Allogeneic Stem Cell Transplants

Allogeneic stem cell transplantation (HSCT) necessitates the collection of a sufficient number of stem cells (SC) from a histocompatible donor and their infusion into a patient after a conditioning regimen. HSCT has progressed from an experimental therapy for terminally sick patients to a curative treatment during the last 35 years. In Italy in 2003, 1170 procedures were registered (Italian Group for Blood and Marrow Transplantation).

Leukemia, lymphoproliferative disorders, myelodysplasia, and nonmalignant illnesses such as thalassemia and severe aplastic anemia were the most commonly reported indications.

Significant changes have occurred in the last 5 years, including the shift from bone marrow to peripheral blood as the SC source, an increase in the number of alternative donors such as unrelated, partially matched family donors and cord blood SC, and the addition of new extra-hematological indications such as solid tumors. Furthermore, the discovery of non-myeloablative conditioning regimens has enabled clinicians to conduct HSCT on patients who are elderly or have significant comorbidities.

In contrast, the availability of the Tyrosine kinase inhibitor (STI-571) for the treatment of patients with chronic myelogenous leukemia, which was formerly the principal indication for HSCT, has resulted in a significant decline in the frequency of transplants in this situation. HSCT conducted in the early stages of illness and in young individuals has a cure rate of greater than 50%.

Despite less toxic conditioning regimens, high-resolution HLA typing, and superior supportive care, transplant-related mortality remains the most significant barrier, ranging from 20% to 30%. GvHD and infections continue to be the leading causes of morbidity. Relapses are associated with disease condition at the time of transplantation. In adult patients, promising outcomes have lately been found using haploidentical and cord blood SC transplantation.

History and evolution of Allogeneic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) was originally explored in humans in the 1950s, based on observational research in mice models that shown that infusing healthy bone marrow components into a myelosuppressed bone marrow might stimulate recovery of function in the recipient.

When the first successful bone marrow transplant was conducted in monozygotic twins in New York in 1957 (syngeneic transplant) in a patient with acute leukemia, these animal-based research quickly found therapeutic applicability in humans.

As a result, the physicians who performed the procedure continued their study into the improvement of bone marrow transplantation and were eventually awarded the Nobel Prize in physiology and medicine.

A young child with severe combined immunodeficiency syndrome had the first successful allogeneic bone marrow transplant in Minnesota in 1968. Allogeneic and autologous stem cell transplantation has grown in popularity in the United States and across the world since then.

The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogenic transplants performed in the United States in 2016 with a higher number of autologous transplants with a steady and higher increase of autologous compared to allogenic

Indications of Allogeneic stem cell transplantation

Multiple Myeloma: Autologous stem cell transplants accounted for the majority of hematopoietic stem cell transplants in the United States in 2016. Consolidation therapy with melphalan, followed by autologous stem cell transplantation and lenalidomide maintenance therapy, has been found in studies to improve overall survival and progression-free survival in patients younger than 65 years old.

The study found that high-dose melphalan with stem-cell transplantation had a better prognosis than consolidation treatment with melphalan, prednisone, and lenalidomide. It also shown a superior result in those who got lenalidomide maintenance medication.

Hodgkin and Non-Hodgkin Lymphoma: Treatment followed by autologous stem cell transplantation has been found in studies to improve outcomes in cases of recurrent lymphomas (HL and NHL) that do not respond to first conventional chemotherapy. High-dose chemotherapy combined with autologous stem cell transplant had a better 3-year result than harsh conventional treatment in recurrent chemosensitive Hodgkin cancer.

However, there was no statistically significant difference in overall survival between the two groups. According to multiple studies, the number of hematopoietic stem cell transplant recipients is second only to multiple myeloma.

Acute Myeloid Leukemia: Allogenic stem cell transplantation has been found to enhance prognosis in patients with AML who fail initial induction treatment and do not achieve a competitive response, as well as to extend overall survival. The study concluded that early HLA typing for AML patients can be beneficial if induction treatment fails and they are evaluated for bone marrow transplant.

Acute Lymphocytic Leukemia: Allogenic stem cell transplant is appropriate in refractory and resistant patients when induction treatment fails to induce remission for the second time. Some studies show that allogenic hematopoietic stem cell transplantation may be more beneficial in individuals with high risk ALL, especially those with the Philadelphia chromosome.

