Unrelated Bone Marrow Stem Cell Research Articles

Acute myeloid leukemia developed through myeloproliferative features during immunosuppressive therapy for juvenile idiopathic arthritis.

A 17-year-old male with thrombocytosis and exacerbation of arthralgia during intensified immunosuppressive therapy with tocilizumab, prednisolone, and methotrexate for juvenile idiopathic arthritis (JIA) was referred to our department. Bone marrow examination revealed myelodysplastic syndrome/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U). Peripheral myeloblasts disappeared temporarily after discontinuation of tocilizumab but progressed to acute myeloid leukemia six months after the development of MDS/MPN-U. The patient sustained complete remission after unrelated bone marrow stem cell transplantation, followed by chemotherapy. The arthralgia also improved after chemotherapy. The possibility of developing malignancies during immunosuppressive therapy in patients with JIA should be considered. J. Med. Invest. 71 : 335-339, August, 2024.

Detection of HLA-DRB1*16:35 in a Taiwanese unrelated bone marrow stem cell donor.

One nucleotide substitution in codon 93 of HLA-DRB1*16:02:01:01 results in a novel allele, HLA-DRB1*16:35.

The deduced probable HLA-C*03:187-associated human leukocyte antigen haplotype (A*24:02-B*35:01-C*03:187-DRB1*11:01) revealed in Taiwanese unrelated hematopoietic bone marrow stem cell donors.

Objective:HLA-C*03:187 is a rare frequency allele in the human leukocyte antigen (HLA)-C locus. The purpose of this investigation is to indicate the ethnicity of C*03:187 and its deduced plausible HLA haplotype in association in Taiwanese unrelated bone marrow stem cell donors.Materials and Methods:A DNA sequence-based typing procedure was used to verify the rare frequency allele C*03:187. Employing group-specific primer sets’ polymerase chain reaction was carried out to amplify exons 2 and 3 of HLA-A locus, HLA-B locus, exon 1 to exon 7 of the HLA-C locus, and exon 2 of the HLA-DRB1 locus. The amplified gene products were sequenced employing the BigDye® Terminator Cycle Sequencing Ready Reaction kits in both directions according to the manufacturer's instructions.Results:The DNA sequence of C*03:187 is identical to C*03:03:01:01 from exon 1 to exon 7, except for codon 152 of exon 3 where GAG of C*03:03:01:01 is replaced by GTG in C*03:187. The nucleotide replacement causes one amino acid change to the protein sequence of C*03:03:01:01 at position 152 where glutamic acid (E) is changed to a valine (V) in C*03:187. The deduced plausible HLA haplotype in association with C*03:187 in Taiwanese is as A*24:02-B*35:01-C*03:187-DRB1*11:01.Conclusion:The data on the deduced plausible HLA haplotype in association with the low-frequency C*03:187 allele that we described in this report are valuable for immunogenetics laboratories for reference purposes. In addition, they can be utilized by search coordinators in hematopoietic stem cell transplant programs to determine a strategy for locating compatible donors in unrelated bone marrow donor registries for a patient with this unusual HLA allele.

Deduced probable HLA haplotypes associated with HLA-C*04:82 found by case analysis of Taiwanese individuals

ObjectiveHLA-C*04:82 is a low incidence HLA-C allele. The aim here is to report the ethnicity of C*04:82 and its associated HLA haplotypes among Taiwanese individuals. Materials and MethodsA sequence-based typing method was used to confirm this low incidence allele. Polymerase chain reaction was performed to amplify exons 2 and 3 of the HLA-A, HLA-B, and HLA-C loci and exon 2 of the HLA-DRB1 locus using group-specific primer sets. The amplicons were sequenced in both directions using Terminator Cycle Sequencing Ready Reaction kits and the manufacturer’s protocols. The potential unrelated bone marrow stem cell donors in this study were randomized individuals with Taiwanese ethnicity who participated in the Tzu Chi Bone Marrow Donor Registry. The family members in the family part of the study were volunteer blood donors. ResultsThe DNA sequence of C*04:82 was identical to C*04:01:01:01 in exons 2, 3, and 4. It differed from C*04:01:01:01 in exon 5 where a segment of nucleotides (CTAGCTGTC) was inserted between residues 969 and 970 of C*04:01:01:01. The insertion of these nucleotides caused a 35 amino acid alteration to the protein sequence of C*04:01:01:01. Three probable HLA haplotypes that were associated with C*04:82 among Taiwanese individuals were deduced. Confirmation of the DNA and protein sequences of C*04:82 and its Taiwanese ethnicity were established in this study. ConclusionThe ethnicity of the C*04:82 allele and the deduced probable HLA haplotypes associated with the low-incidence C*04:82 allele are of value for reference purposes for HLA testing laboratories. In addition, they can be used by search coordinators to aid the creation of a strategy for finding compatible stem cell donors for patients who carry this uncommon HLA allele.

Recognition of a novel HLA-A*11 variant, HLA-A*11:196, in a Taiwanese unrelated bone marrow stem cell donor.

