Hematopoietic Cell Transplantation for Thalassemia Major and Sickle Cell Anemia

Number: 0626

Policy

Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of thalassemia major (i.e., homozygous beta-thalassemia) in children or young adults (to age 45 years) when the member meets transplanting institution's written eligibility criteria.  In the absence of such criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of thalassemia major (i.e., homozygous beta-thalassemia) in children or young adults with a haploidentical to HLA-matched donor..

Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of sickle cell anemia in children or young adults when the member meets transplanting institution's written eligibility criteria.  In the absence of such criteria, Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the treatment of sickle cell anemia in children or young adults when both of the following criteria are met:

• Members have a haploidentical to HLA-matched donor; and
• Members with either a history of stroke or at increased risk of stroke or end-organ damage (see Note below).

Aetna considers autologous hematopoietic cell transplantation for thalassemia major or sickle cell anemia in children or young adults experimental and investigational due to insufficient evidence in the peer-reviewed literature.

Note: Factors associated with increased risk of stroke or end-organ damage include recurrent chest syndrome, recurrent vaso-occlusive crises, and red blood cell alloimmunization on chronic transfusion therapy.

Note: Requests for allogeneic hematopoietic cell transplantation for thalassemia major or for sickle cell anemia in adults older than age 45 years should be forwarded to the National Medical Excellence (NME) unit for review.

Background

Thalassemia:

Thalassemia is a congenital hemolytic disease that entails a group of disorders of hemoglobin metabolism. It is caused by a partial or complete deficiency of alpha- or beta-globin chain synthesis. Clinical severity ranges from minimal in individuals who are heterozygous carriers of the trait for alpha-thalassemia (i.e., thalassemia minor) to fatal anemia or fatal sequelae of cardiac iron deposits in homozygous beta-thalassemia (i.e., thalassemia major). Conventional treatments for thalassemia include transfusions, splenectomy, and use of medications that increase mobilization and excretion of iron deposits.

Although transfusions and regular iron chelation by means of deferasirox (Exjade) or deferoxamine (Desferal) can extend life expectancy, they are not curative and the disease will be eventually fatal. Allogeneic bone marrow transplant has been introduced as a therapeutic option for patients with thalassemia major. Outcomes following transplantation from human leukocyte antigen (HLA)-matched donors are influenced by the presence of risk factors such as hepatomegaly, portal fibrosis, and ineffective chelation therapy prior to transplantation. Children without any of these risk factors have survival and disease-free survival rates of greater than 90 % 3 years after transplantation. On the other hand, for patients with all 3 risk factors, and in most adults, the rates are about 60 %. A recent study (Mentzer and Cowan, 2000) reported that for children with beta-thalassemia major or hemoglobin E/beta-thalassemia who received allogeneic HLA-matched family donor stem cell transplants, the overall survival and event-free survival rates were 94 % and 71%, respectively.

There is evidence for the effectiveness of bone marrow transplantation for sickle cell anemia and thalassemia using unrelated donors. Hongeng et al (2006) stated that recently published reports indicate that the outcome of unrelated donor transplantations in patients with leukemia is currently comparable to that of transplantation from identical family donors. These investigators examined the possibly favorable outcomes of related and unrelated transplantation in children with severe thalassemia. They reviewed transplantation outcome in 49 consecutive children with severe thalassemia who underwent allogeneic stem cell transplantation with related-donor (n = 28) and unrelated-donor (n = 21) stem cells. Analysis of engraftment, frequency of procedure-related complications, and thalassemia-free survival showed no advantage from use of related-donor stem cells. The 2-year thalassemia-free survival estimate for recipients of related-donor stem cells was 82 % compared with 71 % in the unrelated-donor stem cell group (p = 0.42). This study provided evidence to support the view that it is quite reasonable to consider unrelated-donor stem cell transplantation an acceptable therapeutic approach in severe thalassemia, at least for patients who are not fully compliant with conventional treatment and do not yet show irreversible severe complications of iron overload.

