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J M Hows

Publications and source records attributed to J M Hows.

At least 73 records · Page 4Linked to original sources
PubMed1990

Induction of in vitro graft-versus-leukemia activity following bone marrow transplantation for chronic myeloid leukemia.

We studied the in vitro effects of lymphokine-activated killer (LAK) cells from the peripheral blood of chronic myeloid leukemia (CML) patients after allogeneic and syngeneic bone marrow transplantation (BMT). LAK cells were generated by incubating peripheral blood mononuclear cells from patients post-BMT with recombinant interleukin-2 (IL-2) (500 U/mL) in 10% AB serum for 7 days. They were phenotyped and tested for activity in a standard 4-hour 51Cr release assay (n = 37) and in a CFU-GM assay (n = 24). We found that the LAK cells were mainly activated natural killer cells, but some were CD3+ T cells. In the 51Cr release assay LAK cells from 20 of 33 (61%) allogeneic and 2 of 4 syngeneic recipients killed recipient CML cells and in 22 of 37 (60%) cases also killed the HLA disparate CML cells. In the CFU-GM assay the LAK cells incubated together with the CML cells in liquid culture before plating inhibited (P less than .05) colony growth in 16 of 22 allogeneic and 2 of 2 syngeneic recipients. Cell-cell contact was necessary for optimal effect. There was little or no inhibition of proliferation of donor marrow CFU-GM. This in vitro graft-versus-leukemia (GVL) effect could also be demonstrated after LAK effectors were depleted of CD3+ T cells. It was inducible in recipients of both T cell-depleted and T cell-replete donor marrow and in recipients with or without graft-versus-host disease. These results suggest that a major histocompatibility complex-unrestricted GVL effect is inducible following allogeneic and syngeneic BMT. The use of IL-2/LAK cells after BMT could reduce the risk of relapse.

Antigens, Surface↗
PubMed1990

The hematopoietic defect in aplastic anemia assessed by long-term marrow culture.

Thirty-two patients with aplastic anemia (AA) have been studied using the long-term bone marrow culture (LTBMC) system. Of these patients, 26 had been treated with immunosuppressive therapy including antilymphocyte globulin (ALG) with or without androgens or high-dose methyl prednisolone. The remaining six patients either required no treatment or were studied before therapy was begun. Thirty-one of 32 patients (96%) had defective hematopoiesis in LTBMC with little or no evidence for the generation of primitive progenitor cells. The only exception was a patient with spontaneous recovery of aplasia in whom the defect was less marked. Crossover LTBMC experiments were performed in 23 cases by inoculating (1) patient marrow hematopoietic cells that had been depleted of adherent cells onto preformed, irradiated, normal stromas to assess the proliferative capacity of the hematopoietic cells, and (2) normal marrow hematopoietic cells that were depleted of adherent cells onto preformed, irradiated stromas from patients with AA to assess stromal function. Results of these experiments demonstrated a hematopoietic defect in all patients that was independent of the degree of hematologic recovery after ALG therapy. Only one patient had a probable stromal defect and this coexisted with a defect in the regenerative capacity of hematopoietic cells. We conclude that LTBMC is a sensitive method for detecting and defining the hematopoietic failure in AA. We suggest that the defective hematopoiesis present in all patients studied may be important in the pathogenesis of clonal evolution in AA.

Adolescent↗
PubMed1990

Therapy for chronic myelogenous leukemia with unrelated donor bone marrow transplantation: results in 102 cases.

