Immunobiology

Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions

Abstract

Immune haemolytic anaemia (IHA) is a recognised complication after allogeneic stem cell transplantation (SCT) and occurs more frequently if marrow cells have been subjected to T cell depletion (TCD). Among 58 consecutive patients who underwent TCD-allogeneic SCT from volunteer unrelated donors for the treatment of CML at the Hammersmith Hospital during a 3-year period (1 March 1996 to 28 February 1999) we identified nine cases of IHA. All patients had a strongly positive direct and indirect antiglobulin test and in eight patients the serological findings were typical of warm-type haemolysis often with antibody specificities within the Rh system. All nine cases had clinically significant haemolysis and were treated initially with prednisolone and immunoglobulin. The onset of IHA coincided with the occurrence of leukaemic relapse in six cases, and the presence of host haemopoiesis confirmed by lineage-specific chimerism in all four cases studied. Five patients received donor lymphocyte infusions (DLI); in three molecular remission and the restoration of full donor chimerism coincided with resolution of haemolysis. We conclude that in the context of leukaemic relapse, DLI is an effective therapy for IHA following allografts involving TCD. Bone Marrow Transplantation (2001) 28, 581–586.

Main

Immune-mediated haemolytic anaemia is a well recognised complication after allogeneic haemopoietic stem cell transplantation (SCT). The majority of reported cases, however, have been alloimmune in origin due to ABO or minor red blood cell antigen incompatibilities between donor and recipient1,2 and the haemolysis has been short lived due to the rapid consumption of the remaining host cells and/or antibodies. Autoimmune haemolytic anaemia (AIHA) has been reported anecdotally following allogeneic marrow transplantation, primarily in patients transplanted with T cell-depleted (TCD) grafts.3,4,5 In two large retrospective studies the incidence of AIHA after allogeneic bone marrow transplants was estimated at 3%.6,7 Both series demonstrated that response to conventional treatment was disappointing and a significant proportion of the patients subsequently died from complications related to AIHA or its treatment.

Depletion of T cells from the donor marrow is an effective strategy to reduce the incidence of acute and chronic graft-versus-host disease (GVHD) associated with allogeneic SCT.8,9,10 Although the incidence of relapse is higher in patients undergoing TCD-SCT compared with recipients of T cell-replete allografts, this can be managed effectively by donor lymphocyte infusions (DLI) which can induce durable complete molecular remissions in more than 70% of patients relapsing after a transplant for CML.11,12 Relapse after allografting for CML is associated with the presence of mixed chimerism (MC) in both myeloid and lymphoid lineages,13,14,15,16 and a progressive rise in the numbers of BCR-ABL mRNA transcripts detected in the blood by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) analysis.17 Furthermore, response to DLI is associated with reversion to full donor chimerism in both lineages18,19 and the absence of BCR-ABL RT-PCR positivity.

In this report, we describe a significantly increased incidence (15.5%) of IHA after TCD-SCT. The serological findings were typical of ‘conventional’ idiopathic AIHA with warm-reactive, panspecific antibodies detected. In six of the nine cases identified, the onset of IHA coincided with a diagnosis of leukaemic relapse and in four cases, the finding of mixed chimerism. The achievement of molecular remission and restoration of full donor chimerism coincided with resolution of haemolysis in three of the five patients treated with DLI on an escalating dose schedule.

Patients and methods

Between 1 March 1996 and 28 February 1999, 58 patients with CML underwent allogeneic SCT receiving bone marrow from volunteer unrelated donors at the Hammersmith Hospital. Patients were transplanted in first chronic phase (n = 39) or advanced phase (n = 19). Donor identification involved HLA typing for class I antigens by serological methods and DNA typing for DRb1 alleles.10 In addition the frequency in the donor's peripheral blood of alloreactive cytotoxic T lymphocyte precursors (CTLp) was used in donor selection.10 The median age at SCT was 33 years (range 12–50) and the median interval from diagnosis to SCT was 2 years (range 0.5–10.2). Patients were classified as having IHA if they met all of the following criteria: (1) positive direct antiglobulin test (DAT); (2) positive indirect antiglobulin test reacting with broad specificity; (3) positive eluate with broad specificity; and (4) clinical evidence of haemolysis (jaundice or symptomatic anaemia).

Conditioning regimen and GVHD prophylaxis

The preparative regimen consisted of cyclophosphamide (120 mg/kg), and TBI (1320–1440 cGy in six fractions). GVHD prophylaxis involved in vivo T cell depletion with CD52 monoclonal antibody Campath 1H (n = 43) or Campath 1G (n = 10) from day −5 to day +4. In addition after May 1998, CMV-positive recipients received an abbreviated Campath-1H schedule from day −10 to day −6 (n = 5). All patients received cyclosporin A and ‘short’ methotrexate.

