Spontaneous complete remission and recovery of donor haemopoiesis without GVHD after relapse and apparent marrow graft rejection in poor‐prognosis myelodysplastic syndrome

Forty-nine patients with severe aplastic anemia, 33 due to unknown cause, 11 drug or chemical related, 2 associated with hepatitis, 1 with paroxysmal nocturnal hemoglobinuria, and 2 possibly associated with Fanconi syndrome did not show recovery after 0.5–96 (median 2) mo of conventional therapy. Twenty-two were infected and 21 were refractory to random platelet transfusions at the time of admission. All were given marrow grafts from HLA-identical siblings. Forty-five were conditioned for grafting by cyclophosphamide (CY), 50 mg/kg on each of 4 successive days, and four by 1000 rad total body irradiation. All were given intermittent methotrexate therapy within the first 100 days of grafting to modify graft-versus-host disease (GVHD). Three patients died from infection too early to evaluate (days 1–8). Forty-six had marrow engraftment. Of these, 20 are surviving with good peripheral blood counts between 186 and 999 days, and 18 have returned to normal activities. Chronic GCHD is a problem in five. Twelve patients died of infection following rejection of the marrow graft. Twelve patients died with bacterial or fungal infections or interstitial pneumonia and active GVHD or soon following resolution of GVHD. Two patients died with marrow engraftment and no GVHD, one with an interstitial, and the other with a bacterial pneumonia. Thirty-six patients who had received random donor blood transfusions were randomly assigned to receive either CY or procarbazine-antithymocyte globulin-CY as conditioning regimens to test whether the incidence of graft rejection could be decreased. There was no difference in the incidence of graft rejection between the two regimens. In 13 patients with rejection, second transplants were attempted either with the original marrow donor (9 patients) or another HLA-identical sibling (4 patients). Three of these transplants were not evaluable, seven were unsuccessful and three were successful with only one of the three surviving for more than 468 days. In conclusion, the long-term survival of 41% of the patients in the present study is similar to that achieved in our first 24 patients, and confirms the importance of marrow transplantation for the treatment of severe aplastic anemia. Marrow graft rejection, GVHD, and infections continue to be the major causes of failure.

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N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome

Blood ◽

10.1182/blood.v82.2.590.bloodjournal822590 ◽

1993 ◽

Vol 82 (2) ◽

pp. 590-599 ◽

Cited By ~ 1

Author(s):

RL Paquette ◽

EM Landaw ◽

RV Pierre ◽

J Kahan ◽

M Lubbert ◽

...

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndrome ◽

Poor Prognosis ◽

Polymerase Chain Reaction Amplification ◽

Myelogenous Leukemia ◽

Survival Period ◽

Ras Mutation ◽

Ras Mutations ◽

Increased Risk ◽

Oligonucleotide Hybridization

To evaluate the clinical significance of N-ras mutations in the myelodysplastic syndrome (MDS) archival bone marrow samples from 252 patients were studied for the presence of N-ras exon I mutations using polymerase chain reaction amplification and differential oligonucleotide hybridization. Subsequently, clinical information about these patients was obtained and analyzed. Of 220 evaluable patients, 20 (9%) had point mutation of N-ras involving codon 12. Individuals with N- ras mutation had a significantly shorter survival period than those who were N-ras negative (P = .02). An increased risk of acute myelogenous leukemia (AML) was also found in patients with N-ras mutations (P = .005). N-ras mutations were not associated with any French-American- British (FAB) subtype, with the presence of increased myeloblasts, or with chromosomal aberrations in the bone marrow. However, the presence of increased bone marrow blasts was strongly associated with poor survival rate and risk of AML (P < .001 for each). After stratifying for the percentage of blasts, N-ras mutations remained significantly associated with shorter survival period (P = .04) and increased risk of AML (P = .02). Bone marrow cytogenetic abnormalities, particularly when multiple abnormalities were present, were significantly associated with a poor prognosis (P < .001). In conclusion, N-ras mutation, although relatively infrequent in MDS, is associated with short survival period and increased probability of developing AML.

