| MP 8.01.21 | Allogeneic Stem-Cell Transplantation for Myelodysplastic Syndromes and Myeloproliferative Neoplasms | |
| Medical Policy | ||
| Section Therapy |
Original Policy Date 12/1/99 |
Last Review Status/Date Reviewed with literature search/6:2009 |
| Issue 6:2009 |
Return to Medical Policy Index |
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Description
Hematopoietic Stem Cell Transplantation
Hematopoietic stem-cell transplantation (SCT) refers to a procedure in which hematopoietic stem cells are infused to restore bone marrow function in cancer patients who receive bone marrow toxic doses of cytotoxic drugs with or without whole body radiation therapy. Allogeneic SCT refers to the use of hematopoietic progenitor cells obtained from a donor. They can be harvested from bone marrow, peripheral blood, or umbilical cord blood and placenta shortly after delivery of neonates. Although cord blood is an allogeneic source, the stem cells in it are antigenically “naïve” and thus are associated with a lower incidence of rejection or graft vs. host disease. Cord blood is discussed in greater detail in policy No. 7.01.50.
Myelodysplastic syndromes (MDS) refer to a heterogeneous group of clonal hematopoietic disorders characterized by impaired maturation of hematopoietic cells and a tendency to transform into acute myelocytic leukemia (AML). MDS can occur as a primary (idiopathic) disease, or be secondary to cytotoxic therapy, ionizing radiation, or other environmental insult. Chromosomal abnormalities are seen in 40%–60% of patients, frequently involving deletions of chromosome 5 or 7, or an extra chromosome as in trisomy 8. Signs and symptoms of anemia, often complicated by infections or bleeding, are common in MDS; some patients exhibit systemic symptoms or features of autoimmunity that may be indicative of their disease pathogenesis. The vast majority of MDS diagnoses occur in individuals over the age of 55–60 years, with an age-adjusted incidence of about 62% among individuals over age 70 years. Patients either succumb to disease progression to AML or to complications of pancytopenias. Patients with higher blast counts or complex cytogenetic abnormalities have a greater likelihood of progressing to AML than do other patients.
For the past 20 years, the French-American-British (FAB) system has been used to classify MDS into 5 subtypes as follows: 1) refractory anemia (RA); 2) refractory anemia with ringed sideroblasts (RARS); 3) refractory anemia with excess blasts (RAEB); 4) refractory anemia with excess blasts in transformation (RAEBT); and, 5) chronic myelomonocytic leukemia (CMML). However, the FAB system has been supplanted by that of the World Health Organization (WHO), which records the number of lineages in which dysplasia is seen (unilineage versus multilineage), separates the 5q- syndrome, and reduces the threshold maximum blast percentage for the diagnosis of MDS from 30% to 20% (see Policy Guidelines for WHO classification scheme for myeloid neoplasms). Several prognostic scoring systems for MDS have been proposed; the most commonly used is the International Prognostic Scoring System (IPSS). The IPSS groups patients into one of four prognostic categories based on the number of cytopenias, cytogenetic profile and the percentage blasts in the bone marrow (see Policy Guidelines). This system underweights the clinical importance of severe, life-threatening neutropenia and thrombocytopenia in therapeutic decisions and does not account for the rate of change in critical parameters, such as peripheral blood counts or blast percentage. However, the IPSS has been useful in comparative analysis of clinical trial results and its utility confirmed at many institutions. A second prognostic scoring system incorporates the WHO subgroup classification that accounts for blast percentage, cytogenetics, and severity of cytopenias as assessed by transfusion requirements. The WPSS uses a 6-categorysystem which allows more precise prognostication of overall survival duration as well as risk for progression to AML. This system, however, is not yet in widespread use in clinical trials. Treatment of smoldering or nonprogressing MDS has in the past involved best supportive care including red blood cell (RBC) and platelet transfusions and antibiotics. Active therapy was given only when MDS progressed to AML or resembled