From April, 1985, to February, 1989, 102 consecutive patients received unrelated donor bone marrow transplantation therapy for chronic myelogenous leukemia (CML) at four centers. Median age of the group was 31 years (range, 4.5 to 51 years). Fifty-four patients were in first chronic phase (CP) at time of transplantation, and 48 had evidence of more advanced disease (AD) (accelerated phase, 32; blast crisis, 9; second CP, 7). In 44 cases, the donor and recipient were identical at the HLA A, B, and DR loci and were nonreactive in bidirectional mixed leukocyte culture (MLC) ("matched"). In 58 cases, nonidentity between donor and recipient could be determined at at least one HLA locus or in bidirectional MLC ("mismatched"). Fifty-eight patients were prepared for transplantation with a combination of cyclophosphamide and fractionated total body irradiation (FTBI) and received acute graft-versus-host disease (GVHD) prophylaxis consisting of methotrexate alone or in combination with cyclosporine, prednisone, or antithymocyte globulin (ATG). In 44 cases, patients received preparative agents in addition to cyclophosphamide and FTBI, and marrow depleted of mature T lymphocytes by ex vivo incubation with either anti-CD3 antibody plus complement (n = 24) or Campath-1 (n = 20). Engraftment defined by a peripheral blood neutrophil count greater than 0.5 X 10(9)/L was demonstrated in 92 cases and occurred at a median of 22 days (range, 11 to 46 days). In 10 cases, peripheral blood evidence of engraftment did not occur, and in one case, engraftment was followed by aplasia. Hematologic relapse was seen in four cases. Recurrence or persistence of the Ph1 chromosome without evidence of hematologic relapse occurred in four additional cases. The incidence of grade II to IV acute GVHD is 65% (95% confidence interval [CI], +/- 10%). After adjustment for recipient age and donor matching status, recipients of T lymphocyte-depleted donor marrow had a significantly lower incidence of grade II to IV acute GVHD (P less than .01); however, T depletion was not significantly associated with improved survival (P = .34), disease-free survival (P = .51), or increased incidence of relapse (P = .39). Of 102 patients, 46 are alive, with a median survival of 12 months (range, 3 to 46 months), and the Kaplan-Meier estimate of disease-free survival is 29% (95% CI, +/- 9%) for the entire group at 2 1/2 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1990

Unrelated donor marrow transplantation between 1977 and 1987 at four centers in the United Kingdom.

Retrospectively we analyzed the histocompatibility data and clinical results of bone marrow transplantation in 51 patients who received marrow from unrelated donors (UD) from 1977 to 1987 at one of four UK BMT centers. We compared the results with those obtained in 51 transplants carried out at the same centers using HLA-identical (ID) sibling donors. Of the UD/recipient pairs 32 (63%) were serologically identical for HLA A, B, and DR antigens, and 37% showed varying degrees of mismatch. UD-BMT primary diagnoses were: severe aplastic anemia or Fanconi's anemia (n = 17), acute leukemia (n = 11), chronic myeloid leukemia (n = 21), and other conditions (n = 2). T cell depletion of the graft was associated with a significant improvement in survival in both UD and ID-BMT. Graft failure was more common in recipients of UD than of ID transplants (13 [25%] vs. 5 [10%] P = 0.05) but there was no significant difference in the frequency of acute or chronic graft-versus-host disease. Actuarial survival was superior for recipients of ID transplants (UD vs. ID: 49% vs. 78%, respectively, at 3 months; 32% vs. 63% at one year). Reduced survival for recipients of UD-BMT was confirmed in case control regression analysis (relative risk 3.0, P = 0.01). Nevertheless in patients whose only alternative is a partially mismatched family donor we think that UD-BMT is justified.

Bone Marrow Transplantation↗
PubMed1990

Pretransfused patients with severe aplastic anaemia exhibit high numbers of cytotoxic T lymphocyte precursors probably directed at non-HLA antigens.

Patients with severe aplastic anaemia (SAA) have a relatively high risk of graft rejection after transplantation of bone marrow from HLA-identical siblings compared with patients transplanted for leukaemia. This is presumed to be due to pretransplant blood transfusions which sensitize the recipient's immune system to non-HLA antigens expressed on donor marrow cells. To test this hypothesis, we estimated in the peripheral blood of 18 SAA patients, the frequencies of alloreactive cytotoxic T lymphocyte precursors (CTL-p) directed against mononuclear cells from syngeneic twins, HLA-identical siblings or HLA-matched unrelated individuals. The results were compared with the frequencies of CTL-p in 13 healthy subjects or leukaemia patients who had not been transfused. Pretransfused patients with SAA had significantly higher frequencies of CTL-p directed against HLA-identical siblings (P = 0.002), and against HLA-matched unrelated individuals (P = 0.004), than did untransfused individuals. In contrast, the frequency of CTL-p in two pretransfused patients against syngeneic mononuclear cells was very low. We propose that the increased numbers of CTL-p in the blood of pretransfused SAA patients are directed against non-HLA antigens on target cells and may be the result of prior blood transfusion.