Myelodysplastic Syndrome: Allogenic stem cell transplant is considered being curative in cases of disease progression and is only indicated in intermediate- or high-risk patients with MDS.

Chronic Myeloid Leukemia/Chronic Lymphocytic Leukemia: Patients with these two disorders are towards the bottom of the list of allogeneic stem cell transplant recipients in 2016. Hematopoietic stem cell transplantation offers a high cure rate, but with current medications such as tyrosine kinase inhibitors and good success rates with a low adverse risk profile, HSCT is reserved for patients with CML who are resistant to first-line medicines.

Myelofibrosis, Essential Thrombocytosis, and Polycythemia Vera: Allogenic stem cell transplantation has been demonstrated to enhance outcomes in individuals with myelofibrosis as well as those who had myelofibrosis preceded by essential thrombocytosis and polycythemia vera.

Solid Tumors: In patients with germ cell cancers (testicular tumors) that are resistant to chemotherapy, autologous stem cell transplant is regarded the gold standard of treatment (after the third recurrence with chemotherapy). HSCT has also been studied in the treatment of medulloblastoma, metastatic breast cancer, and other solid tumors.

Aplastic Anemia: Systematic and retrospective investigations have found that hematopoietic stem cell transplant improves outcomes in acquired aplastic anemia when compared to standard immunosuppressive treatment. In a research involving 1886 individuals with acquired aplastic anemia, allogenic stem cell transplant performed better when harvested from bone marrow rather than peripheral blood.

Patients with aplastic anemia require a preparatory regimen because they may develop immunological rejection to the transplant.

Severe Combined Immune Deficiency Syndrome (SCID): Large retrospective investigations have found that infants with SCID who got the transplant before the beginning of infections had a higher overall survival rate.

Thalassemia: Allogenic stem cell transplantation from a matched sibling donor is considered a treatment option for Thalassemia, with a 15-year survival rate of 80 %. In the instance of thalassemia, however, new retrospective data indicated comparable overall survival when compared to standard therapy, which consists of several transfusions.

Sickle Cell Anemia: Allogenic stem cell transplant is recommended for the treatment of sickle cell disease.

Advantages and disadvantages of different hematopoietic Stem Cells transplantation

Peripheral blood stem cells transplant (PBSCTs): The advantages of PBSCTs include a faster engraftment rate compared to bone marrow, which takes around 2 weeks to recover and is delayed for 5 days longer in the latter, although the use of a post-transplant immunosuppressive regimen to avoid GVHD might extend the rise in bone marrow products.

Furthermore, when HLA-identical matched related donors are transplanted, the rate of acute GVHD appears to be comparable to bone marrow transplantation. However, persistent GVHD appears to be more common following peripheral blood stem cell transplant, which may lead to further problems.

However, studies showed more stable grafts with decreased graft failure in the group which received peripheral blood stem cell transplant but also this group had a higher incidence of chronic GVHD.

Cord blood transplant: The benefits of cord blood transplant include the ability to collect and provide blood quickly, which aids in the treatment of urgent illnesses, a lower frequency of infections, lower rates of GVHD with the same rate of GVT, and a reduced requirement for a rigorous exact HLA match. The downsides include delayed engraftment, which increases the likelihood of graft rejection, as well as increased rates of disease relapse.

Cord blood transplants are most commonly applied in patients who do not have a matched related or unrelated donor. Several trials have established the efficacy of cord blood transplant in patients with thalassemia major and sickle cell anemia, with CBT and BMT groups showing comparable 6-year overall survival.

The total nucleated cell dosage and HLA matching are the most critical elements that influence the success of CBT, with a suggested minimum dose of total nucleated cells.

Haploidentical stem cell transplantation: The use of bone marrow products from a first degree related haplotype-mismatched donor. Non-white patients, such as African Americans, Hispanics, and patients from countries with limited access to resources, benefit from this since they have a lower probability of finding a matched unrelated donor. The benefits include cheaper costs and quicker availability of hematopoietic cell products.

However, there are also drawbacks, such as hyperacute GVHD, which increases mortality and graft rejection. This has been addressed by depleting the T cells responsible for the aforementioned response, but this also results in delayed immune recovery and a diminished graft versus tumor impact. When compared to typical ex vivo depletion of broad T-cell populations, techniques such as selective depletion of subsets of T cells, particularly alpha-beta, have produced better results.