AML with severe cytopenias. A diverse array of therapies are now available to treat MDS, including hematopoietic growth factors (e.g., erythropoietin, darbepoetin, granulocyte colony-stimulating factor), transcriptional-modifying therapy (e.g., U.S. Food and Drug Administration-approved hypomethylating agents, nonapproved histone deacetylase inhibitors), immunomodulators (e.g., lenalidomide, thalidomide, antithymocyte globuliln, cyclosporine A), low-dose chemotherapy (e.g., cytarabine), and allogeneic HSCT. Given the spectrum of treatments available, the goal of therapy must be decided upfront, whether it is to improve anemia, thrombocytopenia, or neutropenia; eliminate the need for RBC transfusion; achieve complete remission (CR); or, cure the disease. Allogeneic HSCT is the only approach with curative potential, but its use is governed by patient age, performance status, medical comorbidities, the patient’s risk preference, and severity of MDS at presentation. Chronic Myeloproliferative Neoplasms In 2008, a new WHO classification scheme replaced the term chronic myeloproliferative disorder (CMPD) with the term myeloproliferative neoplasms (MPN). These are a subdivision of myeloid neoplasms that includes the four classic disorders chronic myeloid leukemia (CML), polycythemia vera (PCV), essential thrombocytopenia (ET), and primary myelofibrosis (PMF); the WHO classification also includes chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), mast cell disease (MCD), and MPNs unclassifiable (see Policy Guidelines). The MPNs are characterized by the slow but relentless expansion of a clone of cells with the potential evolution into a blast crisis similar to AML. They share a common stem cell-derived clonal heritage, with phenotypic diversity attributed to abnormal variations in signal transduction as the result of a spectrum of mutations that affect protein tyrosine kinases or related molecules. The unifying characteristic common to all MPNs is effective clonal myeloproliferation resulting in peripheral granulocytosis, thrombocytosis, or erythrocytosis that is devoid of dyserythropoiesis, granulocytic dysplasia, or monocytosis.As a group, about 8,400 MPNs are diagnosed annually in the U.S. Like MDS, MPNs occur primarily in older individuals, with about 67% reported in patients aged 60 years and older. In indolent, nonprogressing cases, therapeutic approaches are based on relief of symptoms. Myeloablative allogeneic HSCT has been considered the only potentially curative therapy, but because most patients are of advanced age with attendant comorbidities, its use is limited to those who can tolerate the often severe treatment-related adverse effects of this procedure. However, the use RIC of conditioning regimens for allogeneic HSCT has extended the potential benefits of this procedure to selected individuals with these disorders.
Chronic myeloid leukemia is considered separately in policy No. 8.01.30Policy
Allogeneic HSCT may be considered medically necessary as a treatment of
-
myelodysplastic syndromes (see Policy Guidelines) or
-
myeloproliferative neoplasms (see Policy Guidelines). .
Reduced-intensity conditioning allogeneic HSCT may be considered medically necessary as a treatment of
-
myelodysplastic syndromes or
-
myeloproliferative neoplasms
in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen. (see Policy Guidelines)
2008 WHO Classification Scheme for Myeloid Neoplasms
1. Acute myeloid leukemia
2. Myelodysplastic syndromes (MDS)
3. Myeloproliferative neoplasms (MPN)3.1 Chronic myelogenous leukemia
3.2 Polycythemia vera
3.3 Essential thrombocythemia
3.4 Primary myelofibrosis
3.5 Chronic neutrophilic leukemia
3.6 Chronic eosinophilic leukemia, not otherwise categorized
3.7 Hypereosinophilic leukemia
3.8 Mast cell disease
3.9 MPNs, unclassifiable4. MDS/MPN
4.1 Chronic myelomonocytic leukemia
4.2 Juvenile myelomonocytic leukemia
4.3 Atypical chronic myeloid leukemia
4.4 MDS/MPN, unclassifiable5. Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
5.1 Myeloid neoplasms associate with PDGFRA rearrangement
5.2 Myeloid neoplasms associate with PDGFRB rearrangement
5.3 Myeloid neoplasms associate with FGFR1 rearrangement
(8p11 myeloproliferative syndrome)
2008 WHO Classification of MDS
1. Refractory anemia (RA)
2. RA with ring sideroblasts (RARS)
3. Refractory cytopenia with multilineage dysplasia (RCMD)