One nucleotide substitution at residue 484 of HLA-A*11:01:01:01 results in a novel allele, HLA-A*11:196.

Deduced probable HLA-C*07:359-associated human leukocyte antigen haplotypes found by case analysis of Taiwanese unrelated bone marrow hematopoietic stem cell donors

ObjectivesHLA-C*07:359 is a low-incidence allele in the human leukocyte antigen (HLA)-C locus. The objective of this study is to report the ethnicity and haplotypes of HLA-C*07:359 that were found during an analysis of Taiwanese unrelated bone marrow hematopoietic stem cell donors. Materials and methodsA sequence-based typing method was employed to confirm low-incidence alleles. Polymerase chain reaction was performed to amplify exon 2 and exon 3 of the HLA-A, HLA-B, and HLA-C loci, as well as exon 2 of the HLA-DRB1 locus, using group-specific primer sets. The amplicons were sequenced in both directions using BigDye Terminator Cycle Sequencing Ready Reaction kits, according to the manufacturer's protocols. The potential unrelated bone marrow stem cell donors investigated here are individuals with Taiwanese ethnicity who are participating in the Tzu Chi Bone Marrow Donor Registry. ResultsThe DNA sequence of C*07:359 is identical to that of C*07:02:01:01 in exons 2, 3, and 4 except at residue 862, where the G of C*07:02:01:01 is substituted by the A of C*07:359. The nucleotide exchange leads to an amino acid replacement at codon 264, where the glutamic acid of C*07:02:01:01 is replaced by the lysine of C*07:359. We deduced a probable HLA-B and HLA-C haplotype that is associated with C*07:359 in Taiwanese, namely B*39-C*07:359. ConclusionInformation on the ethnicity of the C*07:359 allele and its deduced probable HLA haplotypes that are associated with the low-incidence C*07:359 allele reported here are of value to HLA testing laboratories for reference purposes. In addition, they can be used by stem cell transplantation donor search coordinators to determine a strategy for finding compatible donors using unrelated bone marrow donor registries when patients carry this uncommon HLA allele.

HLA-B*46:65, a novel HLA-B*46 variant, detected in a Taiwanese unrelated bone marrow stem cell donor.

One nucleotide exchange at residue 550 of the HLA-B*46:65 results in a novel allele, HLA-B*46:65.

An autopsy case that manifested no convincing histological changes of severe renal failure after hematopoietic stem cell transplantation.

A 48-year-old Japanese woman, who had been diagnosed with smoldering adult T-cell leukemia, was admitted to our hospital for hematopoietic stem cell transplantation (HSCT) because of an acute exacerbation of her disease. After myeloablative conditioning procedures, comprising cytarabine with cyclophosphamide and total body irradiation, the HLA-matched unrelated bone marrow stem cells were infused (day 0). Her serum creatinine concentration, having been 0.6mg/dL at baseline, began to increase from day 1 and was 2.3mg/L on day 7. Hemodialysis was required to treat fluid overload and worsening uremia on days 8 and 9. On day 10, she presented with refractory hypotension and died due to multi-organ failure on day 12. Renal pathology at autopsy showed no specific histological changes to which her clinically severe acute kidney injury (AKI) was attributable. This case suggests that post-HSCT AKI is not necessarily accompanied by apparent renal histologic damage, even if it is clinically serious.

Probable HLA haplotypes in association with the uncommon HLA-C*03:36, -C*03:56, and -C*03:86 alleles in a Taiwanese population

ObjectiveHLA-C*03:36, -C*03:56 and -C*03:86 are three human leukocyte antigen type C (HLA-C) locus alleles that are rarely observed in the Taiwanese population. The objective of this study is to report the three plausible deduced HLA haplotypes in association with C*03:36, C*03:56, and C*03:86 in Taiwanese unrelated bone marrow stem cell donors. Materials and MethodsThe sequence-based typing method was used to confirm the low-incidence alleles observed. Polymerase chain reaction was carried out to amplify exons 2 and 3 of the HLA-C locus with group-specific primer sets. Amplicons were sequenced using the BigDye Terminator Cycle Sequencing Ready Reaction Kit in both directions according to the manufacturer's protocol. ResultsWe confirmed the DNA sequences of C*03:36, C*03:56, and C*03:86 and deduced the three plausible HLA haplotypes in association with C*03:36 (A*33:03-B*58:01-C*03:36-DRB1*01:01), C*03:56 (A*02:01-B*48:01-C*03:56-DRB1*12:02), and C*03:86 (A*02-B*35-C*03:86-DRB1*09:01) in unrelated Taiwanese bone marrow stem cell donors. ConclusionThe three uncommon HLA-C haplotypes that we provide here are valuable for HLA tissue-typing laboratories for reference purposes and for stem cell transplantation donor search coordinators to determine the likelihood of finding compatible donors in unrelated bone marrow donor registries for patients bearing these three uncommon HLA-C locus alleles.

