplastic anemia or MDS.

In most patients with marrow failure it will be necessary to obtain a marrow aspirate and, at least for the initial assessment, a marrow biopsy. The marrow should be subjected to morphologic interpretation, multiparameter flow cytometry, and cytogenetic testing, for example, for the differential diagnosis between aplastic anemia (almost always normal) and MDS (clonal abnormality identifiable in 40-50% of patients by classic banding techniques, in 70% of patients or more by molecular techniques). Treatment of cells with diepoxybutan can identify patients with underlying Fanconi anemia (although the diagnosis can now also be established by molecular studies and DNA sequencing). It is important to rule out Fanconi anemia as an underlying diagnosis, because standard conditioning regimens used for aplastic anemia cause excessive toxicity.

The diseases discussed here are acquired (rather than inherited), although it is possible that certain genetic characteristics (DNA polymorphisms) could predispose a person to the development of hematopoietic failure. There is some evidence, for example, that the HLA-DR15 genotype is more frequent in patients with MDS than in other patient populations. Details are discussed in the respective disease chapters.

The diagnoses are generally established with the tests described above, the focus being on a detailed analysis of peripheral blood and bone marrow aspirates. For autoimmune disorders, incorporation of panels for auto-antibodies is mandatory, as are the tests for organ dysfunction (pulmonary function tests, creatinine clearance, cardiac ejection fraction). Invasive tests may become necessary to diagnose or confirm complications that may develop after HCT, in particular infections, organ toxicity, and GVHD (see below).

Imaging studies are of limited use in diagnosing marrow failure disorders, although magnetic resonance imaging (MRI) of the marrow-carrying skeleton may be informative in the differential diagnosis of aplastic anemia and MDS (empty space versus patchy appearance). In patients with autoimmune disorders, MRI of the brain (for MS and SLE) and of the lungs (SLE, SSc, rheumatoid arthritis) is frequently informative.

HCT is, of course, therapy by itself. The entire HCT procedure, including the conditioning regimen, the collection of stem cells from the donor (be it marrow or PBPC), the type of GVHD prophylaxis, airway protection, and additional measures, follows detailed protocols, developed either empirically or based on pre-clinical animal models (see discussion of complications below under “What should you tell the patient and family about prognosis?”).

Discussed under the individual diseases under “What features of the presentation will guide toward possible causes and next treatment steps?”

HCT carries the risk of various complications. The three most important problem complexes after HCT are toxicity related to transplant conditioning, GVHD with the associated increased risk of infection, and recurrence of the underlying disease.

GVHD is the most frequent complication of allogeneic HCT. The main target organs of GVHD are the immune system, skin, liver, and intestinal tract, although other organs can be involved. The diagnosis is made clinically, assisted by skin biopsy, upper and lower gastrointestinal (GI) endoscopy and biopsies (occasionally liver biopsies).

Methods of GVHD prevention include T cell depletion in vitro (by anti-T cell antibodies, and other methods) or in vivo (by various immunosuppressive agents, such as methotrexate, CSP, tacrolimus, MMF, sirolimus, polyclonal [ATG] or monoclonal antibodies [such as anti-CD3 or anti-CD52 antibodies]). With a combination of CSP (given daily) and methotrexate (MTX) (given on days 1, 3, 6, and 11) as prophylaxis, acute GVHD occurs in 10-50% of patients after HLA-identical transplants, and in 50-75% of patients transplanted from HLA-matched unrelated donors. The corresponding figures for chronic GVHD are 20% to 50% and 30% to 60%, respectively.

Other combinations have yielded similar results. There is evidence that the addition of sirolimus to a combination of tacrolimus (or CSP) and MMF, or the incorporation of ATG into the conditioning regimen will further reduce the incidence of GVHD, particularly in its chronic form. Recent studies on the elimination of naÏve T cells (CD45RA+) suggest that the incidence of chronic GVHD can be reduced to 10%. Very encouraging results have also been observed with post-HCT administration of Cy.