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Multiple Isolated Extramedullary Relapse and Long-term Survival of One AML Patient

10.21203/rs.3.rs-48876/v1 ◽

2020 ◽

Author(s):

Jiman Li ◽

Yang Liu ◽

Yunzhu Li ◽

liu weiping

Keyword(s):

Complete Remission ◽

Poor Prognosis ◽

Unusual Case ◽

Granulocytic Sarcoma ◽

Accurate Diagnosis ◽

Physical Damage ◽

Term Survival ◽

Case Presentation ◽

Extramedullary Relapse

Abstract Background: Granulocytic sarcomas (GS) are very rare. If it occurs after complete remission of acute myeloblastic leukemia（AML）, it indicates a recurrence of AML and a poor prognosis. In such cases, relapse of leukemia occurs within a mean of 10 months following granulocytic sarcoma.Case presentation: Here we present an unusual case of 78-year-old male who presented with AML-M1 38 years ago. After complete remission from AML-M1 6 years later, he developed unusual multiple isolated extramedullary relapses. And the extramedullary relapse occurred 7 times and involved 8 anatomic sites during 15 years. Despite repeated relapses, treatment and physical damage, the patient managed to survive into 2016.However, we did not detect any signs of leukemia after 1992 and his bone marrow and peripheral blood remained normal Until his death. Immunohistochemical results of our case are all the same, suggesting that they were all derived from the recurrence of the same tumor.Conclusions: Extramedullary relapses may occur in AML patients after complete relieve and without the blood count and BM involvement. Accurate diagnosis of GS is important so the patient could to be treated timely. It is a challenge for the pathologist to make the diagnosis, and without immunohistochemistry (IHC), it may be misdiagnosed as another tumor.

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Ultraviolet irradiation of blood prevents transfusion-induced sensitization and marrow graft rejection in dogs

Blood ◽

10.1182/blood.v67.2.537.537 ◽

1986 ◽

Vol 67 (2) ◽

pp. 537-539 ◽

Cited By ~ 39

Author(s):

HJ Deeg ◽

J Aprile ◽

TC Graham ◽

FR Appelbaum ◽

R Storb

Keyword(s):

Ultraviolet Irradiation ◽

Graft Rejection ◽

Uv Light ◽

Canine Model ◽

Donor Blood ◽

Histocompatibility Antigens ◽

Marrow Graft ◽

Accessory Cells ◽

In Vitro Exposure

Abstract In a canine model using DLA-identical littermate pairs, we have shown that a regimen of three transfusions of donor blood given 24, 17, and 10 days before transplant uniformly leads to marrow graft rejection, presumably due to sensitization to minor (non-DLA) histocompatibility antigens. Untransfused dogs uniformly achieve sustained engraftment. In the present study, we investigated whether the exposure of blood to ultraviolet (UV) light (220–300 nm) prior to transfusion prevented sensitization of the recipient and allowed for successful marrow engraftment. Ten dogs were each given three pretransplant transfusions from the marrow donor. Each transfusion consisted of 50 mL of whole blood exposed in vitro to UV light for a total of 1.35 J/cm2. All ten dogs achieved engraftment. In contrast, all four dogs that had received sham-exposed transfusions rejected their grafts. In vitro studies revealed that although cell viability was not affected, leukocytes contained in UV-exposed blood were unable to function as stimulator cells in mixed leukocyte cultures or as accessory cells in mitogen- stimulated cultures. These data are consistent with the hypothesis that accessory cells are involved in transfusion-induced sensitization. We conclude that in vitro exposure of blood to UV light before transfusion prevents sensitization and allows for subsequent marrow engraftment.

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Bone marrow graft rejection as a function of antibody-directed natural killer cells.

Journal of Experimental Medicine ◽

10.1084/jem.161.3.563 ◽

1985 ◽

Vol 161 (3) ◽

pp. 563-576 ◽

Cited By ~ 41

Author(s):

J F Warner ◽

G Dennert

Keyword(s):

Bone Marrow ◽

Nk Cells ◽

Natural Killer ◽

Graft Rejection ◽

Transplant Rejection ◽

Conclusive Evidence ◽

Antigenic Determinants ◽

Marrow Graft

There is conclusive evidence that acute bone marrow transplant rejection in lethally irradiated mice is caused by natural killer (NK) cells. The rejection of marrow allografts is exquisitely specific and is controlled by antigenic determinants encoded in or near the H-2 gene complex. The specificity of in vivo marrow graft rejection contrasts with the in vitro specificity pattern of NK cells in cytotoxicity assays. We therefore examined how NK cells cause H-2-specific marrow graft rejection in vivo. Several experimental approaches are presented that suggest that natural antibody, present in responder strains of mice, specifically directs NK cells in an antibody-dependent cytolytic and/or cytostatic reaction, resulting in marrow graft rejection. The following evidence for this mechanism is documented. The ability to reject a marrow graft can be passively transferred by serum from responder to allogeneic nonresponder mice and the specificity of rejection can be mapped within the H-2 region. Serum-induced marrow graft rejection is abrogated following depletion of immunoglobulin, and the serum of responder mice is able to induce a specific antibody-dependent cytotoxic reaction in vitro.

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Differential U2AF1 mutation sites, burden and co-mutation genes can predict prognosis in patients with myelodysplastic syndrome

Scientific Reports ◽

10.1038/s41598-020-74744-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Haiqiong Wang ◽

Yongbo Guo ◽

Zhenkun Dong ◽

Tao Li ◽

Xinsheng Xie ◽

...