Myeloablative preparative regimens

The myeloablative conditioning regimens used in allogeneic HSCT serve three purposes: eradication of malignant disease, suppression of the recipient's immune system, reducing the likelihood of graft rejection, and creation of space in the bone marrow microenvironment to allow donor stem cells to engraft.

There have been several myeloablative conditioning regimens utilized, but no one regimen has been proved to be superior. To generate a full state of immunosuppression in patients with aplastic anemia, high-dose cyclophosphamide treatment was employed alone or in conjunction with either modest doses of total body irradiation or thoraco-abdominal irradiation.

Uncontrolled trials revealed that cyclophosphamide and antithymocyte globulin combined treatment reduces the risk of transplant failure. However, randomized controlled trials are required to establish this advantage. High-dose cyclophosphamide has been routinely utilized in patients with acute myeloid or lymphoid leukemias, CML in the chronic, accelerated, or blastic phase.

The chemoradiotherapy regimens may cause severe acute side effects such as nausea, vomiting, diarrhea, and alopecia. Mucositis can be severe, necessitating systemic opioid pain relief. Hemorrhagic cystitis caused by high-dose cyclophosphamide administration is uncommon and can be avoided by rigorous hydration and diuresis coupled with continuous bladder irrigation or by the use of mesna as a preventative measure. Cardiomyopathy and abrupt renal failure are two more possible early-onset harmful consequences.

The current pretransplant preparing regimens have been pushed to their limits. New conditioning regimens that can specifically target cancer cells without creating major nonhematopoietic toxic consequences are being researched. Animals have been subjected to two techniques of training regimen creation. Radiolabeled monoclonal antibodies have been demonstrated to cause deadly marrow aplasia, which can be reversed by infusing marrow 8 days later, when negligible radioactivity remains.

The use of high-energy -emitting isotopes with short linear energy transfer may result in less adverse effects, better cancer control, and decreased graft failure. The second strategy utilizes bone-localizing isotopes. Initial data in animals using samarium demonstrated that marrow ablation may be accomplished with little toxicity to other organs. The eventual purpose and long-term usefulness of these techniques in people is unknown.

Acute complications of Allogeneic stem cell transplantation

Patients receiving allogeneic HSCT are highly susceptible to infections because of immunodeficiency, neutropenia, and the immunosuppressive therapy used to prevent or treat GVHD. Bacterial and fungal infections can occur during the first 2 weeks after allogeneic HSCT, and the mortality from these infections is approximately 3% to 5% despite intensive supportive care and appropriate antimicrobial drug therapy.

Viral infections:

Herpesviruses are prevalent and are generally triggered by the reactivation of a latent virus. Infection with the herpes simplex virus may develop 1 to 2 weeks after transplantation in up to 80% of seropositive individuals not receiving acyclovir prophylaxis, resulting in mucocutaneous lesions of the oropharynx, esophagus, or genital tract.

Cytomegalovirus (CMV) infection typically occurs 4 to 10 weeks following transplantation, with CMV pneumonitis occurring in 20% to 30% of GVHD patients.

The risk of CMV infection and disease increases in direct proportion to the prevalence and severity of acute GVHD. For chronic GVHD, no such association has been discovered. Dyspnea, tachypnea, fever, hypoxemia, and widespread interstitial lung involvement are all symptoms of CMV pneumonitis. Despite treatment, this condition is associated with a significant death rate (30% -50%).

The use of CMV-negative blood products in CMV patients can provide effective prevention. -seronegative donor-patient pairings, intravenous immunoglobulin, prestorage leukocyte-depleted blood products, leukocyte-filtered blood products, and prophylactic ganciclovir are all available.

Interstitial pneumonia affects 25% to 35% of patients, with CMV infection accounting for half of these instances. Cytomegalovirus pneumonitis occurs 7 weeks following transplantation on average, with the majority of cases occurring during the first 4 months. Acute GVHD, older age, CMV seroconversion and seropositivity of the recipient, and transplantation for hematologic malignancy are all risk factors for CMV pneumonitis.

Veno-occlusive Disease of the Liver (VOD):

Veno-occlusive disease of the liver affects 20% to 50% of individuals receiving high-dose chemotherapy, as well as 20% to 50% of patients receiving high-dose cyclophosphamide plus busulfan. This issue is unusual in people with aplastic anemia who are just taking cyclophosphamide.

Elevated serum aminotransferase levels (particularly aspartate aminotransferase) prior to transplantation, rigorous conditioning therapy, graft from a mismatched or unrelated donor, and use of antimicrobial medication with acyclovir, amphotericin B, or vancomycin are all risk factors (possibly reflecting persistent fever).