Pre-engraftment supportive care and follow-up

All patients received supportive care as previously described.20 Ganciclovir was administered prophylactically from engraftment to day +90 to all cytomegalovirus (CMV) seropositive recipients. Monitoring for CMV reactivation using CMV antigenaemia directed ‘pre-emptive’ ganciclovir therapy.

Assessment of GVHD and relapse

Acute GVHD was graded as 0–IV according to criteria of Glucksberg et al,21 and chronic GVHD was graded as none, limited and extensive.22 After transplantation blood samples were studied 3-monthly after transplant for the presence of BCR-ABL transcripts by a multiplex and/or a two-step reverse transcriptase polymerase chain reaction (RT-PCR).23 Results were expressed as the ratio between BCR-ABL and ABL transcript numbers (BCR-ABL/ABL ratio).23,24 Relapse was defined at the molecular, cytogenetic or haematologic levels as previously described.20

Management of relapse with DLI

At diagnosis of relapse, immunosuppression was reduced or discontinued and the administration of DLI was considered. RT-PCR was performed at 4-weekly intervals or more frequently after initiation of treatment by DLI. Molecular remission was defined as the absence of detectable BCR-ABL transcripts by RT-PCR analysis of peripheral blood on two consecutive occasions.

Serological testing

Standard serological methods were employed.25 The direct antiglobulin test (DAT) was performed using polyspecific antihuman globulin reagent. When the DAT was found to be positive, further testing with specific anti-IgG, IgM and anti-C3d reagents was performed. Antibodies were eluted using a commercial chloroform elution test. Appropriate allo- or autoabsorption was done to determine whether underlying alloantibodies were present. Serum antibody identification studies were performed by manual polybrene techniques to detect free antibody in the patients' serum.

Lineage separation

Chimerism was not monitored routinely after BMT. However, patients who presented with IHA were studied at a single time point prior to DLI and serially post DLI using short tandem repeat polymerase chain reaction (STR-PCR) to assess chimeric status in peripheral blood fractions. For lineage-specific analysis, 10 ml of PB were separated into mononuclear and granulocyte fractions by Ficoll–Hypaque density gradient centrifugation (Lymphoprep; Nycomed Pharma AS, Oslo, Norway). CD2+ve T cells were isolated from the mononuclear cell fraction using Dynabead separation according to the manufacturer's recommendations (Dynal, Oslo, Norway).

Lineage-specific STR-PCR

DNA was extracted from PB fractions (whole blood, mononuclear, granulocyte, CD2+ve and CD2−ve) using QIAamp DNA Blood Mini Kit (Qiagen, West Sussex, UK) and from Buccal swabs using a standard SDS/proteinase K extraction. An informative polymorphism was identified by amplifying pre-transplant/buccal swab and donor DNA samples using a panel of STR markers. The STR-PCR protocol was as previously described.13,18 Routine sensitivity of the STR-PCR technique is 0.1–0.01%. The STR-PCR assay is semi-quantitative; significant increases or decreases in donor or recipient cell populations can be identified from analysis of serial samples. All results are confirmed using two polymorphic STR-PCR markers and results are analysed by two independent observers.

Definitions

The degree of chimerism was defined as follows: D, donor chimerism, >95% of cells were donor in origin; MR, mixed predominantly recipient, >95% of cells were of recipient origin; MC, mixed chimera, cells ranged from 95% recipient to 5% recipient in origin.

Results

Retrospective analysis of the 58 patients revealed nine cases of IHA giving an incidence of 15.5% (9/58). All nine patients underwent allogeneic SCT during the latter 2 years of the study. The clinical details of the patients are outlined in Table 1. All patients were matched with their donor at class I loci using serological methods and at DRB1 alleles (except case 4) by DNA typing. All CTLp frequencies were detected at <1:100 000. Eight patients received Campath-1H (day −5 to day +4), and one patient (No. 2), Campath-1G as GVHD prophylaxis. The median age at SCT of the affected patients was 32 years (range 15–41). The median interval from SCT to diagnosis was 15 months (range 5–38).