In patients prepared with conventional high-dose conditioning regimens, acute GVHD usually presents within a month of HCT. With HLA-non-identical transplants, the presentation may be “hyperacute” within days of HCT. In patients prepared with RIC regimens, clinical manifestations of typical acute GVHD may develop even 4-5 months after HCT. Conversely, clinical and histologic features of chronic GVHD may be present as early as 50-60 days after HCT. A new (NIH consensus) classification of GVHD, also acknowledging an acute/chronic overlap form (with an inferior prognosis) has recently been presented.

GVHD is the most important risk factor for long-term morbidity and mortality after HCT. Therefore, if GVHD develops, it requires aggressive therapy for both the acute and chronic form. Current first-line therapies for acute GVHD are glucocorticoids, CSP, monoclonal antibodies, ATG, and immunotoxins. Cytokine blockade, for example with α1 anti-trypsin, may add benefit. More than half of all patients treated with steroids will require additional therapy. Patients with grade II acute GVHD have a high probability of responding. The response rates are lower in the 15-20% of patients who develop grades III to IV GVHD, particularly of the gastro-intestinal tract, which may prove fatal.

Recent data suggest that the current incidence of chronic GVHD may be around 30% in patients who have received triple combination prophylaxis (tacrolimus, methotrexate, sirolimus) or ATG as part of the conditioning regimen. First-line therapy for chronic GVHD are steroids. However, promising results have been reported with the use of PUVA (sensitization with psoralen and exposure to ultraviolet light in the A spectrum) or extracorporeal photopheresis, approaches that also have a steroid sparing effect, thereby reducing complications associated with steroid use (infection risk, musculoskeletal wasting). Numerous additional agents directed at various signaling pathways or at B lymphocytes are currently being tested.

Though graft failure is not a significant issue with HCT from HLA matched related or unrelated donors following high-intensity conditioning, it remains an issue when cord blood is the source of stem cells, when the type of transplant is haploidentical and other forms of HLA-non-identical transplant, or if RIC regimens are used. Delayed engraftment of neutrophils and platelets is an additional significant concern with cord blood transplants following high-intensity conditioning.

Graft failure and rejection, that is, a lack of sustained engraftment of donor-derived cells, may be due to allosensitization of the recipient or histocompatibility barriers between patient and donor, but also to defects in the recipient marrow microenvironment in maybe 5% of patients with aplastic anemia; it also occurs in MDS. Certain anti-human monoclonal antibodies (for example, Campath Ig [immunoglobulin] anti-CD52, or ATG), or immunotoxin conjugates, administered during the peri-transplant period, may reduce the graft failure rate without increasing toxicity.

The prognosis of graft failure depends upon the clinical circumstances. If the patient is in good condition (without significant organ failure or infections), a second HCT, either from the original donor or from a different donor, is an option. The decision on how to proceed best requires consideration of all clinical and laboratory parameters and should only be made after discussion with a panel of experts. An important consideration is whether the patient still has evidence of donor chimerism or is left with patient cells only. In some patients it may be useful to administer G-CSF for a period of time in an attempt to raise the granulocyte count (be it donor or patient-derived) and allow the patient to overcome an infection that may be present.

Graft failure is of particular concern following HLA haploidentical HCT. High intensity conditioning followed by large doses of G-CSF mobilized and CD34+ selected haploidentical cells (17.5 ± 5 × 106 CD34+cells/kg) has improved the success of engraftment. A promising strategy is the use of early post-HCT administration of Cy (50 mg/kg/day on days +3 and +4) aimed at eliminating nascent proliferation of activated T cells that would cause GVHD.

Neutropenic fever and infections are frequent in recipients of HCT and are a major cause of transplant-related morbidity and mortality. Bacterial, fungal, and viral infections are very common, particularly early after HCT and in patients with GVHD (they will not be discussed here in detail). All patients receive anti-bacterial, -viral and -fungal prophylaxis (for example, with ciprofloxacin, co-trimoxazole, acyclovir, and fluconazole, respectively, but other regimens are used).