Anemia, Aplastic↗
PubMed1990

Bone marrow transplantation for chronic myeloid leukemia: the use of histocompatible unrelated volunteer donors.

We treated 17 patients with chronic myeloid leukemia (CML) by bone marrow transplantation using marrow from human leukocyte antigen (HLA)-matched unrelated donors. Patients were conditioned with a combination of in vivo monoclonal antibodies, chemotherapy with daunorubicin (n = 7) or busulfan (n = 10) and cyclophosphamide, and both total body and total lymphoid irradiation. Donor marrow was depleted of T cells by incubation with monoclonal antibodies of the Campath series. Fourteen (88%) of 16 evaluable patients had sustained engraftment. Four (27%) of the 15 evaluable patients developed acute graft-versus-host disease (GVHD) of grade II or greater, and 4 of 12 evaluable patients developed chronic GVHD. Three patients developed hematological and two developed cytogenetic evidence of relapse. Eight patients (47%) survive at a median follow-up of 32 months (range 10-51 months), giving an actuarial survival of 44%. Five patients remain alive without evidence of hematological or cytogenetic relapse, giving an actuarial disease-free survival of 27%. Pneumonitis caused or contributed to death in six of the nine patients who died. We conclude that T-cell depletion can prevent the severest forms of GVHD but also increases the risk of relapse after transplant with unrelated donors, as it does with HLA-identical siblings. Nevertheless the use of matched unrelated donors should be considered for CML patients who lack HLA-identical siblings.

Adolescent↗
PubMed1990

Induction of a syngeneic graft-versus-leukemia effect following bone marrow transplantation for chronic myeloid leukemia.

Although clinical data support the concept of a graft-versus-leukemia (GVL) effect following allogeneic bone marrow transplantation (BMT), there are few data to support a similar GVL activity following syngeneic BMT in man. To identify cells with a potential antileukemic activity post-BMT, we monitored the immunological reconstitution in a patient with chronic phase chronic myeloid leukemia (CML) who received a syngeneic BMT from his identical twin brother. Peripheral blood mononuclear cells (PBMC) from the donor prior to the transplant and from the recipient posttransplant were cultured with recombinant interleukin-2 to generate lymphokine activated killer (LAK) cells. LAK cells from both sources lysed the cell line target cells K562 and LCL and also recipient and allogeneic CML target cells in a 51Cr release cytotoxicity assay. Donor-derived LAK cells did not kill normal donor marrow. LAK cells had similar effects on granulocyte-macrophage progenitor cells (CFU-GM): LAK cells from both donor pre-BMT and recipient post-BMT inhibited the proliferation of CFU-GM from the patient's CML cells, but again donor LAK cells did not inhibit the colony growth of normal donor marrow. These results suggest that a syngeneic GVL effect is inducible following BMT in man and that this activity may be truly antileukemic and spare normal marrow progenitors.

Adult↗
PubMed1989

Long-term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Severe Aplastic Anaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT).