Table 1 Clinical characteristics at time of diagnosis of IHA

Serological analysis

The serological data at diagnosis of IHA are shown in Table 2. All patients had a strongly positive direct and indirect antiglobulin test. In eight patients, the serological findings were typical of warm-type AIHA and the relative specificities where present were also typical of AIHA arising in non-transplant settings, being primarily within the Rh system. An alloantibody (anti-E) was identified in patients 5 and 6 where the respective donors were both group E negative. An eluate prepared from the cells of all patients (except case 4) was strongly positive with broad reactivity. Case 4 had a cold-reacting anti-I antibody which had a thermal amplitude up to 30°C. The onset of IHA in case 4 was early (3 months) post transplant, which is typical of the pattern previously described.6

Table 2 Results of serological investigation

Relation of diagnosis of AIHA to clinical course

The clinical course of each case is shown in Table 3. Detection of viral infection preceded the haemolysis in four patients and two patients were receiving antiviral therapy when AIHA was diagnosed. Case 6 presented with disseminated varicella-zoster viral (VZV) infection and retinal necrosis 4 months before the diagnosis of IHA. CMV, VZV and parvovirus infection were noted in cases 2, 9 and 8, respectively, prior to the onset of haemolysis. All nine patients with IHA received the 10-day Campath (-1H (n = 8); -1G (n = 1) regimen). GVHD preceded or coincided with the detection of autoantibody in three cases (Nos 4, 5 and 6). However at the time of diagnosis of IHA only patient 4 had active GVHD requiring immunosuppressive treatment. Regular monitoring for the BCR-ABL transcript revealed that six cases (Nos 3–8) satisfied the criteria for molecular relapse at the onset of haemolysis. Cytogenetic relapse occurred 1 month prior to haemolysis in patient 3.

Table 3 Clinical course of the patients

Treatment and outcome

All nine cases had clinically significant haemolysis requiring treatment, and were initially treated with prednisolone and immunoglobulin. Case 1 responded to this therapy, whilst all other patients required adjunctive treatment. Two patients (Nos 2 and 8) responded to splenectomy which was performed in four patients (Nos 2, 6, 8 and 9) as second-line therapy.

DLI was administered on an escalating dose regimen26 to five of the six patients who had evidence of leukaemic relapse at the onset of IHA. The achievement of molecular remission coincided with resolution of haemolysis in cases 3, 5 and 6. Case 3 received DLI therapy as treatment for cytogenetic relapse 2 months after the diagnosis of IHA. The patient required steroid therapy to treat haemolysis at the time of DLI administration. The patient suffered no complications after the administration of DLI and durable complete remissions of both the haemolysis and leukaemia (molecular remission) were seen coincidentally 2 months after the administration of DLI.

Case 6 received the first dose of DLI of 106 CD3+/kg 2 months after the coincidental diagnoses of AIHA and leukaemic relapse. At the time of DLI administration, criteria for cytogenetic relapse were satisfied. Analysis of chimerism of the lymphoid lineage demonstrated that 80% of the CD2+ fraction was of donor origin and 20% recipient (MC). The second dose of DLI (107 CD3+/kg) was administered 3 months later. At this time 25/50 marrow metaphases remained Ph-positive and lineage-specific chimerism was mixed (ratio of donor:recipient was approximately 50:50) (MC). Subsequent to the second DLI, he developed acute GVHD of gut, liver and skin (grade III) and extensive chronic GVHD. However, 4 months after the second DLI, haemolysis resolved (DAT negative, haemoglobin stable, normal bilirubin and LDH) and he became BCR-ABL-negative on RT-PCR analysis. Assessment of lineage-specific chimerism demonstrated a switch to full donor chimerism (D). He remains on a low dose of oral steroids as treatment for chronic GVHD.

IHA and molecular relapse were diagnosed simultaneously 17 months post allograft in case 5, and DLI was administered on an escalating dose schedule 2 and 6 months later. Four months after the second dose of donor lymphocytes, criteria for molecular remission were satisfied and haemolysis resolved. These observations coincided with a switch from mixed chimerism to full donor chimerism.

IHA and molecular relapse were diagnosed 7 months post-SCT in case 7 and DLI was administered 4 months later at which time criteria for cytogenetic relapse were satisfied. A second dose of donor lymphocytes was infused after a further interval of 4 months with a subsequent reduction in the BCR-ABL transcript number on RT-PCR analysis and an improvement in the degree of haemolysis recorded. Intravenous immunoglobulin has been stopped and steroid doses have been reduced. Chimerism analysis performed at the onset of haemolysis and on three occasions in the following 12 months confirmed mixed chimerism (20–30% donor in all lineages) and currently remains unchanged.

Haematological relapse was noted 2 months after the onset of haemolysis in case 8. The patient was treated with four different modalities (steroids, intravenous immunoglobulin, splenectomy and DLI) within a 3-month period, but died of infectious complications with ongoing haemolysis. Case 4 had moderately severe GVHD of the liver and lungs. The patient refused DLI therapy and died in haematological relapse with ongoing haemolysis, requiring steroid therapy 12 months post transplant.

