mismatched transplantation for chronic myelogenous leukemia

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INTRODUCTION. Allogeneic bone marrow transplantation (BMT) offers a potential cure for chronic myelogenous leukemia (CML), albeit at the price of ...
Biology of Blood and Marrow Transplantation 4:151–156 (1998) © 1998 American Society for Blood and Marrow Transplantation

Prolonged erythroid aplasia after major ABOmismatched transplantation for chronic myelogenous leukemia Richard J. Benjamin,1,2 Jean M. Connors,1 Siobhan McGurk,2 W. Hallowell Churchill,1 Joseph H. Antin1 1

Dana Farber/Partners Cancer Care and the 2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA Offprint requests: R.J. Benjamin, MBChB, PhD, Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115 (Received 22 April 1998; accepted 12 August 1998)

ABSTRACT Erythroid engraftment after non–T cell–depleted allogeneic bone marrow transplant (BMT) is reviewed in 112 patients treated for chronic myelogenous leukemia (CML). Twenty-two of 76 evaluable patients were transplanted over a major ABO-mismatch compatibility barrier. These patients showed an increased delay in erythroid engraftment and in time to red blood cell transfusion independence when compared with ABO-identical or minor mismatched recipients. No difference in granulocyte or platelet engraftment was evident. Erythroid engraftment usually occurred spontaneously without specific intervention. One patient was found to have erythroid hypoplasia at day 201 after BMT, despite therapy with intravenous immunoglobulin and high-dose erythropoietin. An anti-A titer of 16,000 was documented. This patient was successfully treated with an aggressive course of 18 plasmapheresis procedures and with donor-type plasma replacement. Delayed erythroid engraftment is common after non–T cell–depleted major ABO-mismatched BMT in CML, but rarely requires intervention other than transfusion support. Rare cases of refractory erythroid aplasia may be treated without additional immunosuppression by aggressive plasma exchange with donor-type plasma.

KEY WORDS CML • Plasmapheresis • BMT

INTRODUCTION Allogeneic bone marrow transplantation (BMT) offers a potential cure for chronic myelogenous leukemia (CML), albeit at the price of transplant-related mortality and morbidity. Allogeneic BMT across ABO-mismatch barriers carries additional risks for these patients, including hemolysis and delayed red blood cell (RBC) engraftment. In particular, major ABO blood group–mismatched graft recipients may show signs of hemolysis at the time of transplant due to lysis of RBCs in the graft or at the time of erythroid engraftment due to reticulocytosis in the presence of persistent anti-ABO antibodies, or of prolonged RBC transfusion dependence due to delayed or absent eythroid engraftment [1–5]. Immediate hemolysis at the time of BMT may be avoided by RBC depletion of the graft before infusion or by lowering the recipient anti-ABO titer in vivo before BMT by plasmapheresis or immunadsorption [1–8]. Hemolysis at the

time of engraftment is usually not clinically significant, but in rare severe cases may be treated with plasmapheresis [9]. Delayed erythroid engraftment is well documented and usually responds to supportive care or erythropoietin therapy [9–12]. Rare cases of erythroid aplasia refractory to these measures have been reported; however, no consensus exists as to optimal management [8,13–17]. Nevertheless, major ABO-mismatched BMT has not generally been associated with poor patient survival [1–4]. Recently we reported that in our institution, patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who received an ABO-mismatched BMT were significantly more likely to die of regimen-related toxicity than recipients of ABO-identical grafts [18]. This increased risk was not apparent in a larger group of similarly treated CML patients. In our AML and MDS patients, major ABO-mismatch transplantation was associated with a

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Table 1. Patient characteristics

Total b

Age Gender Men Women Total Donor Related Matched unrelated Conditioning Cy/TBI AraC/Cy/TBI GVHD prophylaxis MTX/CSA FK506/MTX MTX/CSA/Pred Syngeneic

40 (22–60)

Number of patients ABOMajor ABO- Minor ABOcompatible mismatcha mismatch 40

42

40

64 48 112

33 22 55

19 16 35

12 10 22

60 52

35 20

13 22

12 10

98 14

49 6

32 3

17 5

60 8 43 1

36 2 16 1

14 4 17 0

10 2 10 0

a

Includes six major plus minor ABO-mismatched graft recipients. Median and (range). ABO, ABO blood group; AraC, cytosine arabinoside; CSA, cyclosporine A; Cy, cytoxan; FK506, tacrolimus; GVHD, graft-vs.-host disease; MTX, methotrexate; Pred, prednisone; TBI, total-body irradiation. b

significant delay in erythroid engraftment. Given the discrepancy in early survival rates, we asked whether major ABO-mismatch affected the rate of hematopoietic recovery in our CML patient group.