Dependent upon the clinical course, the development of fever or the isolation of a particular organism will lead to empiric or organism-specific changes in the regimen. It is important to act promptly: if fever continues despite what is considered appropriate therapy, the antibiotic regimen must be adjusted. If bacteremia or fungemia continues despite appropriate coverage, indwelling vascular access lines need to be removed. Cardiac echography should be done to exclude valvular lesions (endocarditis). All patients on steroid therapy should be monitored by surveillance blood cultures, maybe twice a week.

Pulmonary infections can develop without obvious clinical signs. A chest radiograph, maybe weekly, is a useful monitoring tool. Any clinical indication (dyspnea, O2 desaturation) must be worked up aggressively with a radiograph, and often a computed tomography (CT) scan. Bronchoscopy and bronchoalveolar lavage may allow for an etiologic diagnosis.

If bronchoscopy is not informative, a VATS (video-assisted thoracic surgery) procedure or an open lung biopsy may be required. Obtaining fluid from a pleural effusion may assist in the diagnosis. Unexplained abdominal pain, particularly in a neutropenic patient, requires immediate attention to rule out or establish a diagnosis of perityphlitis, perforation, peritonitis, pancreatitis (possibly steroid related), acalculous cholecystitis, abscess formation, GVHD of the intestine, or other problems. An abdominal CT is often useful; MRI may further delineate a diagnosis. Sinusoidal obstruction syndrome (SOS or VOD) of the liver may be accompanied by pain; an ultrasound of the liver can be helpful (in addition to the documentation of weight gain and ascites) to establish this non-infectious complication.

Pneumatosis cystoides intestinalis is another infrequent complication that can generally be diagnosed radiographically. It may occur in patients on steroids or may be associated with infections of the gut. Of course, endoscopy is a very powerful tool to diagnose diseases of the colon and the upper gastrointestinal tract.

The longest surviving patients have now been followed for four decades after allogeneic HCT, and most are leading normal lives. However, some have developed late complications. Complications are related either to pre-transplant events, the conditioning regimen (irradiation and chemotherapy), or transplant-associated events (chronic GVHD, immunodeficiency). Those complications are less frequent in patients with non-malignant than in those with malignant diseases. Potentially life-threatening problems include infections and pulmonary dysfunction, particularly bronchiolitis obliterans, which is usually associated with chronic GVHD.

Some patients have developed severe respiratory failure, rendering them dependent upon supplementary oxygen, and a few patients have received lung transplants for respiratory failure. New autoimmune disorders may develop due to adoptive transfer (from a donor who is affected), due to GVHD, or may occur in an idiopathic way.

Patients may also develop a metabolic syndrome, early cardiovascular disease, dental decay, osteopenia or osteoporosis, among others. Close monitoring, prophylaxis, or early intervention and management by a multidisciplinary team (as discussed for chronic GVHD), have significantly improved the quality of life and survival in these patients.

The omission of high-dose TBI as part of the conditioning regimen has reduced the frequency and severity of transplant-related complications such as interstitial pneumonitis, cataracts, and impairment of growth and development. It is desirable to avoid irradiation completely, at least in very young children where growth and development of the skeleton, the teeth, and the central nervous system, occur at an exponential rate.

Sexual maturation is often delayed or even arrested (particularly in patients given high-dose TBI or Bu), and fertility in both men and women is impacted, again dependent upon the intensity of the conditioning regimen and the presence of chronic GVHD. However, several series have reported multiple pregnancies and delivery of healthy babies in women conditioned with Cy regimens or the partners of men transplanted with Cy conditioning.

Systematic psychosocial studies investigating the effects of HCT on personal development, family dynamics, and partner relationships are currently being pursued. Active rehabilitation is necessary in many instances. In particular, adolescent patients have difficulties with adjusting to the disrupted development, with self image, sexuality, and other issues.

Discussed above under “What should you tell the patient and the family about prognosis?”