4. RCMD with ring sideroblasts
5. RA with excess blasts 1 and 2 (RAEB 1 and 2)
6. del 5q syndrome
7. unclassified MDS
Risk Stratification of MDS
Risk stratification for MDS is performed using the IPSS. This system was developed after pooling data from 7 previous studies that used independent, risk-based prognostic factors. The prognostic model and the scoring system were built based on blast count, degree of cytopenia, and blast percentage. Risk scores were weighted relative to their statistical power. This system is widely used to divide patients into two categories: (1) low risk and (2) high-risk groups. The low-risk group includes low risk and Int-1 IPSS groups; the goals in low-risk MDS patients are to improve quality of life and achieve transfusion independence. In the high-risk group — which includes Int-2 and high-risk IPSS groups — the goals are slowing the progression of disease to AML and improving survival. The IPSS is usually calculated on diagnosis. The role of lactate dehydrogenase, marrow fibrosis, and beta 2-microglobulin also should be considered after establishing the IPSS. If elevated, the prognostic category becomes worse by one category change.
IPSS: MDS Prognostic Variables
| Variable |
0 |
0.5 |
1.0 |
1.5 |
2.0 |
| Marrow blasts (5) |
<5 |
5-10 |
- |
11-20 |
21-30 |
| Karyotype |
Good |
Intermediate |
Poor |
|
|
| Cytopenias |
0/1 |
2/3 |
- |
- |
- |
IPSS: MDS Clinical Outcomes
| Risk Group |
Total score |
Medican survival, yrs |
Time for 25% to progress to AML, years |
| Low |
0 |
5.7 |
9.4 |
| Intermediate-1 |
0.5-1.0 |
3.5 |
3.3 |
| Intermediate-2 |
1.5-2.0 |
1.2 |
1.12 |
| High |
2.5 or more |
0.4 |
0.2 |
Given the long natural history of MDS, allogeneic HSCT is typically considered in those with increasing numbers of blasts, signaling a possible transformation to acute myeloid leukemia. Subtypes falling into this category include refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or chronic myelomonocytic leukemia.
Patients with refractory anemia with or without ringed sideroblasts may be considered candidates for allogeneic HSCT when chromosomal abnormalities are present or the disorder is associated with the development of significant cytopenias (e.g., neutrophils less 500/mm3, platelets less than 20,000/mm3). Patients with MPNs may be considered candidates for allogeneic HSCT when there is progression to myelofibrosis, or when there is evolution toward acute leukemia. In addition, allogeneic HSCT may be considered in patients with essential thrombocythemia with an associated thrombotic or hemorrhagic disorder. There are no suitable U.S. Food and Drug Administration (FDA) -approved therapies for these patients, only supportive care. The use of allogeneic HSCT should be based on cytopenias, transfusion dependence, increasing blast percentage over 5%, and age. Some patients for whom a conventional myeloablative allotransplant could be curative may be considered candidates for RIC allogeneic HSCT. These include those patients whose age (typically older than 60 years) or comorbidities (e.g., liver or kidney dysfunction, generalized debilitation, prior intensive chemotherapy, low Karnofsky Performance Status) preclude use of a standard myeloablative conditioning regimen. The ideal allogeneic donors are HLA-identical siblings, matched at the HLA-A, B, and DR loci (6 of 6). Related donors mismatched at one locus are also considered suitable donors. A matched, unrelated donor (MUD) identified through the National Marrow Donor Registry is typically the next option considered. Recently, there has been interest in haploidentical donors, typically a parent or a child of the patient, where usually there is sharing of only 3 of the 6 major histocompatibility antigens. The majority of patients will have such a donor; however, the risk of GVHD and overall morbidity of the procedure may be severe, and experience with these donors is not as extensive as that with matched donors. Clinical input suggests RIC allogeneic HSCT may be considered for patients as follows: MDS-
IPSS intermediate-2 or high risk
-
RBC transfusion dependence
-
Neutropenia
-
Thrombocytopenia
-
High risk cytogenetics
-
Increasing blast percentage
MPN
-
Cytopenias
-
Transfusion dependence
-
Increasing blast percentage over 5%
-
Age 60-65 years
Benefit Application
BlueCard/National Account Issues
No applicable information.