MATERIALS AND METHODS Patients One hundred twelve patients undergoing HLA-matched or single-antigen–mismatched, non–T cell–depleted allogeneic BMT at the Brigham and Women’s Hospital between January 1993 and June 1997 were studied retrospectively, as previously described [18]. Surviving patients were followed for a median of 537 days (range 120–1512 days). The patient characteristics are shown in Table 1. All protocols were approved by the Brigham and Women’s Hospital Institutional Review Board, and both recipients and donors gave written informed consent. Patients were divided into four groups based on donorrecipient ABO compatibility: ABO-identical (group I); ABO major-mismatched (e.g., group A grafts given to group O recipients; group II); major plus minor ABO-mismatched (e.g., group A grafts given to group B recipients; group III); and minor ABO-mismatched (e.g., group O grafts given to group A recipients; group IV). Group I and IV stem cell products were infused without manipulation, while group II and III grafts were infused after RBC depletion as described [19]. Our transfusion policy dictated that all transplant recipients receive leuko-depleted irradiated blood products and single-donor apheresis platelets. RBC and plasma components were restricted to an ABO type compatible with both donor and recipient RBCs (e.g., group A donor receiving group B bone marrow [BM] would be restricted to

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group O RBCs and group AB plasma). ABO-compatible platelets were given preferentially, if available, but no routine policy was in place to remove incompatible plasma from either platelet or RBC components. Conditioning regimen and graft-vs.-host disease prophylaxis The conditioning regimen and supportive care were described previously [18,20,21]. Graft-vs.-host disease (GVHD) prophylaxis comprised cyclosporine (CSA) and methotrexate (MTX) with or without added steroids [22]. Outcomes Evaluable patients were those who survived at least 100 days after BMT. Endpoints included: granulocyte engraftment, defined as the first day after transplant that 200106/L granulocytes was attained for at least 3 days; RBC transfusion dependence, defined as the number of days from transplant until the first RBC transfusion that was followed by at least 30 days without RBC transfusion; and RBC engraftment, defined as the number of days from transplant until a reticulocyte count of 0.5% was attained. Reticulocyte counts were performed once a week until engraftment and complete data were available for 64 (84%) of 76 patients who survived at least 100 days after transplant. Case history Universal patient number (UPN) 1449 is a 44-year-old Caucasian male who presented for transplant with a 21-month history of stable-phase, Philadelphia chromosome-positive CML. His disease was well controlled on hydroxyurea and interferon therapy. He underwent an HLA-matched, unrelated donor, non–T cell–depleted BMT following cytoxan and total-body irradiation (Cy/TBI) conditioning. At the time of transplant, he had no significant family, surgical, or medical history and had not received prior transfusions. Clinical examination was unremarkable. Laboratory investigations showed that he was blood group O, Rh-positive and confirmed CMVnegative status. Immunoglobulin (Ig) G anti-A titer was measured at 256 at the antihuman globulin phase using standard techniques [23]. He received a blood group A, Rh-negative, CMV-negative, RBC-depleted BM graft, and GVHD prophylaxis consisted of CSA, MTX, and Pred. The early posttransplant course was marked by moderate mucositis, mild venoocclusive disease, and a single episode of coagulase-negative Staphylococcus bacteremia, which responded to vancomycin. Granulocyte engraftment (200106/L) occurred on day 30 and platelet counts 20,000/mL were maintained without transfusion by day 40. At discharge from the hospital, the patient had grade II GVHD, which was evidenced by a fine maculo-papular rash that was responsive to increased steroid therapy. GVHD prophylaxis consisted of CSA 450 mg b.i.d. and Pred 200 mg q.d., which was gradually tapered over the ensuing months. He remained RBC transfusion-dependent, requiring approximately two units of group O, Rh-negative, packed RBCs every two weeks. Erythropoietin levels taken at day 96 were elevated at 109 U/mL (normal 0–27 U/mL) and haptoglobin levels were within normal range. At that time, white blood cell count (WBC) was 2570/L, platelet count was 25,000/L, and reticulocytes were 0.1%. There were no signs of GVHD and CMV cultures, and Parvovirus serology were negative. He was given 32 g intravenous (i.v.) Ig on day

Prolonged Erythroid Aplasia

A

B

Figure 1. Cumulative proportion of patients remaining erythroid aplastic (A) or RBC transfusion dependent (B) after allogeneic BMT In each case, major ABO-mismatched ( ) recipients are significantly different from ABO-identical ( ) (p  0.003) and minor ABO-mismatched ( ) (p  0.05) recipients.