The pathophysiology underlying the various disorders is discussed in the respective disease chapters. A brief description of known mechanisms of complications after HCT is provided in the “What should you tell the patient and the family about prognosis?” section.

Laboratory studies required to make the diagnosis of a particular marrow failure or autoimmune disease are discussed in the respective disease chapters, and only briefly summarized above. Tests required for the diagnosis of post-HCT complications are discussed in the “What should you tell the patient and the family about prognosis?” section.

Aiuti, A, Cattaneo, F, Galimberti, S. “Gene therapy for immunodeficiency due to adenosine deaminase deficiency”. N Engl J Med.. vol. 360. 2009. pp. 447-458. (An expert overview of the current status of gene therapy, focused on adenosine deaminase deficiency, but with many principles that are broadly relevant.)

Anasetti, C, Logan, BR, Lee, SJ. “Peripheral-blood stem cells versus bone marrow from unrelated donors”. N Engl J Med.. vol. 367. 2012. pp. 1487-1496. (Randomized trial in patients with malignant disorders transplanted from unrelated donors, showing similar survival with marrow and PBPC as a source of stem cells, but a higher incidence of chronic GVHD with PBPC.)

Anderlini, P, Wu, J, Gersten, I, Ewell, M, Tolar, J, Antin, JH. “Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study”. The Lancet Haematology. vol. 2. 2015. pp. e367-e375. (A multi-institutional prosepctive trial aimed at determining the optimum dose of cyclophosphamide to be given in combination with fludarabine, ATG and low dose total body irradiation.)

Cassinotti, A, Annaloro, C, Ardizzone, S. “Autologous haematopoietic stem cell transplantation without CD34+ cell selection in refractory Crohn’s disease”. Gut.. vol. 57. 2008. pp. 211-217. (While improvements of concurrently present inflammatory bowel disease have been observed in patients transplanted, for example for leukemia, it is shown that transplantation may be an option for the treatment of Crohn’s disease itself.)

Deeg, HJ, Sandmaier, BM.. “Who is fit for allogeneic transplantation?”. Blood.. vol. 116. 2010. pp. 4762-4770. (A comprehensive discussion of patient and disease characteristics as well as socio-economic factors that should be considered when advising patients about hematopoietic cell transplantation.)

Kanakry, CG, Fuchs, EJ, Luznik, L.. “Modern approaches to HLA-haploidentical blood or marrow transplantation”. Nat Rev Clin Oncol. vol. 13. 2016. pp. 132(A comprehensive review of the current state of HLA haplotype mismatched transplantation and the benefit of post-transplant administration of cyclophosphamide.)

Malfuson, JV, Amor, RB, Bonin, P. “Impact of nonmyeloablative conditioning regimens on the occurrence of pure red cell aplasia after ABO-incompatible allogeneic haematopoietic stem cell transplantation”. Vox Sang.. vol. 92. 2007. pp. 85-89. (Description of PRA in patients conditioned with low intensity conditioning regimens.)

Nash, RA, McSweeney, PA, Nelson, JL. “Allogeneic marrow transplantation in patients with severe systemic sclerosis: resolution of dermal fibrosis”. Arthritis Rheum.. vol. 54. 2006. pp. 1982-1986. (Documentation of the feasibility of allogeneic hematopoietic cell transplantation for systemic sclerosis and the resolution of sclerosis over time.)

Nash, RA., Appelbaum, FR, Forman, SJ, Negrin, RS, Blume, KG. “Hematopoietic cell transplantation for autoimmune diseases”. Thomas’ Hematopoietic Cell Transplantation. 2009. pp. 1014-1029. (A comprehensive discussion of the current state of transplantation for patients with autoimmune diseases.)

Nash, RA, Hutton, GJ, Racke, MK, Popat, U, Devine, SM, Griffith, LM. “High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for relapsing-remitting multiple sclerosis (HALT-MS): a 3-year interim report”. JAMA Neurology. vol. 72. 2015. pp. 159-169. (An update on a large trial using immunosuppressive therapy and autologous hematopoietic cell transplantation for the treatment of relapsing-remitting Multiple Sclerosis.)