Discussion

We have observed a higher incidence (15.5%) of IHA following unrelated SCT than has been reported previously.6,7 The pathogenetic basis of the haemolysis is not clear, but in six of the nine cases a diagnosis of leukaemic relapse was made concomitant with the onset of haemolysis. The majority of cases of IHA occurring after allogeneic SCT are alloimmune and reflect donor/recipient ABO or Rh incompatibilities.1,2 In this situation the haemolysis is usually short-lived due to the rapid elimination of the remaining host red cells and/or antibodies. The patients in our study fit the criteria used in previous reports of non-alloimmune haemolysis3,6,7 with absence of alloantibody and the presence of autoantibodies.

Non-alloimmune haemolysis has been reported primarily in patients transplanted with TCD grafts.6,7 It is known that there is an increased incidence of autoimmunity in patients with primary immune deficiency.27 In many instances this is thought to be due to a quantitative or qualitative T cell deficiency resulting in impaired B cell regulation and consequent autoantibody formation.28 Recipients of a TCD-SCT have impaired T cell function for prolonged periods of time29 and adults have limited thymic regenerative capacity.29,30,31 In addition CDR3 spectrotyping has been used to show that adult recipients of a TCD-SCT have abnormal and markedly skewed T cell repertoires for up to 3 years post SCT.32

In contrast to the series reported by Drobyski et al,7 in which none of the seven patients with non-alloimmune haemolysis demonstrated evidence of leukaemic relapse, in our series leukaemic relapse was diagnosed in six of the nine cases concomitant with the onset of haemolysis. One notable difference between the two studies is the T cell depletion strategy employed. In our study, Campath, an anti-CD52 antibody which depletes both T and B lymphocytes33 was administered. In contrast, Drobyski et al used ex vivo TCD with the T cell receptor antibody, T10B9, which depletes the marrow solely of T lymphocytes. In the context of relapse post SCT, there is partial reconstitution of the recipient immune system demonstrable in our patients by the emergence of both BCR-ABL transcripts and mixed chimerism, thus allowing two possible mechanisms of IHA: recipient–anti-donor and donor–anti-recipient. Our analysis does not exclude recipient–anti-recipient antibodies underlying the immune process. In those patients in whom DLI was effective donor–anti-donor antibodies are unlikely to underlie the immune process.

All nine patients with IHA received a 10 day (day −5 to day +4) Campath regimen. Prolonged Campath administration post transplant is associated with a high prevalence of mixed chimerism and leukaemic relapse.8,11 Only five patients in our study group received the abbreviated Campath schedule (days −10 to −6) and although none of these patients experienced IHA, the number is too small to allow direct comparison.

Donor lymphocyte infusion (DLI) is an effective therapeutic option to treat relapsed CML after allogeneic SCT11,12,34 and the exogenous administration of donor T cells could therefore be an effective strategy to augment T cell reconstitution and restore immunoregulatory control over autoreactive B cell populations. Indeed there is evidence from CDR3 spectrotyping that patients with relapsed CML have markedly abnormal and skewed TCR repertoires, but that T cell repertoire heterogeneity is restored after DLI.35 Alternatively, the donor lymphocytes may be effective in the treatment of IHA by the eradication of target host erythrocytes, or the recipient lymphocytes that may be involved in the pathogenesis of the haemolysis. In our series, five patients received DLI as treatment for relapse and the concomitant IHA, and in three cases the achievement of molecular remission coincided with resolution of haemolysis. In addition, DLI induced a switch from mixed chimerism (MC) to full donor chimerism (D) in the successful cases. In contrast, persistence of host leukaemic haemopoiesis and MC was observed in the two cases where haemolysis was refractory to DLI.

In summary, IHA is a clinically significant complication which occurs with increased frequency after allogeneic T cell-depleted bone marrow transplants. We have observed an intimate association between the onset of immune haemolysis and the diagnosis of relapse of leukaemia. Effective treatment of relapse with DLI was coincident with resolution of immune haemolysis in three patients. Conversion of mixed chimerism, observed in patients at the time of relapse and the onset of haemolysis, to full donor T cell chimerism in remission patients has been demonstrated. We conclude that DLI is a novel and effective strategy to treat immune haemolysis after TCD-SCT, especially in the setting of leukaemic relapse.

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Cwynarski, K., Goulding, R., Pocock, C. et al. Immune haemolytic anaemia following T cell-depleted allogeneic bone marrow transplantation for chronic myeloid leukaemia: association with leukaemic relapse and treatment with donor lymphocyte infusions. Bone Marrow Transplant 28, 581–586 (2001). https://doi.org/10.1038/sj.bmt.1703206

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Keywords

  • haemolytic anaemia
  • T cell depletion
  • chronic myeloid leukaemia
  • relapse
  • donor lymphocyte infusion

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