Hematopoietic Cell Transplantation for Thalassemia Major and Sickle Cell Anemia

Number: 0626

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hematopoietic cell transplantation for thalassemia major and sickle cell anemia.

1. Medical Necessity

   Aetna considers allogeneic hematopoietic cell transplantation medically necessary for the following:

   1. 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 human leukocyte antigen (HLA)-matched donor.
      
      
   2. 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:
      1. Members have a haploidentical to HLA-matched donor; and
      2. Members with either a history of stroke or at increased risk of stroke or end-organ damage (see Note below).
         
         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.

2. Experimental and Investigational

   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.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
CPT codes covered if selection criteria are met:
38205	Blood-derived hematopoietic cell harvesting for transplantation, per collection; allogeneic
38230	Bone marrow harvesting for transplantation
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
CPT codes not covered for indications listed in CPB:
38206	Blood-derived hematopoietic cell harvesting for transplantation, per collection; autologous
38232	Bone marrow harvesting for transplantation; autologous
38241	Hematopoietic progenitor cell (HPC); autologous transplantation
Other CPT codes related to the CPB:
38206 - 38215	Transplant preparation procedures
86813	HLA typing; A, B, or C, multiple antigens
86817	HLA typing; DR/DQ, multiple antigens
86821 - 86822	HLA typing; lymphocyte culture
86920 - 86923	Compatibility test each unit
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
S2150	Bone marrow or blood-derived stem-cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days pre-and post-transplant care in the global definition
Other HCPCS codes related to the CPB:
J0895	Injection, deferoxamine mesylate, 500 mg
J9000 - J9999	Chemotherapy drugs
Q0083 - Q0085	Chemotherapy administration
ICD-10 codes covered if selection criteria are met:
D56.1	Beta thalassemia
D57.00 - D57.819	Sickle-cell disorders

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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 …. "

Second Hematopoietic Stem Cell Transplant for Thalassemia Major

Korula and colleagues (2018) noted that graft rejection (GR) after allogeneic SCT (allo-SCT) occurs in 10 % to 20 % of patients with β-thalassemia major (TM).  There are limited data on the clinical profile and long-term outcome of patients who have had a GR.  These investigators undertook a retrospective analysis of patients who had a graft failure after allo-SCT for TM at their center.  From October 1991 to June 2016, 55 of 506 patients (11 %) transplanted for TM had a graft failure.  An additional 7 patients with graft failure after allo-SCT done at other centers were referred to these investigators for a second transplant.  The median age was 8 years (range of 1 to 19), and there were 38 males (61.2 %); 32 patients (52.4 %) were primary graft failures (15 with aplasia and 17 with autologous recovery) and 30 (47.6 %) were secondary graft failures (5 with aplasia and 25 with autologous recovery).  On conventional risk stratification 40 patients (64.5 %) were class III; 17 patients (53.12 %) with primary graft failure and 16 (53.3 %) with secondary graft failure did not receive a second transplant; 29 patients (46 %) with GR underwent a second allo-SCT.  With the exception of 1 patient (first allo-SCT with an unrelated cord blood product), the donor for the second transplant was the same as the first transplant.  Conditioning regimen for the second SCT was busulfan-based myeloablative (MAC) in 7 patients (24 %), treosulfan-based MAC in 12 patients (41.3 %), and the remaining received non-MAC regimens in view of pancytopenia and perceived inability to tolerate MAC.  None of the patients conditioned with a treosulfan-based regimen had a GR, although 1 patient died with complications secondary to chronic GVHD.  Of the remaining 17 patients, 10 died after the second GR and 3 of regimen-related toxicity; 4 were alive, of which 1 had recurrent TM and the rest were well and transfusion-independent at 55, 80, and 204 months, respectively, from second transplant (all busulfan-based MAC).  On a uni-variate analysis a non-treosulfan-based conditioning regimen and time from GR to second transplant of less than 1 year was significantly associated with an adverse impact.  However, on a multi-variate analysis only a non-treosulfan-based regimen was associated with a significant adverse impact on event-free survival (EFS) (hazard ratio [HR], 11.5; 95 % CI: 1.13 to 116.4; p = 0.039).  The authors concluded that there had been a significant improvement in clinical outcomes in their experience with the use of a treosulfan-based reduced-toxicity MAC regimen for second allo-SCT for TM.  It would be reasonable, where feasible, to defer the second transplant by a year after the first GR.

Iron Chelation Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Thalassemia Patients

Kupesiz et al (2022) noted that studies on the increased body iron load in patients with thalassemia major have revealed the problems caused by iron overload.  In patients who have undergone HSCT as curative therapy, iron overload continues long after transplantation.  There are few pediatric studies on chelation therapy in the post-ransplant period.  In a retrospective, observational study, these researchers presented the outcomes of patients who received post-transplant oral chelation therapy.  This trial examined the outcomes of pediatric patients with thalassemia major who used oral chelation therapy following allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019.  Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia.  Prior to treatment, mean serum ferritin was 2,166 ± 1,038 ng/ml.  Treatment was initiated at a mean of 12 ± 6.7 months after transplantation and continued for a mean of 15.7 ± 11.5 months.  At treatment discontinuation, the mean serum ferritin was 693 ± 405 ng/ml; and the mean reduction was -1,472.75 ± 1,121.09 ng/ml (p < 0.001 versus post-treatment).  Serum ferritin was below 500 ng/ml in 52 % of the patients at treatment discontinuation.  Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17 % of the patients, while 1 patient developed ototoxicity.  The authors concluded that deferasirox therapy effectively reduced iron overload in the post-transplant period.  These researchers stated that studies examining the effects of early treatment on the graft may aid in establishing guidelines for post-transplant chelation therapy; clear guidelines are needed regarding when to initiate and discontinue treatment.