468 severe aplastic anaemia (SAA) patients registered in the EBMT-SAA registry who did not undergo bone marrow transplantation and were treated with immunosuppressive therapy (IS; 96% of patients received ATG) were evaluated. Their median age was 23 years (range 1-73) at initial IS therapy, 59% were males; in 69% the aetiology of SAA was idiopathic. Of these 468 patients, 245 had a follow-up of less than 2 years after IS 166/245 died, 71/245 are still alive, 8/245 are lost to follow-up. Of 223 patients who survived greater than or equal to 2 years (LTS long-term survivors), 191 are alive, 21 died greater than 2 years and 11 are lost. Median follow-up of 223 LTS was 4.1 years (range 2.0-10.9). Comparison of 166 patients who died less than 2 years and 223 LTS revealed no difference at time of initial IS therapy as regards sex, duration of AA, or its aetiology, but the age distribution and, in particular, severity of SAA differed significantly: more LTS were between 21 and 40 years old (44% v. 32%, P less than 0.02), less LTS had reticulocytes less than 20 x 10(9)/l (63% v. 80%, P less than 0.001), polymorphonuclear granulocytes (PMN) less than 0.2 x 10(9)/l (30% v. 57%, P less than 0.001), haemorrhages (58% v. 79%, P less than 0.002) and infection (30% v. 49%, P less than 0.005) at time of IS. A gradual improvement of blood counts was seen in patients alive greater than or equal to 2 years after IS. At 2 years after IS 80% had a normal haemoglobin and PMN greater than 0.5 x 10(9)/l, but only after 5 years 80% of cases had platelets greater than 50 x 10(9)/l. Development of clonal disease was reported of 31 LTS: 19 developed paroxysmal nocturnal haemoglobinuria (PNH), one acute leukaemia, 11 myelodysplastic syndromes and of these 11 five subsequently acute leukaemia. The majority of these patients (23/31) are still alive. Actuarial mortality of LTS is 22% at 8 years, but so far no plateau was achieved. It is concluded that SAA patients who become LTS following IS, show an improvement in haematological status but are probably not cured and are prone to develop clonal (malignant) disease.

Adolescent↗
PubMed1989

Pregnancy associated aplastic anaemia: a report of five cases and review of current management.

The occurrence of aplastic anaemia in pregnancy has been long recognized but its rarity has made it difficult to establish the relationship between the two conditions and the optimal management. We now report five cases of aplastic anaemia in pregnancy and offer some recommendations for treatment. In two patients the pregnancy was allowed to continue to term and the disease persisted post-partum leading to death in one case. The other three patients had their pregnancies terminated; one subsequently deteriorated and died, two had spontaneous remissions of their aplasia. We suggest that patients presenting with severe aplastic anaemia in early pregnancy should be offered termination because this may be followed by haematological improvement. If haematological improvement does not occur allogeneic bone marrow transplantation (BMT) may be considered. Aplastic anaemia presenting in late pregnancy should be treated with supportive care until delivery. On the basis of our experience, antilymphocyte globulin may safely be given during pregnancy.

Abortion, Induced↗
PubMed1989

Unrelated donor bone marrow transplantation. Current concepts and future prospects.

The use of unrelated donor bone marrow transplantation (UD-BMT) has the potential to extend the availability of BMT to the majority of patients in whom allogeneic BMT is the preferred treatment. Within the next five years it is likely that sufficient clinical and laboratory data will be available to decide if wider investment of health resources into this procedure is justified.

Bone Marrow Transplantation↗
PubMed1989

Bone marrow transplantation for severe aplastic anaemia using cyclosporin: long-term follow-up.

Between 1980 and 1986 we transplanted 49 patients from genotypically identical sibling donors for severe aplastic anaemia (SAA). Patients were predominantly adults, median age 22 years (3-47). Forty-six were multiply transfused prior to referral. The median pre-transplant disease duration was 4 months (1-72). Pre-transplant conditioning was with cyclophosphamide (CY) 200 mg/kg. Cyclosporin A (CSA) was given from 1 day before the transplant and continued for 9-12 months. Eight of 48 evaluable patients did not achieve initial engraftment (early graft failure). Six of these episodes occurred in the eight cases transplanted more than 1 year after diagnosis, four of whom died. Thirteen of 44 (30%) evaluable patients (with stable engraftment after one or two transplants) had grade III-IV acute graft-versus-host disease (GVHD). Only three of 35 patients surviving more than 100 days with sustained engraftment developed generalized chronic GVHD; two died. An additional 10 patients developed localized chronic GVHD, which was very mild, transient and related to CSA withdrawal. Four long-term survivors are known to have autologous marrow function. All survivors have Karnofsky scores of greater than 90%. We conclude that the use of CSA after bone marrow transplantation for SAA is associated with good long-term survival and minimal on-going chronic GVHD. Early graft failure was frequent when transplantation was delayed beyond 1 year from diagnosis.