118 to enhance erythroid engraftment. By day 131, his WBC fell to 1000/L and platelets were 16,000/L. The possibilities of viral-induced marrow suppression or late graft failure were entertained. At this time, GVHD prophylaxis included CSA 200 mg b.i.d. and prednisone 5 mg q.d. The patient was started on acyclovir and granulocyte-macrophage colonystimulating factor (GM-CSF), and BM biopsy revealed a hypocellular marrow with 10% cellularity, consisting predominantly of myeloid precursors. No erythroid or megakaryocytic elements were seen. By day 152, his WBC had risen to 10,400/mL and the GM-CSF was stopped. Platelet count remained at 24,000/mL, hematocrit at 28.5, and reticulocytes at 0.6%. Given the lack of appropriate reticulocytosis, erythropoeitin was started on day 173 at 4000 U 3 times a week. On day 188, this was increased to 10,000 U 3 times a week. A peak reticulocyte count of 0.8% was obtained and the patient remained transfusion-dependent. An anti-A IgG titer performed on day 201 post-BMT was 16,000, and a diagnosis of refractory antibody-mediated RBC hypoplasia was made. At this time, the direct antiglobulin test (DAT) was negative and haptoglobin and direct and indirect bilirubin levels were within normal range. A polymerase chain reaction test for the BCR/ABL oncogene product was negative, confirming his CML remission status. Statistical analysis All statistics were performed using SPSS for Windows, Release 6.1 (SPSS, Chicago, IL). Univariate analyses of patient survival were performed using Kaplan-Meier survival analysis [24]. Comparison of the distributions of binomial variables between patients receiving ABO-identical and -incompatible transplants were performed using the SPSS Exact Test (based on Fischer’s exact test). For all analyses, p  0.05.

RESULTS Erythroid engraftment after ABO-mismatched BMT We reviewed all patients receiving an allogeneic BMT for CML. One hundred ten stable-phase and two accelerat-

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ed-phase CML patients received allogeneic non–T cell–depleted grafts from related (60 patients) or unrelated (52 patients) donors (Table 1). Most patients received Cy/TBI (98 patients) conditioning followed by MTX/CSA (60 patients) or MTX/CSA/Pred (43 patients) GVHD prophylaxis. We analyzed the effect of graft ABO-mismatch on survival and hematopoietic recovery in this population. Thirty-six (32%) of 112 patients died within 100 days of BMT. There was no significant difference in survival rate between ABO-identical and -incompatible graft recipients [18]. The surviving 76 patients were considered evaluable for this study. These included 40 ABO-identical, 16 major ABO-, 14 minor ABO-, and 6 major plus minor ABO-mismatched graft recipients. Hematopoietic recovery and transfusion requirements were examined. Overall, in the evaluable patients, granulocytes and reticulocytes recovered on median day 21 and 22, respectively, and a median of 10 units of RBCs and 8 units of single-donor apheresis platelets were transfused in the first 100 days after transplant. There was no significant difference in granulocyte engraftment or platelet transfusion requirements between the ABO-identical and -incompatible groups (major plus minor ABO-mismatched patients were grouped with the major ABO-mismatched graft recipients for these analyses). In contrast, major ABO-mismatched recipients received significantly more RBC transfusions, took significantly longer to engraft RBCs, and remained RBC transfusiondependent longer than ABO-identical recipients (Figure 1). Indeed, median time to RBC engraftment was delayed from 21 to 32 days ( p  0.003) and median duration of RBC transfusion independence from 26 to 47 days (p  0.001) in major mismatched compared with ABO-identical recipients (Table 2). Major ABO-mismatched recipients also required an average of six more RBC transfusions (p  0.03) than did the other groups. We conclude that major ABO-mismatched recipients showed delayed erythroid engraftment, without an effect on granulocyte or platelet engraftment. Note that our BMT protocol did not routinely assess anti-ABO titers and no

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Table 2. Transfusion and engraftment parameters of all patients surviving 100 days Graft ABO match (Number of patients)