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 first year after, 0.19 (95 % CI: 0 to 0.45) the second year after, and 0.11 (95 % CI: 0.04 to 0.19) the third 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".

Khemani and colleagues (2019) noted that sickle cell disease (SCD) is an inherited hemoglobinopathy associated with severe morbidity, impaired quality of life (QOL), and pre-mature mortality.  Hematopoietic stem cell transplantation is the only curative treatment available for patients with SCD and has a greater than 90 % EFS when a matched related donor is used.  However, availability of (HLA-identical sibling donors for the SCD population is limited.  The use of HLA-matched unrelated donors or related haplo-identical donors has the potential to expand the donor pool.  These investigators reviewed the current literature on the indications for SCD transplantation, donor options, and the emerging use of gene therapy as a therapeutic option.  Google Scholar and PubMed were searched using the terms SCD, bone marrow transplantation, donor sources, gene therapy, HSCT, and HLA matching.  Additional articles were identified from the bibliographies of retrieved articles.  All articles were reviewed for pertinent information related to SCD and transplantation.  HSCT has the potential to establish donor-derived normal erythropoiesis with stable long-term engraftment, amelioration of symptoms, and stabilization of organ damage.  The majority of HSCT has been performed in children from HLA-identical sibling donors and has resulted in excellent rates of survival.  The use of alternate donors such as HLA-matched unrelated donors and haplo-identical donors has the potential to expand the applicability of HSCT for SCD.  Early results in gene therapy for SCD are encouraging.

Krishnamurti (2020) stated that availability of an HLA-identical sibling donor raises the question, "should young children with SCD, and an available HLA identical sibling donor be considered for hematopoietic cell transplantation (HCT) even before they manifest severe clinical presentations of sickle cell disease (SCD)?"  The overall survival (OS) and EFS following HCT from an HLA identical sibling is excellent in young children, and worsen with increasing age at HCT.  SCD related complications, organ dysfunction, QOL, and risk for pre-mature mortality all worsen with age.  The author concluded that the ethical principles of non-maleficence, beneficence, autonomy and justice all support the consideration of this life, QOL, and organ-saving therapy at a young age.

Ruxolitinib in Graft-Versus-Host Disease Prophylaxis for Pediatric β-Thalassemia Major Patients after Allogeneic Stem Cell Transplantation

In a retrospective, cohort, single-center study, Hong et al (2023) examined the effect of addition of ruxolitinib in graft-versus-host disease (GVHD) prophylaxis on pediatric patients with β-thalassemia major following allo-SCT.  This trial included 49 consecutive β-thalassemia major pediatric patients who underwent HSCT from unrelated or haploidentical donors from February 2018 to October 2022.  All transplantation recipients received cyclosporine A (CsA), mycophenolate mofetil (MMF), and short-term methotrexate (MTX) as GVHD prophylaxis, while 27 of them in the ruxolitinib group had added ruxolitinib oral to GVHD prophylaxis regimen at 2.5 mg twice-daily once successful engraftment after January 2020.  The results showed that the ruxolitinib group had a lower cumulative incidence than the control group regardless of acute GVHD (22.2 % versus 40.9 %; p = 0.153) or chronic GVHD (18.5 % versus 40.9 %; p = 0.072); especially, the incidence of grade III to IV acute GVHD was reported significantly less frequently in ruxolitinib group than that of the control group (0 % versus 27.3 %, p = 0.005).  No significant difference was detected between the 2 groups in Epstein-Barr virus (EBV)/cytomegalovirus (CMV) re-activation and BK virus (BKV) infection (p = 0.703, 1.000, and 0.436, respectively).  A total of 26 patients (96.3 %) in the ruxolitinib group were alive, while 2 patients (9.1 %) in the control group died of intestinal acute GVHD.  The 2-year OS and thalassemia-free survival (TFS) were both 96.296 % in the ruxolitinib group, while both 90.909 % in the control group.  The authors concluded that this study showed that ruxolitinib prophylaxis is a promising option to decrease the incidence of grade III to IV acute GVHD in pediatric patients with β-thalassemia major.  These researchers stated that the findings of this study provided a basis for the analysis of Janus kinase inhibitors (JAK inhibitors) in the prevention and treatment of GVHD and contributed toward alternative transplantation strategies for β-thalassemia major pediatric patients.  They stated that prospective, large-scale trials are needed to verify the safety and effectiveness of ruxolitinib in real-world clinical practice.

The authors stated that this study had several drawbacks.  First, due to the retrospective design of this study, there might be selection bias, although all patients with β-thalassemia major treated at the authors’ center during the specified time and adhered to the inclusion and exclusion criteria were included in this study.  Second, the sample size was small (n = 49), and the study was not designed and powered for searching statistically significant differences.  Third, there was no pharmacokinetic study to determine the minimum best tolerated dose of ruxolitinib in children, which made it difficult to compare these findings directly with other studies; therefore, caution is needed when interpreting these results.  Fourth, since this was a single-center study, the data reflected the long-term experience of using ruxolitinib for GVHD prophylaxis in the authors’ hospital and might differ from that in other regions.

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References