This disorder can manifest itself within 3 weeks of undergoing allogeneic HSCT and is clinically characterized by jaundice, right upper quadrant abdominal pain, hepatomegaly, fluid retention, and weight gain.

Many research trials are being carried out in an attempt to avoid VOD. In randomized trials, pentoxifylline, a xanthine derivative capable of suppressing tumor necrosis factor production, was shown to be ineffective in decreasing the incidence of VOD.

According to a randomized experiment, utilizing low-dose heparin decreased the incidence of VOD without increasing the risk of bleeding. Ursodiol therapy reduced the incidence of VOD in a randomized, double-blind, placebo-controlled trial50 of patients receiving a preparative regimen of cyclophosphamide and busulfan.

Graft-vs-Host Disease

Graft-vs-host disease is still one of the most common consequences following allogeneic HSCT, particularly with the rising use of grafts from mismatched and unrelated donors. This illness is classified into two types depending on its onset and clinical characteristics. The acute type appears within the first two to three months of transplantation, while the chronic form appears later in the post-transplant period:

Acute GVHD:

Acute GVHD develops within 2 to 10 weeks after allogeneic HSCT. Clinically severe grade II to IV acute GVHD occurs in about 20% to 50% of patients who get stem cells from an HLA-identical sibling donor and 50% to 80% of patients who receive stem cells from an HLA-mismatched sibling or an HLA-identical unrelated donor.

Dermatitis, hepatitis, and enteritis are symptoms of acute GVHD. A maculopapular rash encompassing the body, face, limbs, palms, soles, and ears is generally the first sign of acute GVHD.

In severe cases, the rash may progress to bullous lesions, followed by epidermal necrolysis. Mild disease is characterized histologically by vacuolar degeneration and lymphocytic infiltration of the basal cell layer, which develops to necrotic dyskeratotic cells with acantholysis and cell membrane separation in moderate disease and epidermolysis in severe cases. These findings can not rule out GVHD because they can be produced by chemoradiotherapy and other drugs.

Bilirubin, alkaline phosphatase, and aminotransferase levels may rise with the onset of nausea, vomiting, abdominal pain, and copious watery or bloody diarrhea. A liver biopsy may be necessary to confirm the diagnosis of GVHD in patients with a single hepatic derangement since liver dysfunction in these patients may be caused by a variety of mechanisms, including VOD, infectious hepatitis, and drug-induced liver injury.

However, in this patient population, a liver biopsy is a risky procedure that should not be conducted without a complete assessment of the patient's hemostatic and clinical condition. Histologic patterns on liver biopsy findings show lymphocytic infiltration of the portal triads, with hepatocellular necrosis evident in certain cases, similar to that found in acute hepatitis.

Rectal punch biopsies may confirm the diagnosis of GVHD due to histologic observations of epithelial cell necrosis, vacuolar degeneration, crypt dropout, and, in extreme cases, epithelial denudation.

Prophylactic immunosuppressive therapy with cyclosporine and methotrexate, cyclosporine alone, or cyclosporine in conjunction with prednisone has resulted in a significant reduction in the incidence of acute GVHD and an increase in survival. Prednisone, cyclosporine, and methotrexate were more effective than cyclosporine and prednisone alone in preventing acute GVHD of grades II to IV.

To treat established acute GVHD, high-dose methylprednisolone, cyclosporine, and antithymocyte globulin are utilized. Responses can be produced in around 40% of patients after high-dose corticosteroid therapy, with just 20% achieving a complete response.

Patients who do not react to this therapy may only get a minimal improvement from second-line therapy, and their long-term outcome is poor due to viral comorbidities, interstitial pneumonitis, and progression to chronic GVHD.

Chronic GVHD:

Chronic GVHD affects less than half of long-term survivors. It is a complicated late complication that most commonly occurs 3 to 6 months after hematopoietic engraftment. There is no indication of past acute GVHD in around 20% of the patients.

Chronic GVHD seems clinically similar to autoimmune disorders, most notably scleroderma. Patients with this disease may experience sicca syndrome (dryness of the mouth and eyes), skin lesions (hypopigmentation or hyperpigmentation, decreased elasticity, and loss of hair follicles and sweat glands), keratoconjunctivitis, oral mucositis, esophageal strictures, malabsorption, hepatic involvement with hyperbilirubinemia, and suppressed hematopoietic reconstitution.