Anemia, Aplastic↗
PubMed1989

The use of unrelated bone marrow donors in the treatment of patients with chronic myelogenous leukemia: experience of four marrow transplant centers.

Thirty-seven patients with chronic myelogenous leukemia who lacked an HLA-identical sibling were transplanted with bone marrow from an HLA-A,B,DR-matched, one locus-mismatched, or two locus-mismatched unrelated volunteer donor. Twenty-two were in chronic phase and 15 had advanced to either accelerated phase or blast crisis. The projected 1000-day survival is 55% for chronic phase patients and 22% for accelerated or blast phase patients. For patients transplanted during chronic phase, results appeared to be comparable whether the donor was fully HLA-matched or HLA one locus-mismatched. These results indicate that marrow grafting from either HLA-identical or HLA one locus-mismatched volunteer donors may be effective therapy for patients with chronic myelogenous leukemia who lack an acceptable related donor.

Adolescent↗
PubMed1989

Bone marrow transplantation for Fanconi's anaemia: the Hammersmith experience 1977-89.

Twenty-one patients with Fanconi's anaemia (FA) were treated by allogeneic bone marrow transplantation (BMT). Two, transplanted before 1980, received high dose cyclophosphamide conditioning and both died. Subsequently 19 patients received conditioning with low dose cyclophosphamide 5 mg/kg x 4 and total body irradiation 200 cGy x 3. Ten of 19 received HLA identical sibling marrow (ID-BMT) and nine marrow from alternative donors (MM-BMT). Marrow was T cell depleted in 9/19 cases. Sustained engraftment was observed in 13 cases (eight ID-BMT, five MM-BMT). Nine patients developed greater than or equal to grade II acute graft-versus-host disease (GVHD) (six ID-BMT, nine MM-BMT). Chronic GVHD occurred in 5/11 evaluable patients. Overall survival of the low dose cyclophosphamide group was 9/19 (47%) at a median follow-up of 1257 days post-BMT (110-1825). Six of 10 (60%) survived after ID-BMT compared with two of nine (22%) after MM-BMT. We conclude that allogeneic BMT using a low dose cyclophosphamide protocol is a satisfactory treatment for FA patients who have a normal HLA identical sibling. The results of MM-BMT have been poor, and must improve before these transplants can be generally recommended for treatment of FA.

Adolescent↗
PubMed1989

Recurrent graft failure following syngeneic bone marrow transplantation for aplastic anaemia.

We present the case of a 60-year-old woman with drug-induced aplastic anaemia with a healthy monozygotic twin. Proof of monozygosity was confirmed by studies using the hypervariable minisatellite probe to obtain identical DNA fingerprints in donor and recipient. In vitro co-culture studies performed showed no evidence of a recipient-derived cellular or humoral inhibitor of donor haemopoiesis. Despite this, there was no engraftment following simple marrow infusion without preconditioning. A second syngeneic transplant following high dose cyclophosphamide therapy produced trilineage engraftment but severe thrombocytopenia developed at 3 months, followed later by pancytopenia with generalized marrow failure. Following a third syngeneic transplant with cyclophosphamide and total lymphoid irradiation there was good initial engraftment but graft failure occurred at 14 weeks. A fourth transplant using Campath 1G as preconditioning resulted in no engraftment and the patient died of septicaemia 8 weeks following her fourth transplant. We suggest that the cause of the recurrent aplastic anaemia in this case was a defect of marrow stroma as neither an inhibitor of donor haemopoiesis nor an intrinsic defect of donor stem cell growth could be demonstrated in vitro.

Anemia, Aplastic↗