Successful treatment of isohemagglutinin-mediated pure red cell aplasia after ABO-mismatched allogeneic hematopoietic cell transplant using bortezomib

Pure red cell aplasia (PRCA) is a rare but well-recognized immunohematological complication that occurs in the setting of major ABO-incompatible hematopoietic stem cell transplant (HSCT).1 It has been attributed to the persistence of Ab-producing plasma cells of recipient origin, which survive the conditioning regimen and produce isohemagglutinins causing inhibition of donor erythroid progenitors in the marrow.2 Historically, patients have been treated with various strategies including high-dose EPO, plasma exchange, donor lymphocyte infusion (DLI), steroids, and more recently, with rituximab and even MSCs, with varying degree of success.1, 3, 4

We report a case of PRCA following a matched sibling donor allogeneic PBSC transplant (PBSCT) with a bidirectional ABO mismatch. He was refractory to discontinuation of immunosuppresants, rituximab and donor lymphocyte infusions. We decided to use bortezomib, a 26S proteosome inhibitor, which has been approved for the treatment of multiple myeloma5 and mantle cell lymphoma.6 This resulted in favorable response, with resolution of PRCA at about 80 days after initiation of therapy.

A 39-year-old Chinese man with poor risk acute myeloid leukemia underwent PBSCT in March 2009 from his human leukocyte Ag-matched sibling. The preparative regimen consisted of i.v. BU 130 mg/m2/day over 4 days and i.v. CY 60 mg/kg/day over 2 days. Tacrolimus and short course MTX were used as GVHD prophylaxis. The recipient was B Rh-positive, whereas the donor was A Rh-positive; other minor blood groups Ags were not tested. The recipient's pre-transplant anti-A isohemagglutinin IgG titer was 1:32. A total of 138 mL of PBSC was infused with a total nucleated cell dose of 8.71 × 108/kg and CD34+ cell count of 6.97 × 106/kg. No manipulation of the graft was carried out and there were no hemolytic complications during or after infusion. He had uneventful engraftment of neutrophils and platelets, with absolute neutrophil and platelet count's exceeding 0.5 × 109 and 20 × 109/L on D+13 and D+19, respectively, and a 100% donor chimerism at 1 month post transplant.

Following the transplant, the patient remained dependent on RBC transfusions at two weekly intervals. The diagnosis of PRCA was made on the basis of (1) his transfusion-dependent anemia of 50–70 g/L, associated with a low reticulocyte count of 0.1–0.2%, and absence of other causes for the anemia; (2) BM aspiration showing normal myeloid and megakaryocytic lineages with absent erythroid cells, and normal karyotype; (3) sustained complete donor chimerism of 100% based on STR analysis; and (4) persistent presence of anti-A isohemagglutinin titer ranging between 1:8 and 1:32. The blood group remained B (recipient's pre-transplant blood group) on both the forward and reverse grouping.

In view of the high requirement for blood transfusion, therapeutic strategies as listed below were attempted. These did not result in any improvement in transfusion requirement or increase in reticulocyte counts:

  1. 1)

    Tacrolimus was stopped at D+150 with no improvement in transfusion requirements.

  2. 2)

    Four doses of weekly rituximab 375 mg/m2, starting on D+222. This led to a transient twofold reduction in anti-A isohemagglutinin titer, but with no reticulocyte response or improvement in transfusion requirement. The anti-A isohemagglutinin titer subsequently increased back to 1:64 again after completion of rituximab.

  3. 3)

    Three doses of DLIs delivered on D+365, D+475 and D+548, with doses of 1.6 × 108, 11.6 × 108 and 5.83 × 108 CD3/kg, respectively. This was associated with a transient twofold decrease in red cell isohemagglutinin titer, but again with no reticulocyte response or improvement in transfusion requirement.

Finally, he was started on i.v. bortezomib 1.3 g/m2 weekly for 4 weeks between D+596 and D+617. He had a significant response, with undetectable anti-A isohemagglutinin titer 30 days after the first dose of bortezomib and a conversion of his blood group to A Rh-positive (donor's blood group). He also had a marked reticulocyte response with reticulocyte count increasing from 0.4% pre-bortezomib to 1.2, 2 and 5% at 30, 60 and 75 days post first dose of bortezomib therapy. This was associated with rising hemoglobin levels, and by D+726, he had become transfusion independent. Currently, he is 9 months post initiation of bortezomib and remains asymptomatic with a hemoglobin count of 130 g/L and a reticulocyte count of 1.0%, and undetectable anti-A isohemagglutinin titer. He does not have any signs of chronic GVHD and continues to have excellent performance status of 90% on the Karnofsky performance score.

The decision to use bortezomib to treat PRCA was made on the following grounds: (i) its known ability to target differentiated plasma cells, which are postulated to be responsible for the antidonor isohemagglutinin production; (ii) unpublished observations of its efficacy in patients with refractory PRCA after ABO-mismatched allogeneic HSCT.7 Our case demonstrates that bortezomib may be a useful option for patients with PRCA after ABO-incompatible HSCT, which is resistant to conventional treatment. For our patient, the improvement was unlikely to be due to spontaneous resolution of PRCA, given the prior significant transfusion requirement. We believe the obvious temporal relationship between the administration of bortezomib and the rapid recovery of erythropoiesis (see Figure 1), in parallel with the disappearance of anti-A isohemagglutinin and blood group conversion (see Figure 2) are further evidence to suggest the efficacy of this drug.

Figure 1

Response of reticulocyte (retic) and hemoglobin (Hb) with treatment. Solid line represents trend of Hb and dotted line represents reticulocyte trend. , Hb; - - -, reticulocyte; DLI, donor lymphocyte infusion.

Figure 2

Anti-A titers.

In contrast to rituximab, which targets CD20-positive B lymphocytes, bortezomib targets differentiated plasma cells that typically do not express CD20, but may be responsible for the persistent production of antidonor isohemagglutinins responsible for PRCA. This may explain both the efficacy of bortezomib in the treatment of IgM-mediated autoimmune hemolytic anemia7 as well as in our case, in which CD20 Ab rituximab was ineffective. Given the good safety profile of this treatment, bortezomib represents an important new treatment option for patients with ABO-mismatched HSCT-associated PRCA mediated by residual host isohemagglutinins.


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We thank Dr Jayesh Mehta (The Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, USA) and Dr Rainer Storb (Fred Hutchinson Cancer Research Center, University of Washington, Seattle, USA) for their invaluable advice given in the management of this case.

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Correspondence to L P Koh.

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Poon, L., Koh, L. Successful treatment of isohemagglutinin-mediated pure red cell aplasia after ABO-mismatched allogeneic hematopoietic cell transplant using bortezomib. Bone Marrow Transplant 47, 870–871 (2012).

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