Keyword(s):

Survival Rate ◽

Myelodysplastic Syndrome ◽

Gene Mutation ◽

Poor Prognosis ◽

Gene Mutations ◽

Chromosome 8 ◽

Common Mutation ◽

Mutation Load ◽

Mutation Site ◽

Increased Risk

Abstract To investigate the U2AF1 gene mutation site, mutation load and co-mutations genes in patients with myelodysplastic syndrome (MDS) and their effects on prognosis. Gene mutation detection by next-generation sequence and related clinical data of 234 MDS patients were retrospectively collected and analyzed for the relationship between the clinical characteristics, treatment efficacy and prognosis of U2AF1 gene mutation. Among the 234 MDS patients, the U2AF1 gene mutation rate was 21.7% (51 cases), and the median variant allele frequency was 39.5%. Compared with the wild type, the U2AF1 mutant had a higher incidence of chromosome 8 aberration, and was positively correlated with the occurrence of ASXL1, RUNX1, SETBP1 gene mutation, negatively correlated with SF3B1, NPM1 genes mutation (p < 0.05). The most common mutation site of U2AF1 was S34F (32 cases), while U2AF1 Q157P site mutations had a higher incidence of chromosome 7 abnormalities (p = 0.003). The U2AF1 gene mutation more frequently coincided with signal pathway related gene mutations (p = 0.043) with a trend of shortened overall survival. Among patients with U2AF1 gene mutations, those with ASXL1 mutations were prone to develop into acute myeloid leukemia, those with RUNX1 mutations had an increased risk of relapse, and those with TET2 mutations had higher 1-year survival rate. Compared with the patient group of lower mutation load (VAF ≤ 40%), the group with higher mutation load of U2AF1 (VAF > 40%) had a significantly lower 1-year survival rate (46.1% and 80.5%, p = 0.027). The criteria of U2AF1 VAF > 40% is an independent indicator for poor prognosis of MDS patients. VAF > 40% of U2AF1 is an independent factor of short OS in MDS patients. MDS patients with a mutation in the Q157P site of U2AF1 and a higher U2AF1 mutation load suggests poor prognosis, and co-mutated genes in U2AF1 can affect disease progression and prognosis.

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Involvement of Donor T-Cell Cytotoxic Effector Mechanisms in Preventing Allogeneic Marrow Graft Rejection

Blood ◽

10.1182/blood.v92.6.2177 ◽

1998 ◽

Vol 92 (6) ◽

pp. 2177-2181 ◽

Cited By ~ 68

Author(s):

Paul J. Martin ◽

Yoshiki Akatsuka ◽

Michael Hahne ◽

George Sale

Keyword(s):

T Cells ◽

T Cell ◽

Graft Rejection ◽

Fas Ligand ◽

Conditioning Regimen ◽

Marrow Graft ◽

Hematopoietic Stem ◽

Cd8 Cells ◽

Allogeneic Marrow ◽

Cytotoxic Effector

Abstract Donor CD8 cells play a pivotal role in preventing allogeneic marrow graft rejection, possibly by generating cytotoxic effectors needed to eliminate recipient T cells remaining after the pretransplant conditioning regimen or by producing cytokines needed to support the growth and differentiation of hematopoietic stem cells. In the present study, we assessed the role of donor T-cell cytotoxic effector function as a mechanism for eliminating recipient CD8 cells that cause marrow graft rejection in mice. The ability to prevent rejection was minimally affected by the presence of a defect in Fas ligand binding or by the absence of granzyme B but was severely affected by the absence of perforin. Doubly mutant perforin-deficient, Fas ligand-defective CD8 cells were completely unable to prevent rejection. Our results indicate first that recipient CD8 effectors responsible for causing marrow graft rejection are sensitive to cytotoxicity mediated by both perforin- and Fas-ligand-dependent mechanisms, and second that donor T cells must have at least one functional cytotoxic mechanism to prevent allogeneic marrow graft rejection. © 1998 by The American Society of Hematology.

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Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia

Blood ◽

10.1182/blood.v84.3.941.941 ◽

1994 ◽

Vol 84 (3) ◽

pp. 941-949 ◽

Cited By ~ 221

Author(s):

R Storb ◽

R Etzioni ◽

C Anasetti ◽

FR Appelbaum ◽

CD Buckner ◽

...

Keyword(s):

Survival Rate ◽

Aplastic Anemia ◽

Graft Rejection ◽

Antithymocyte Globulin ◽

Chronic Gvhd ◽

Immunosuppressive Agents ◽

Buffy Coat ◽

Marrow Graft ◽

Actuarial Survival ◽

Actuarial Survival Rate

Abstract Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor“s peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

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