Bronchiolitis obliterans affects 10% to 20% of those with chronic GVHD and is associated with hypogammaglobulinemia and a bad prognosis. Biopsies of the skin and oral mucosa may be useful in identifying the existence of chronic GVHD.

The treatment of chronic GVHD is the use of immunosuppressive drugs early in the course of the disease, before the onset of functional impairment. Oral cyclosporine drug used every other day in conjunction with prednisone treatment has been associated to improved complete responses and overall survival rates.

In certain situations, azathioprine, UV radiation, and psoralen–UV-A have been used to assist control the illness. Thalidomide has been shown to be effective in refractory cases by blocking IL-2 activation. In the absence of more study, mycophenolate mofetil may be useful in the treatment of these individuals.

In 50% of patients, treatment can be stopped after 9 to 12 months. Self-tolerance often occurs a few years after allogeneic HSCT, and the majority of patients can reduce or discontinue immunosuppressive treatment at that point. Infections caused mostly by encapsulated gram-positive bacteria can occur in people with prolonged GVHD and can be deadly. Preventive use of antibacterial medications such as co-trimoxazole or penicillin is advised in these patients.

Graft failure after Allogeneic stem cell transplantation

Graft failure can happen early, as seen by a lack of initial hematopoietic recovery, or late, as evidenced by disease recurrence or the return of host cells after initial donor cell engraftment. Failure of sustained marrow engraftment is unusual in individuals with hematologic malignancies who receive complete HLA-compatible marrow (2%). This effect, however, is more common in patients with aplastic anemia who have received allogeneic BMT, particularly those who have received several transfusions.

The use of antithymocyte globulin as part of the conditioning protocol, or infusing donor buffy coat after transplantation, lowered the risk of graft failure in aplastic anemia patients from 30% to 60% to less than 10%. Graft failure is more prevalent in myelofibrosis and mixed hematopoietic chimerism patients. Other risk factors for nonengraftment include a low number of infused mononuclear cells, past blood transfusions, graft modification for T-cell decrease, and donor-recipient HLA incompatibility.

The pathophysiology of prolonged and total engraftment failure is not completely known. There is some evidence that this failure might be the result of a graft-vs-marrow (recipient's marrow microenvironment) interaction or an abnormal microenvironment. Graft failure is thought to be caused by a mismatch between donor and recipient immunocompetence in individuals undergoing T-cell deficient marrow transplants.

How much does a stem cell transplant cost?

Pediatric patients paid more for the index HSCT hospitalization as well as the 100-day inpatient and outpatient healthcare services than adult patients for both transplant types. The median expenses of the index HSCT hospitalization for myeloablative allogeneic and autologous transplants in pediatric patients were $363,379 and $154,266 respectively, compared to $191,541 and $109,113 in adults. In pediatric patients, the median inpatient costs for myeloablative allogeneic and autologous transplants were $406,195 and $194,125, respectively, compared to $212,332 and $111,419, respectively, in adults.

Conclusion

Allogeneic stem cell transplantation is the process of transplanting stem cells from a healthy individual (the donor) to the patient's body following high-intensity chemotherapy or radiation. The stem cells might be provided by a related or unrelated donor.

A conditioning regimen of chemotherapy and, in certain cases, radiation treatment is administered to the patient prior to an allogeneic stem cell transplant. This conditioning therapy is administered to the patient in order to eradicate any leftover cancer cells in the body. This weakens the patient's immune system, preventing the body from rejecting the donor cells following the transplant.

It also enables the donor cells to travel via the circulation to the bone marrow, where they will begin to develop and generate new blood cells such as red blood cells, platelets, and white blood cells. This is known as "engraftment."

When a transplant is successful, the donor stem cells can replace bone marrow stem cells. It may also be the patient's sole long-term cure for the condition. One of the advantages of allogeneic stem cell transplantation is that the given cells establish a new immune system in the patient once they engraft. White blood cells produced by the donor cells fight any leftover cancer cells in the patient's body.

This is known as the "graft-versus-tumor impact," and it may be more essential than the extremely severe conditioning program used to eliminate cancer cells. This advantage is only available with allogeneic stem cell transplantation.

The median expenses of the index HSCT hospitalization for myeloablative allogeneic and autologous transplants in both pediatric and adult patients were ranging from $150,000 to $350,000.