Rationale
Myelodysplastic Syndrome (MDS)
Despite the successes seen with new drugs now available to treat MDS (e.g., decitabine, azacitadine, lenalidomide), allogeneic HSCT is the only treatment capable of complete and permanent eradication of the MDS clone. (1) A recent review of allogeneic HSCT using myeloablative conditioning for MDS included 24 studies (prospective and retrospective) published between 2000 and 2008 that included a total 1,378 cases with age range of 32–59 years. (2) A majority of patients (n = 885) received MRD allogeneic HSCT, with other donor types including syngeneic, MUD, mismatched URD, and umbilical cord blood. Most studies included de novo and secondary MDS, chronic myelomonocytic leukemia, MPNs, de novo and secondary AML and transformed AML. Peripheral blood and bone marrow stem-cell grafts were allowed in most studies. The most commonly used conditioning regimens were busulfan plus cyclophosphamide (BU/CY) and CY plus total body irradiation (CY/TBI), with cyclosporine A (CYA) used for GVHD prophylaxis. Length of follow-up ranged from 5 months to about 8 years. Grades II-IV acute GVHD varied from 18% to 100%. Relapse risk ranged from a low of 24% at 1 year to 36% at 5 years.
Overall survival ranged from 25% at 2 years to 52% at 4 years, with NRM ranging from 19% at day 100 to 61% at 5 years.
A growing body of evidence from more than 30 largely heterogeneous uncontrolled studies of RIC with allogeneic HSCT shows long-term remissions (i.e., longer than 4 years) can be achieved, often with reduced treatment-related morbidity and mortality, in patients with MDS/AML who otherwise would not be candidates for myeloablative conditioning regimens. (2-13) These prospective and retrospective studies included cohorts of 16–215 patients similar to those in the myeloablative allogeneic HSCT studies. The most common conditioning regimens used were fludarabine based, with CYA and tacrolimus used for GVHD prophylaxis. The reported incidence of grades II–IV GVHD was 9-63%, with relapse risk of 6–61%. The OS rates ranged between 44% at 1 year to 46% at 5 years, with a median follow-up range of 14 months to over 4 years. In general, these RIC trials showed a low rate of engraftment failure and low NRM, but at the cost of a higher relapse rate than with myeloablative allogeneic HSCT. However, in the absence of prospective, comparative, randomized trials, only indirect comparisons can be made between the relative clinical benefits and harms associated with myeloablative and RIC regimens with allogeneic HSCT. Furthermore, no randomized trials have been published in which RIC with allogeneic HSCT has been compared with conventional chemotherapy alone, which has been the standard of care in patients with MDS/AML for whom myeloablative chemotherapy and allogeneic HSCT are contraindicated. Nonetheless, given the absence of curative therapies for these patients, coupled with clinical input (see below) RIC allogeneic HSCT may be considered medically necessary for patients with MDS who could benefit from allogeneic HSCT but who for medical reasons (see Policy Guidelines) would be unable to tolerate a myeloablative conditioning regimen. Myeloproliferative Neoplasms (MPN) Data on therapy for MPN remain sparse. (12) As outlined previously in this policy, with the exception of myeloablative chemotherapy and allogeneic HSCT, no therapy has yet been proven to be curative or to prolong survival of patients with MPN. However, the significant toxicity of myeloablative conditioning and allogeneic HSCT in MPN has led to study of the use of RIC regimens for these diseases. A recent series included 27 patients (mean age: 59 years) with MPN who underwent allogeneic HSCT using a RIC regimen of low-dose (2 Gy) total body irradiation alone or with the addition of fludarabine. (17) At a median follow-up of 47 months, the 3-year relapse-free survival was 37% and overall survival was 43%, with a 3-year nonrelapse mortality of 32%. Data