All patients (76)

Number of platelet transfusions in first 100 days Number of RBC transfusions (units) RBC transfusion dependence (days) RBC engraftment (days) Granulocyte engraftment (days)

8 10 29 22 21

(0–81)a (0–58) (0–273) (13–152) (13–35)

ABO compatible (40) 7 8 26 21 20

(1–81) (0–58) (0–144) (13–70) (13–34)

Major mismatch (22) 9 14 47 32 23

(0–67) (4–41)b (16–273)c (14–152)c (13–35)

Minor mismatch (14) 7 9 25 21 19

(2–71) (2–38) (7–157) (17–50) (17–25)

Statistical significance determined relative to ABO-compatible recipients. a All data are shown as median and (range). b p  0.03 (Student’s t-test). c p  0.003 (Kaplan-Meier statistics).

attempt was made to reduce anti-ABO titers either before or after BMT. Nevertheless, 21 of 22 major ABO-mismatch recipients showed spontaneous erythroid engraftment without the need for specific therapy. The one notable exception was UPN 1449, who was found to have anti-A antibody mediated RBC hypoplasia on day 201 after unrelated BMT (anti-A titer 16,000) despite high-dose erythropoietin and i.v. gammaglobulin therapy (see “Case history” above). Successful treatment of refractory erythroid aplasia without additional immunosuppression Because most previously described strategies for enhancing RBC engraftment in the setting of major ABO-mismatched BMT advocate the use of immunosuppressive modalities, we elected to pursue a novel approach: UPN 1449 received an aggressive course of therapeutic plasma

exchange (TPE) with donor-type plasma replacement. Eight single-volume plasma exchanges were performed over 2 weeks on the Cobe Spectra cell separator (Cobe, Lakewood, CO), followed by 10 similar procedures over the following 6 weeks. This therapy was well tolerated and no unusual allergic reactions were noted. After five procedures, the IgG antiA titer dropped to 256 (Fig. 2), and after 12 procedures, to 8. Thereafter, the patient noted an increase in appetite, his platelet counts increased to within normal range, and reticulocyte counts rose progressively to a maximum of 7.2%. These changes were accompanied by the development of a positive DAT, an RBC eluate notable for anti-A1 antibodies, and a progressive blood group switch on forward typing to donor blood group A. Lactate dehydrogenase and total and indirect bilirubin levels remained within normal range. The patient required his last RBC transfusion on day 271, 2

Figure 2. UPN 1449 Anti-A titers () and percentage reticulocytes () during the course of therapeutic plasma exchange with donor-type plasma replacement. , timing of plasma exchange procedures.

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months after initiating TPE therapy. Over the subsequent 6 months, he demonstrated a rising hematocrit with no clinical evidence of hemolysis and the DAT became negative.

DISCUSSION Major ABO-mismatched BMT has previously been associated with acute hemolysis at the time of transplant and with delayed erythroid engraftment in patients transplanted for a variety of diseases. Acute hemolysis may be avoided by reduction of the recipient anti-ABO titer in vivo, by TPE or donor-type RBC transfusion, or by simply removing the RBC from the graft before infusion [1–8]. Delayed erythroid engraftment is associated with the use of CSA for GVHD prophylaxis and is independent of the recipients’ pretransplant anti-ABO titer [5,8]. Major ABO-mismatched BMT does not affect the rate of granulocyte or platelet engraftment and prior reports have shown no effect on patient survival [1–4]. Recently, we have shown that in our institution, patients receiving both major and minor ABO-mismatched, non–T cell–depleted BMT for AML or MDS were at significantly increased risk of death within the first 100 days of transplant [18]. This was not the case for 112 CML patients. In that study, AML or MDS patients who received major ABO-mismatched grafts showed delayed erythroid engraftment and prolonged RBC transfusion dependence. Given the difference in the overall effect on survival, we asked whether major ABO-mismatch had any effect on erythroid engraftment in the same cohort of CML patients. We now report that in 22 of 76 CML patients who received related or unrelated non–T cell–depleted, major ABO-mismatched BMT and who survived at least 100 days posttransplant, erythroid engraftment and RBC transfusion independence was delayed to a median of 32 and 47 days, respectively. The major ABO-mismatched recipients also required six more RBC transfusions than ABO-identical recipients. No significant effect on granulocyte engraftment or platelet transfusion requirements was apparent. The overall effect of major ABO-mismatch on erythroid recovery in CML patients was similar to that previously reported in our AML and MDS patient group [18]. These data suggest that delayed hematopoeitic recovery is not responsible for the previously documented differences in early mortality rates. In most of our CML patients, the erythroid engraftment occurred spontaneously and did not require specific therapy other than RBC transfusion support. In five patients, prolonged transfusion dependence led to the measurement of peripheral blood erythropoietin levels, which were raised in all but one patient who manifested inappropriately low erythropoietin synthesis that was secondary to renal insufficiency (data not shown). We describe in detail one patient who developed prolonged erythroid hypoplasia that was refractory to i.v. Ig and erythropoietin therapy, with raised endogenous erythropoietin levels and an IgG anti-A titer of 16,000 assessed on day 201 posttransplant. This patient responded to an aggressive course of 18 TPE procedures with donor-type plasma replacement. This led to erythroid engraftment, RBC transfusion independence, and an increased feeling of well-being and appetite, with no signs of ongoing hemolysis.