Recognition of HLA‐A*24:137 allele in a Taiwanese unrelated bone marrow stem cell donor and the plausible HLA haplotype associated with A*24:137

We detected a rare HLA-A*24:137 allele in an unrelated Taiwanese haematopoietic stem cell donor during a routine SBT (sequence-based typing) HLA typing exercise. The DNA sequence of A*24:137 is identical to the sequence of A*24:02:01:01 in exons 2 and 3 except at codon 21 where CGC was replaced with CAA. The DNA variation caused an amino acid alteration at amino acid residue 21 (R->Q). The HLA haplotype in association with A*24:137 may be deduced as A*24:137-B*15-DRB1*14. The formation of A*24:137 was probably the result of a nucleotide point mutation involving A*24:02:01:01. It remains to be determined whether A*24:137 is restricted to Taiwanese/Chinese ethnicity.

Discovery of the novel HLA‐DRB1*16:16 allele in a Taiwanese unrelated bone marrow stem cell donor by a sequence‐based typing method and the probable haplotype associated with DRB1*16:16

We report here a de novo HLA-DRB1 allele, DRB1*16:16, discovered in a Taiwanese unrelated volunteer bone marrow stem cell donor by a sequence-based typing (SBT) method. In exon 2, the DNA sequence of DRB1*16:16 is identical to the sequence of DRB1*16:02:01 except the nucleotides at positions 258 (C→T), 260 (C→A) and 261 (T→G). The nucleotide substitution produced an amino acid replacement at residue 58 (A→E). The formation of DRB1*16:16 was probably generated by a DNA sequence recombination event involving DRB1*11:01:01 and DRB1*16:02:01. The probable HLA-A, -B and -DRB1 haplotype in association with DRB1*16:16 may be deduced as A*02-B*38-DRB1*16:16.

Gentuzumab Ozogamicin (GO:Mylotarg) Monotherapy for Relapsed AML after Hematopoietic Stem Cell Transplantation: from Morphological Target to Molecular Target.

Background: The treatment for acute myeloid leukemia patients with relapse after stem cell transplantation is limited to dose reduction of immunosuppressive agents, donor leukocyte infusion (DLI), and a second transplantation. The prognosis of such patient is very poor if these therapies cannot be tolerated or are unsuccessful. Gentuzumab ozogamicin(GO) is an antibody targeted chemotherapy consisting of a humanized anti-CD33 monoclonal antibody linked to calicheamycin. The CD33 antigen is expressed on most AML cells and myeloid progenitor cells, but is not expressed on lymphocytes which play an important role in GVL effect. Therefore, GO can potentially eradicate AML cells without harming these lymphocytes.Patients: We retrospectively studied 9 patients with AML, who relapsed following allogeneic stem cell transplantation (SCT) and had difficulty tolerating DLI. Their donor sources included one 6/6 HLA-matched sibling bone marrow cells, four 6/6 HLA-matched unrelated bone marrow stem cells, and four 4/6 HLA-matched unrelated cord blood. The status of leukemia at SCT was 1st complete remission (CR) in one patient, 2nd CR in one patient, and active disease in seven patients. Treatment protocol: GO was administered at 6 mg/m2 for 2 doses separated by 2 weeks. Treatment was initially performed at morphological relapse but after April 2006 patients received treatment at molecular relapse. The molecular relapse was diagnosed by the quantitative expression of WT1 (Wilms tumor gene). (Blood. 2003; 101:1698–1704)Results: Five patients were treated at morphological relapse (group A) and four patients were treated at molecular relapse (group B). Eight received both doses of GO. The period from SCT to relapse ranged from 36 days to 193 days (median: 85 days). The period from SCT to GO administration ranged from 54 days to 229 days (median: 98 days). Seven of 9 patients achieved a remission (3/5 in group A, 4/4 in group B). Three CR patients in group A relapsed (day 48, 95, and 106, respectively). All of the patients in group A died within 447 days. (at 42 days, 131 days, 158 days, 173 days and 447 days, respectively, after GO). Two of the 4 patients in group B relapsed, one on day 300 and one on day 350. One patient died in CR from multiple organ failure following CMV infection; the fourth patient is still in CR. Three patients in group B are alive at 276 days, 410 days, and 443 days. Three patients developed infusion-related fever, one patients nausea. All patients developed grade 4 neutropenia and thrombocytopenia. Febrile neutropenia was observed in four patients. Five patients developed elevation of ALT, grade 3 in 1 patient and grade 1 in 4 patients. Three patients developed grade 1 hyperbilirubinemia. Only one patient developed reversible VOD. VOD occurred on thirteenth day after the administration of GO. The period between SCT and GO administration was 77 days.Conclusion: The administration of GO is effective in inducing remission in relapsed AML patients after SCT. The ability of GO therapy to induce durable response may possibly be enhanced by early therapeutic intervention before the onset of hematologic relapse. This approach is feasible and well tolerated with minimal toxicity. Additional studies in a large group of patients will be required to adequately assess the safety and efficacy of this approach.