from direct comparison of outcomes of myeloablative conditioning and allogeneic HSCT versus RIC and allogeneic stem-cell support in MPN are not available. However, the absence of curative therapies coupled with clinical input permit the conclusion that allogeneic HSCT using either a myeloablative or RIC conditioning regimen is medically necessary in appropriately selected patients 2009 National Comprehensive Cancer Network Guidelines The 2009 National Comprehensive Cancer Network treatment guidelines (v.1.2009) for the use of allogeneic HSCT indicate this procedure is preferred in patients with high-risk disease. RIC conditioning prior to use of MRD or MUD cells are becoming an option at some centers. However, the timing of HSCT relative to remission induction using chemotherapy is unsettled. National Cancer Institute (NCI) Clinical Trials Database A search of the NCI clinical trials database in May 2009 identified 16 active phase III trials that involve stem-cell support for patients with MDS/AML or MPN. Numerous phase II trials of various treatments for these diseases are actively recruiting patients. Information on these trials can be accessed via the following link (http://www.cancer.gov/search/ResultsClinicalTrials.aspx?protocolsearchid=6164128). Physician Specialty Society and Academic Medical Center Input In response to requests, input was received from 2 Academic Medical Center specialists prior to review for May 2009. While the various Physician Specialty Societies and Academic Medical Centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the Physician Specialty Societies or Academic Medical Centers, unless otherwise noted. There was consensus among reviewers that RIC allogeneic HSCT was of value in patients with MDS or MPN who would be medically unable to tolerate a myeloablative HSCT.
References:
- Kasner MT, Luger SM. Update on therapy for myelodysplastic syndrome. Am J Hematol 2008; 84(3):177-86.
- Kindwall-Keller T, Isola LM. The evolution of hematopoietic SCT in myelodysplastic syndrome. Bone Marrow Transplant 2009; 43(8):597-609.
- Deschler B, de Witte T, Mertelsmann R et al. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006; 91(11):1513-22.
- Kroger N, Bornhauser M, Ehninger G et al. Allogeneic stem cell transplantation after a
fludarabine/busulfan based reduced intensity conditioning inpatients with myelodysplastic syndromes or secondary acute myeloid leukemia. Ann Hematol 2003; 82(6):336-42. - Martino R, Caballero R, Simon JA et al. Evidence for a graft-versus-leukemia effect after allogeneic
peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100(6):2243-5. - Tauro S, Craddock C, Peggs K et al. Allogeneic stem-cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23(36):9387-93.
- Blaise D, Vey N, Faucher C et al. Current status of reduced intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica 2007; 92(4):533-41.
- Barrett AJ, Savani BN. Allogeneic stem cell transplantation for myelodysplastic syndrome. Semin Hematol 2008; 45(1):49-59.
- Huisman C, Meijer E, Petersen EJ et al. Hematopoietic stem cell transplantation after reduced intensity conditioning in acute myelogenous leukemia patients older than 40 years. Biol Blood Marrow Transplant 2008; 14(2):181-6.
- Valcarcel D, Martino R. Reduced intensity conditioning for allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and acute myelogenous leukemia. Current Opin Oncol 2007; 19(6):660-6.
- Valcarcel D, Martino R, Caballero D et al. Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26(4):577-84.
- Mesa RA. Navigating the evolving paradigms in the diagnosis and treatment of myeloproliferative disorders. Hematology (Am Soc Hematol Educ Program) 2007; 2007:355-62.
- Laport GG, Sandmaier BM, Storer BE et al. Reduced-intensity conditioning followed by allogeneic hematopoietic cell transplantation for adult patients with myelodysplastic syndrome and myeloproliferative disorders. Biol Blood Marrow Transplant 2008; 14(2):246-55.