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We were unable to examine risk factors for prolonged erythroid hypoplasia because of the retrospective nature of this study. It is, however, noteworthy that UPN 1449 had a relatively high pre-BMT anti-A titer of 256 and received CSA prophylaxis for GVHD. These factors have previously been implicated in delayed erythroid engraftment [8]. Prolonged erythroid aplasia following major-mismatched BMT is thought to be due to persistently raised isohemagglutinin titers that suppress erythropoiesis. BM biopsies reveal an absence of erythroid precursors, while in vitro culture reveals exuberant blast forming unit-erythroid (BFU-E) colony formation [25–27]. These data support the notion that ABO antigens are increasingly expressed after the BFU-E developmental stage and that these cells are specifically lysed by anti-A or -B isohemagglutinins. In most major ABOmismatched patients, the incompatible anti-A or -B titer decreases spontaneously after transplant and reticulocytosis occurs when the IgG titer falls to 8–16 [5,8]. This is often accompanied by a transiently positive DAT with signs of extravascular hemolysis. The process of engraftment in these cases can be accelerated by the use of erythropoietin therapy or by single TPE procedures with donor-type plasma replacement [9–12,28,29]. Prolonged erythroid aplasia that persists for 6 months and is refractory to erythropoietin therapy is a rare occurrence, and the published experience consists of a collection of case reports [8,15,17,26]. There is, therefore, no consensus as to optimum therapy. Various modalities have proven ineffective, including the use of i.v. Ig, steroids, and plasmapheresis with albumin solution replacement. Successful therapies have included exchange transfusion with donor-type RBCs or immunosuppressive modalities, such as antithymocyte globulin or the combination of erythropoietin and bolus methylprednisone [12–17,30]. We reasoned that the risks of exchange transfusion were unacceptable and that further immunosuppressive therapy was undesirable in our patient [31]. We therefore attempted a novel protocol consisting of aggressive plasma exchange with donor-type plasma. This approach was based on the rationale that plasma from donors who are secretors (80% of the population) contains A or B substance capable of neutralizing anti-A or -B isohemagglutinins. Previous studies showed that plasma is equivalent in neutralizing power to a 1% solution of RBCs [4]. A one-to-one mixture of secretor plasma and group O (containing both anti-A and -B antibodies) plasma results in a 16- to 64-fold decrease in anti-A titer or a zero- to eightfold decrease in anti-B titer [32]. Donor-type plasma has also been shown to be effective in reducing anti-A or -B titers when used in plasma exchange before allogeneic BMT and to decrease anti-A or -B titers after BMT by simple infusion [4,33]. We have not proven that the use of donor-type plasma was necessary for the success of our approach; however, the step-wise decrease in anti-A titer after each plasma exchange and the poor results previously reported with conventional TPE argue in favor of its efficacy. The use of donor-type plasma may interfere with the determination of patient isohemagglutinin titers. For this reason, we continued TPE therapy in our patient until we documented an erythroid ABO type switch rather than a fall in isohemagglutinin titers to 8, as has previously been suggested [5,8]. Finally, we have shown that delayed erythroid engraftment is not uncommon after major ABO-mismatched BMT

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for CML; however, this does not routinely require specific intervention such as erythropoietin therapy. Conversely, refractory erythroid aplasia is rare and may be responsive to plasma exchange with donor-type plasma, without a requirement for additional immunosuppressive modalities.

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