Feng et al (2006) reported unrelated bone marrow tranplantatation (BMT) in 9 thalassemic children using a high-resolution HLA typing technique to identify donors. HLA mismatches between donors and recipients were 0, 1 and 2 in 2, 5 and 2 cases, respectively. The results showed that white blood cells, platelets and hemoglobin all returned to normal at various time points, and blood transfusion was eliminated from 13 to 62 days after transplantation. Full engraftment was achieved in 8 patients while ABO blood types were replaced with that of donors in 5 of the 6 ABO mismatched recipients. Acute skin graft-versus-host disease (GVHD) was found in 7 patients and acute liver GVHD in 1. One patient with acute intestinal GVHD eventually developed chronic GVHD. One patient died of pulmonary hemorrhage in spite of having a fully functional graft. The authors concluded that this is the first successful application of unrelated BMT for thalassemia major in Chinese people and that the results will certainly expand donor resources and greatly enhance the survival and quality of life of thalassemic patients.

An UpToDate review on “Efficacy of hematopoietic cell transplantation in beta thalassemia major” (Angelucci, 2015) states that “Nonmyeloablative conditioning regimens -- Nonmyeloablative HCT conditioning regimens have the theoretical advantage of obtaining allogeneic engraftment with very low rates of early transplant-related mortality.  However, the delicate balance of immunological effects required to sustain engraftment and to prevent graft rejection requires a prudent approach to the wide use of this regimen, and very few cases have been reported so far.  The limited international experience in thalassemia and sickle cell disease using such regimens has been reviewed showing overall poor results and a markedly reduced rate of sustained engraftment (only 1 of 11 transplants).  A successful trial has been published in a small cohort of 11 adult patients with sickle cell disease conditioned with 300 cGy of total body irradiation and alemtuzumab.  However, this study is not immediately applicable to thalassemia as there are several relevant differences between the two disorders …. ”.

Sickle Cell Anemia:

Sickle cell anemia accounts for 60 to 70 % of sickle cell disease in the United States, affecting 1 out of 600 African-Americans. It afflicts more than 50,000 individuals in this country.

The sickle cell mutation is responsible for increased rigidity and adherence of red blood cells, resulting in the hallmark features of chronic hemolytic anemia as well as both acute and chronic hemolytic anemia and tissue injury. The clinical presentation of patients with homozygous sickle cell disease can vary from an asymptomatic course or relative states of well being with periodic crises to severe and rapid progression to end-stage disease of the brain, kidneys, and lungs. Vaso-occlusive crisis is the commonest form of acute morbidity and the most frequent cause for hospitalization among patients with sickle cell disease. Symptoms vary from mild to excruciating pain, with fever and leukocytosis, and may simulate a life-threatening event or progress to one.

Chronic transfusion is considered standard treatment of severe complications of sickle cell disease. Another approach is the administration of cytotoxic agents such as hydroxyurea (Droxia, Hydrea). Hydroxyurea increases the production of fetal hemoglobin by stimulating erythropoiesis in more primitive erythroid precursors. Although hydroxyurea has been demonstrated to lower the frequency of painful crises, no effect on stroke recurrence has been shown. Chronic transfusion and hydroxyurea are both palliative, while allogeneic bone marrow or peripheral stem cell transplant is currently the only potentially curative therapy.

Mentzer (2000) reported that in patients with hemoglobinopathy who were treated by allogeneic matched sibling bone marrow transplantation before the onset of disease-associated organ damage, long-term, disease-free survival rate was approximately 90 %, and transplant-associated mortality was 5 % or less. This is in agreement with the findings of Walters and colleagues (2000) who monitored 26 children a median 57.9 months following allogeneic stem cell transplant. These patients had survival and event-free survival rates of 94 % and 84 %, respectively. Furthermore, 22 of the 26 patients experienced complete resolution of complications of sickle cell disease, and none experienced further pain episodes, stroke, or acute chest syndrome. The authors concluded that these findings confirm that allogeneic bone marrow transplant establishes normal erythropoiesis and is associated with improved growth and stable central nervous system imaging and pulmonary function in most patients.

Hsieh and colleagues (2009) performed non-myeloablative stem-cell transplantation in adults with sickle cell disease. A total of 10 adults (age range of 16 to 45 years) with severe sickle cell disease underwent non-myeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. Patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. All 10 patients were alive at a median follow-up of 30 months after transplantation (range of 15 to 54 months). Nine patients had long-term, stable donor lympho-hematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/- SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3 +/- 8.6 % and 83.3 +/- 10.3 %, respectively, in the 9 patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0 +/- 0.3 and 12.6 +/- 0.5 g/dL, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. The authors concluded that a protocol for non-myeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype in adult patients.