- Myelodysplastic Syndromes. National Comprehensive Cancer Network Clinical Practice Guidelines
in Oncology. v.1.2009; http://www.nccn.org/professionals/physician_gls/PDF/mds.pdf.
|
Codes |
Number |
Description |
| CPT | 38204 | Management of recipient hematopoietic cell donor search and cell acquisition |
| 38205 | Blood-derived hematopoietic progenitor cell harvesting for transplantation, per collection, allogeneic | |
| 38208 | Transplant preparation of hematopoietic progenitor cells; thawing of previously frozen harvest | |
| 38209 | ;thawing of previously frozen harvest with washing | |
| 38210 | ;specific cell depletion with harvest,T cell depletion | |
| 38211 |
;tumor cell depletion |
|
| 38212 | ;red blood cell removal | |
| 38213 | ;platelet depletion | |
| 38214 | ;plasma (colume) depletion | |
| 38215 | ;cell concentration in plasma, mononuclear, or buffy coat layer | |
| 38230 | Bone marrow harvesting for transplantation | |
| 38240 | Bone marrow or blood-derived peripheral stem-cell transplantation: allogeneic | |
| 86812, 86813, 86816, 86817, 86821, 86822 | Histocompatibility studies code range (e.g., for allogeneic transplant) |
|
| ICD-9 Procedure | 41.02 | Allogeneic bone marrow transplant with purging |
| 41.03 | Allogeneic bone marrow transplant without purging | |
| 41.05 | Allogeneic hematopoietic stem-cell transplant | |
| 41.08 | Allogeneic hematopoietic stem-cell transplant with purging | |
| 41.91 | Aspiration of bone marrow from donor for transplant | |
| 99.79 | Other therapeutic apheresis (includes harvest of stem cells) | |
| ICD-9 Diagnosis | 238.7-238.79 | Myelofibrosis or myelodysplastic syndrome, code range (myeloproliferative syndrome is included in 238.79) |
| HCPCS | S2150 | Bone marrow or blood-derived peripheral stem-cell harvesting and transplantation, allogeneic or autologous, including pheresis, high-dose chemotherapy, and the number of days of post-transplant care in the global definition (including drugs; hospitalization; medical surgical, diagnostic and emergency services) |
| Type of Service | Therapy | |
| Place of Service | Inpatient/Outpatient | |
Index
High-dose Chemotherapy, Myeloproliferative Syndrome
Myelodysplastic Syndrome, High-dose Chemotherapy
Myelofibrosis
Stem-Cell Transplant, Myelodysplastic Diseases
Policy History
|
Date |
Action |
Reason |
|
12/01/99 |
Add to Therapy section |
New policy; policy represents revision of policy No.7.03.10 to focus on myelodysplasia and myelofibrosis. New policy statement on high-dose chemotherapy for myelofibrosis |
|
07/12/02 |
Replace policy |
Policy updated without literature review; new review date only |
|
04/16/04 |
Replace policy |
Policy updated with literature review; policy statement also includes mini-transplant. References added, cross-referenced to policy No. 8.01.38 on mini-transplants |
|
4/1/05 |
Replace policy |
Policy updated with literature review; no change in policy statement. No further scheduled review |
| 04/17/07 | Replace policy | Policy updated with literature review. References 6 and 9–11 added. No change in policy statement; policy scheduled for annual review. Code table updated. |
| 05/08/08 | Replace policy | Policy updated with literature review; reference 11 updated; references 12-18 added. No change in policy statements. “Myeloproliferative” Diseases added to policy title. |
| 06/12/08 | Replace policy | Policy updated with literature review; reference 11 updated; references 12-18 added. Minor terminology changes to policy statements; however, the intent of the policy statements remains unchanged. “Myeloproliferative” Diseases added to policy title’ “High-Dose Chemotherapy” removed from title. |
| 06/11/09 | Replace policy | Policy completely rewritten with literature review and input from external clinical vetting. References 1 and 2 added, outdated references deleted. Term “Myeloproliferative Disorders” replaced with “Myeloproliferative Neoplasms” in title and text. Policy statements revised to indicate that RIC HSCT may be considered medically necessary as a treatment of myelodysplastic syndrome and myeloproliferative neoplasms in patients who for medical reasons would be unable to tolerate a myeloablative conditioning regimen. |
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