Petersdorf, EW, Malkki, M, O’Huigin, C, Carrington, M, Gooley, T, Haagenson, MD. “High HLA-DP expression and graft-versus-host disease”. New England Journal of Medicine. vol. 373. 2015. pp. 599-609. (An update on the role of the degree of HLA matching, particularly the impact of HLA-DP, on transplant outcome.)

Oyama, Y, Barr, WG, Statkute, L. “Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis”. Bone Marrow Transplant.. vol. 40. 2007. pp. 549-555. (Discussion of the use of allogeneic stem cells to treat systemic sclerosis. Even though autologous cells are re-infused, the concurrent immunosuppression does allow for stabilization of the disease for various time intervals.)

Ravelli, A, Martini, A.. “Juvenile idiopathic arthritis (Review)”. Lancet.. vol. 369. 2007. pp. 767-778. (A comprehensive discussion of the management of juvenile arthritis and its management by experts in the field.)

Robin, M, Sanz, GF, Ionescu, I, Rio, B, Sirvent, A, Renaud, M. “Unrelated cord blood transplantation in adults with myelodysplasia or secondary acute myeloblastic leukemia: a survey on behalf of Eurocord and CLWP of EBMT”. Leukemia. vol. 25. 2011. pp. 75-81. (Overview of European results with cord blood transplants in adults with MDS or AML.)

Nakamura, Ryotaro, Forman, SJ, Negrin, RS, Antin, JH, Appelbaum, FR. “Hematopoietic cell transplantation for paroxysmal nocturnal hemoglobinuria”. Thomas’ Hematopoietic Cell Transplantation. vol. 1. 2016. pp. 537-544. (A summary of current results with hematopoietic cell transplantation in patients with PNH. Results are superior with related donors and inferior in patients with hemolytic/thrombotic complications. Reduced intensity conditioning regimens may improve results with unrelated donors.)

Scheinberg, P, Cooper, JN, Sloand, EM, Wu, CO, Calado, RT, Young, NS.. “Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia”. JAMA. vol. 304. 2010. pp. 1358-1364. (The authors show that short telomere length in aplastic anemia is associated with inferior prognosis; patients with short telomeres and low reticulocyte counts are also less likely to respond to immunosuppressive therapy.)

Scheinberg, P, Nunez, O, Weinstein, B. “Horse versus rabbit antithymocyte globulin in acquired aplastic anemia”. N Engl J Med.. vol. 365. 2011. pp. 430-438. (Study shows superior results with equine ATG compared to rabbit ATG.)

(Seleroderma: Cyclophosphamide or transplantaion (SCOT) study.)

Sorror, M, Storer, B, Sandmaier, BM. “Hematopoietic cell transplantation-comorbidity index and Karnofsky performance status are independent predictors of morbidity and mortality after allogeneic nonmyeloablative hematopoietic cell transplantation”. Cancer.. vol. 112. 2008. pp. 1992-2001. (Patient co-morbidities in addition to disease characteristics are the major determinants of transplant success. A transplant-specific comorbidity score is useful in assessing the risk of a particular patient.)

van Laar, JM, Farge, D, Sont, JK. “Autologous hematopoietic stem cell transplantation versus intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial”. JAMA. vol. 311. 2014. pp. 2490-2498. (A prospective trial using transplantation versus non-transplant therapy, showing that transplantation conferred a long-term survival advantage.)

Walker, I, Panzarella, T, Couban, S, Couture, F, Devins, G, Elemary, M. “Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trial”. Lancet Oncol. vol. 17. 2016. pp. 164-173. (A randomized trial enrolling patients transplanted from unrelated donors, showing a benefit of incorporating ATG into the transplant conditioning regimen for event-free survival; the results confirm the outcome in several other randomized trials involving unrelated or unrelated donor transplants.)