Sadelain et al (2008) reported that “the beta-thalassemias and sickle cell anemia are severe congenital anemias for which there is presently no curative therapy other than allogeneic bone marrow transplantation.”  The authors further noted, however, that this therapeutic option is only available to patients with an HLA-matched bone marrow donor. Thus, they describe emerging modalities based on cell engineering which offer new options for curative approaches, including transfer of a regulated globin gene in autologous hematopoetic stem cells. However, this strategy raises challenges in controlling transgene expression and several groups have reported that lentiviral vectors encode slightly different combinations of proximal and distal transcriptional control elements of the normal human beta-globin genem, permitting lineage-specific and elevated beta-globin expression in-vivo in animal studies. These advances are encouraging for the future use of curative autologous hematopoietic cell-based therapies.

Sadelain et al (2010) described the initiation of an ongoing multicenter phase I clinical trial designed to evaluate globin gene transfer in adult beta-thalassemia patients. This clinical trial, which is currently underway, uses a reduced intensity conditioning regimen. The investigators' protocol involves transfer of their globin lentiviral vectors in a clinically relevant dosage (averaging 0.8 vector copy per cell in bulk CD34+ cells). The goal of this trial is to use G-CSF mobilized, autologous CD34 (+) cells transduced with a vector similar to the original TNS9 vector.

Hsieh and colleagues (2014) stated that myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults.  Non-myeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and GVHD remain significant.  These investigators determined the safety, effectiveness, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia.  From July 16, 2004, to October 25, 2013, a total of 30 patients aged 16 to 65 years with severe disease enrolled in this non-myeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5 to 31.7 × 10(6) cells/kg) from HLA-matched siblings.  The primary end-point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia.  The secondary end-points were the level of donor leukocyte chimerism; incidence of acute and chronic GVHD; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing.  A total of 29 patients survived a median 3.4 years (range of 1 to 8.6), with no non-relapse mortality.  One patient died from intra-cranial bleeding after relapse.  As of October 25, 2013, 26 patients (87 %) had long-term stable donor engraftment without acute or chronic GVHD.  The mean donor T-cell level was 48 % (95 % confidence interval [CI]: 34 % to 62 %); the myeloid chimerism levels, 86 % (95 % CI: 70 % to 100 %).  Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no GVHD.  The normalized hemoglobin and resolution of hemolysis among engrafted patients were accompanied by stabilization in brain imaging, a reduction of echocardiographic estimates of pulmonary pressure, and allowed for phlebotomy to reduce hepatic iron.  The mean annual hospitalization rate was 3.23 (95 % CI: 1.83 to 4.63) the year before, 0.63 (95 % CI: 0.26 to 1.01) the 1st year after, 0.19 (95 % CI: 0 to 0.45) the 2nd year after, and 0.11 (95 % CI: 0.04 to 0.19) the 3rd year after transplant.  For patients taking long-term narcotics, the mean use per week was 639 mg (95 % CI: 220 to 1,058) of intravenous morphine-equivalent dose the week of their transplants and 140 mg (95 % CI: 56 to 225) 6 months after transplant.  There were 38 serious adverse events: pain and related management, infections, abdominal events, and sirolimus related toxic effects.  The authors concluded that among 30 patients with sickle cell phenotype with or without thalassemia who underwent non-myeloablative allogeneic HSCT, the rate of stable mixed-donor chimerism was high and allowed for complete replacement with circulating donor red blood cells among engrafted participants.  They stated that further accrual and follow-up are needed to assess longer-term clinical outcomes, adverse events, and transplant tolerance.

Furthermore, an UpToDate review on “Hematopoietic cell transplantation in sickle cell disease’ (Khan and Rogers, 2015) states that “Non-myeloablative conditioning remains experimental, and not all transplant centers are prepared to do this type of HCT.  In addition, long-term follow-up of these patients will be required to determine the risks of immunosuppression as well as whether or not immunosuppressive therapy can be safely withdrawn, reduced, or otherwise modified”.

The above policy is based on the following references: