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Published in final edited form as: Bone Marrow Transplant. 2016 Sep 19;51(12):1579–1583. doi: 10.1038/bmt.2016.228

Autoimmune Hemolysis and Immune Thrombocytopenic Purpura After Cord Blood Transplantation (CBT) May be Life-threatening and Warrants Early Therapy with Rituximab

Valkal Bhatt 1, Leyla Shune 2, Emily Lauer 2, Marissa Lubin 2, Sean M Devlin 3, Andromachi Scaradavou 4, Rekha Parameswaran 5, Miguel A Perales 2,6, Doris M Ponce 2,6, Simon Mantha 5, Nancy A Kernan 4, J N Barker 2,6
PMCID: PMC5338737  NIHMSID: NIHMS852187  PMID: 27643868

Abstract

Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9–70) transplanted for hematologic malignancies with myeloablative or non-myeloablative conditioning and calcineurin-inhibitor (CNI)/ mycophenolate mofetil. With a median 5.2 year (range 1.6–9.7) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8–24.5) post-CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin ≤ 6 g/dl and/ or platelets < 20 × 109/L). All AH patients were direct anti-globulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute graft-versus-host disease. All 10 patients received rituximab 2–18 days after diagnosis, and corticosteroids combined with rituximab within < 7 days was the most effective. No patient died of AH/ ITP. AH/ ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.

Keywords: Cord blood transplantation, autoimmune hemolysis, immune thrombocytopenia

Introduction

Autoimmune complications including autoimmune hemolytic anemia (AH) and immune thrombocytopenic purpura (ITP) are well-recognized after hematopoietic stem cell (HSC) transplantation.(REF 1, 2, 3, 4, 5) A recent retrospective registry analysis described the development of autoimmune diseases after cord blood transplantation (CBT).(REF 6) The overall incidence of autoimmune disease was 5% and most commonly manifested as AH or ITP. However, the literature describing the manifestations of AH and ITP after CBT is limited and the optimal therapy is not established.(REF 7, 8, 9, 10, 11). We performed a retrospective study to characterize the incidence, severity, treatment response, and prognosis of these autoimmune cytopenias in CBT recipients transplanted at our center.

Materials and Methods

Patients

Eligibility for study inclusion included patients who underwent CBT October 2005–June 2014 for the treatment of hematologic malignancies who had sustained donor engraftment and were disease-free 100 days post-transplant. This landmark was chosen as no patient developed AH/ITP prior to day 100. Permission to use clinical and laboratory information was obtained from the Memorial Sloan Kettering Cancer Center Institutional Review/Privacy Board.

Conditioning regimens, GVHD prophylaxis and treatment

Conditioning was predominantly cyclophosphamide, fludarabine, and total body irradiation-based, although a small cohort of pediatric patients received chemotherapy-only preparative regimens. A calcineurin-inhibitor (CNI) and mycophenolate mofetil (MMF) were used for graft-versus-host disease (GVHD) prophylaxis.(REF 12, 13, 14, 15) All patients received double unit grafts comprised of 2 units that were 4–6/6 HLA-A, -B antigen, -DRB1 allele matched to the recipient. No patients during the study period received single unit grafts per MSKCC policy. GVHD was diagnosed, graded and treated as previously described (REF 16).

Definitions

AH was diagnosed in the setting of decreasing hemoglobin (Hb), increased lactate dehydrogenase (LDH, range 120–246 U/l), increased unconjugated bilirubin (range 0–1 mg/dL), haptoglobin < 1 mg/dL (range 40–240 mg/dL), and a positive direct antiglobulin test (DAT).(REF 17, 18) Severe AH was defined as a Hb ≤ 6 g/dL. Complete response (CR) was sustained increase in Hb > 8 g/dl, resolution of markers of hemolysis and independence from blood transfusions. ITP was diagnosed according to standard published criteria in patients with a platelet count < 100 × 109/L in the absence of any other causes of thrombocytopenia.(REF 19) Analysis for the presence of platelet antibodies was not performed due to its questionable utility in ITP diagnosis.(REF 20, 21) Severe ITP was defined as a platelet count less than 20 × 109/L. CR was characterized by sustained increase in platelet count > 100 × 109/L and independence from transfusions.

Statistical Analysis

Competing risks methodology was used to estimate the incidence of AH/ ITP following the 100-day landmark. Competing events include relapse or death in the absence of autoimmune cytopenias. Estimation was done using the R statistical platform.

Results

Characteristics of the dCBT cohort

One hundred and fifty-two patients alive and disease-free at day 100 were analyzed. Patient characteristics are described in Table 1. The median age was 37 years (range 0.9–70) and 88 (58%) were male. The most common indication for dCBT was acute leukemia (n = 94, 62%) and the majority of patients (n = 123, 81%) received high dose or intermediate intensity conditioning. The 29 pediatric patient group in the study had a much lower percentage of recipient CMV seropositivity (31% as compared to 61% in adults) and were almost exclusively transplanted for acute leukemia (28 of 29 children) with myeloablative conditioning. Ninety-seven (64%) patients had grade II–IV aGHVD (71 grade II, 22 grade III, 4 grade IV) by day 100 by IBMTR criteria (REF 16). The incidence of cGVHD at 1 year post-transplant was 17%.

Table 1.

Characteristics of Patient Cohort

Characteristic Value
Median (range) age / weight 37 years (0.9– 70) / 69 kg (8.3– 125)
N (%) male / female 88 (58%) / 64 (42%)
N (%) recipient CMV seropositive 84 (55%)
N (%) 0–17 years / ≥ 18 years 29 (19%) / 123 (81%)
N (%) diagnosis
 Acute leukemia 94 (62%)
 MDS/ MPD (< 10% blasts) 7 (5%)
 CLL, NHL, Hodgkin lymphoma 51 (34%)
Median (range) infused CD34+ dose (x 105/kg) Larger: 1.21 (0.26–6.97)
Smaller: 0.64 (0.13–2.12)
Median (range) infused TNC dose (× 107/kg) Larger: 2.67 (1.42–12.79)
Smaller: 1.98 (0.92–7.09)
Median (range) donor-recipient 8 allele HLA-match 5/8 (range 2–8/8)
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Abbreviations: CMV, cytomegalovirus; MDS, myelodysplasia; MPD, myeloproliferative disorder; CLL, chronic lymphocytic leukemia; NHL, Non-Hodgkin lymphoma; TNC, total nucleated cell dose; HLA, human leukocyte antigen.

Incidence and features of AH/ ITP

With a median 5.2 year (range 1.6–9.7) survivor follow-up after dCBT, 10 patients (median age 42 years, range 2–54) developed autoimmune cytopenias (AH, ITP or both) for a cumulative incidence of 7% (95%CI: 3–11) at 3-years after the day 100 landmark (Figure 1). The median onset was 10.4 months (range 5.8–24.5) post-CBT. Eight developed AH, one patient developed ITP alone, and one patient had both AH and ITP. The patient characteristics and the features of the AH/ ITP are shown in Table 2. Many months prior to the onset of AH/ITP, all patients had complete donor-derived hematopoietic recovery, were transfusion independent, and were documented to be 100% donor chimeric. Alternative reasons for cytopenias such as myelosuppressive drugs or relapse were not present in any patient and no patient had an active infection immediately prior to or at the time of AH/ ITP diagnosis.

Figure 1.

Figure 1

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Cumulative incidence of AH/ ITP in dCBT recipients alive, engrafted and disease-free 100 days after CBT.

Table 2.

Characteristics of Patients with AH/ ITP

Pt/ Age @dCBT/Regimen AH/ITP/Both Mos. Onset Lowest Hb/Plts Prior aGVHD/ grade/day of onset Initial Therapy Days to CR after Start of Treatment Flare (Yes/ No)/ Treatment at Flare Splenectomy Survival
1/ 42 yrs/ NMA AH 8.6 Hb 6.5 Yes/ Gr. I/ Day 52 Day 0: observed.
Day 7: rituximab (weekly × 4 doses).		 42 Yes-once/ Rituximab (weekly × 4 doses) No Alive (9.3 years)
2/ 29 yrs/ NMA ITP 12.2 Plts 4 Yes/ Gr. II/ Day 26 Day 0: IVIg (500 mg/kg/day × 4).
Day 8: rituximab (weekly × 3 doses).
Day 9: dexamethasone (40 mg/day × 4 days).
Day 50: splenectomy		 98 No Yes Alive (6.7 years)
3/ 42 yrs/ NMA AH 24.5 Hb 5.0 Yes/ Gr. II/ Day 36 Day 0: observed.
Day 4: prednisone (1 mg/kg/day)
Day 14: rituximab (weekly × 4 doses)		 45 Yes-multiple/ Rituximab (weekly × 4 doses), Prednisone (1 mg/kg), Splenectomy Yes Alive (5.9 years)
4/ 47 yrs/ RIC AH 18.2 Hb 6.7 Yes/ Gr. III/ Day 48 Day 0: CSA increase.
Day 14: rituximab (weekly × 5 doses).		 53 Yes-once/ Rituximab (weekly × 3 doses), Prednisone (1 mg/kg), IVIg (400 mg/kg × 5) No Alive (4.7 years)
5/ 51 yrs/ NMA AH 14.2 Hb 4.6 Yes/ Gr. II/ Day 175 Day 0: IVIg (500 mg/kg/day × 4).
Day 12: MP (1 mg/kg/day).
Day 18: rituximab (weekly × 4 doses).
Day 39: splenectomy		 61 No Yes Died (2.1 years)
6/ 2 yrs/ MA AH 8.4 Hb 6.8 No Day 0: IVIg (500 mg/kg/day × 4) + MP (2 mg/kg/day)
Day 11: rituximab (weekly × 4 doses).		 19 No No Alive (2.7 years)
7/ 34 yrs/ RIC AH 7.2 Hb 2.6 No Day 0: IVIg (500 mg/kg/day × 4) + MP (1 mg/kg/day)
Day 6: rituximab (2 doses week 1 then weekly × 2 doses)		 12 No No Alive (2.2 years)
8/ 50 yrs/ RIC AH 14.8 Hb 9.0 Yes/ Gr. II/ Day 34 Day 0: prednisone (0.5 mg/kg/day).
Day 2: rituximab (weekly × 2 doses).		 7 Yes-once/ Rituximab (weekly × 4 doses), Prednisone (0.5 mg/kg) No Alive (2.1 years)
9/ 26 yrs/ RIC Both 5.8 Hb 4.9/Plts 0 Yes/Gr. II/Day 17 Day 0: IVIg (500 mg/kg/day × 4) +MP (1 mg/kg/day).
Day 2: rituximab (weekly × 6 doses).		 13 No No Alive (1.9 years)
10/ 54 yrs/RIC AH 6.2 Hb 3.3 Yes/ Gr. III/ Day 21 Day 0: IVIg (500 mg/kg/day × 4) + MP (2 mg/kg/day).
Day 4: rituximab (2 doses week 1, then weekly × 2 doses)		 7 No No Alive (1.7 years)
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Abbreviations: NMA, nonmyeloablative; RIC, reduced intensity conditioning; AH, autoimmune hemolysis; ITP, immune thrombocytopenia purpura; Hb, hemoglobin; Plts, platelets; IVIg, intravenous immune globulin; MP, intravenous methylprednisone; CR, complete remission; aGVHD, acute graft versus host disease.

All 9 patients with AH were polyspecific IgG positive with eluate demonstrating a warm panagglutinin. The lowest Hb (median 5 g/dL, range 2.6–9.0) was observed a median of 1 day (range 0–94) after diagnosis, and 5 AH patients had severe disease (Hb ranging 2.6–5.0 g/dL) at presentation. The median peak LDH was 473 U/L and ranged 300–1486 U/L (normal LDH 120–246 U/L), and haptoglobin was < 1 mg/dL in all patients. Both patients with ITP presented with severe disease (platelet count undetectable and 4 × 109/L, respectively).

Eight of the 10 patients had a history of grade II–IV acute GVHD prior to the onset of AH/ ITP (Table 2). One patient had grade I skin aGVHD treated with topical corticosteroids whereas 5 had grade II and 2 had grade III treated with either budesonide (n = 5) or low dose prednisone (n = 2). The median onset of aGVHD in these 8 patients was 35 days (range 17–175) post-transplant. Thus, the median onset of the AH/ ITP was many months later than the median time to onset of the AH/ ITP. At the time of onset, all 10 AH/ ITP patients had either recently tapered off all immune suppression (n = 2) or were on low dose therapy (n = 8). There was no association between recipient age, diagnosis, conditioning intensity, ABO mismatch or recipient CMV serostatus and AH/ ITP (data not shown).

Treatment and response to therapy

Upon recognition of severe hemolysis and/ or thrombocytopenia all patients received packed red blood cell and/ or platelet transfusion support as needed although all were transfusion refractory due to the autoimmune process. Treatment during the first week included single agent or combination therapy with intravenous immune globulin (IVIg), intravenous methylprednisolone, rituximab (375 mg/m2/dose), or CNI dose escalation (Table 1). All 10 patients received rituximab commencing 2–18 days (4–6 total doses) after initial diagnosis. In 6 patients (patients 1–6) who received staggered therapy at diagnosis including treatment delay or only IVIg, and received rituximab 7–18 days from diagnosis, the time to CR ranged 19–98 days, and 3 of 6 underwent splenectomy. In the 4 patients (patients 7–10) who were treated with corticosteroids at diagnosis with rituximab within 2–6 days, the time to CR was shorter ranging 7–13 days and none underwent splenectomy.

Patients 2 and 5 underwent splenectomy as part of initial therapy. Patient 2 with ITP was initially treated with IVIg alone followed by weekly rituximab for 3 doses, dexamethasone (40 mg/day for 4 days), and romiplostim 1–10 ug/kg titrated weekly for 5 doses. Due to sub-optimal response, splenectomy was performed at 50 days and CR was achieved 98 days after diagnosis. Patient 5 with AH was initially treated with IVIg, and subsequently methylprednisolone. Weekly rituximab for 2 doses was started 18 days after diagnosis. Splenectomy was performed at 39 days followed by further rituximab weekly for two doses and continuation of prednisone. CR was documented at 61 days after diagnosis. In all patients, the recovery from AH was accompanied by correction of biochemical parameters associated with hemolysis.

Patients 1, 3, 4, and 8 flared at 1–13 months after initial CR. All patients received additional rituximab (2–4 doses) ± additional corticosteroids and/or IVIg. Patients 1, 4, and 8 achieved CR with pharmacologic therapy. Patient 3 required splenectomy to achieve control of AH with CR documented 4 months later but recurrent flares have required ongoing corticosteroid therapy. There was no recurrent GVHD in any of the 4 patients who flared their AH/ ITP.

Survival and adverse events

Nine of 10 patients with AH/ ITP patients are alive and disease-free whereas one (patient 5) died of GVHD in CR from AH. Eight of the 9 surviving patients remain in CR from AH/ ITP at a median of 1.8 years after AH/ ITP diagnosis (range 0.9–8.6). Rituximab treatment was well tolerated. After rituximab, one patient developed severe neutropenia (< 0.5 × 109/L) documented once, and 2 additional patients became neutropenic (lowest counts 1.0–1.5 × 109/L, respectively). All 3 patients received filgrastim and promptly responded within < 7 days. Four patients required transient IVIg repletion Patients received mold prophylaxis for the period of high dose corticosteroids. All patients were still on Herpes simplex/ zoster and pmeumocystis prophylaxis at the time of AH/ ITP onset and these were continued as guided by the patients’ immune reconstitution. Additionally, patients who underwent splenectomy were placed on long term prophylaxis for encapsulated organisms. With this prophylaxis, no patient developed an infection attributable to AH/ ITP therapy. Patient 5 did develop multiple infections post-AH therapy but this was in the context of active GVHD therapy. This patient was not neutropenic but had undergone splenectomy. The infections were not directly attributable to rituximab but were attributable to GVHD and severe T-cell immune compromise.

Notably, all 3 patients who underwent splenectomy required intensive care unit (ICU) transfer during the course of their surgery. Two patients required peri-surgical ICU management due to the requirement for complex medical care including intravenous medications, hydration, narcotics, antibiotics and intensive transfusion needs whereas in one AH patient despite a normal platelet count, the splenectomy was complicated by life-threatening post-operative hemorrhage into the splenic bed.

Discussion

We analyzed the incidence, characteristics and outcome of autoimmune cytopenias after dCBT in a large, predominantly adult population. Although occurring infrequently (7% at 3 years after the day 100 landmark), the autoimmune cytopenias are often of sudden onset and may be life-threatening. Of the 10 patients, 6 had a Hb ranging 2–5 g/dL and/or platelets < 5 × 109/L, and in both settings these severe cytopenias were unsupportable by red blood cell and/or platelet transfusions. The fact that the median onset of this complication is relatively late post-transplant is of further concern as patients may be undergoing less frequent follow-up and returned to community physicians away from the transplant center. Most of the patients had a prior history of aGVHD and all autoimmune cytopenias occurred in the setting of immunosuppression taper. This suggests that the mechanism is related to transient immune dysregulation and highlights the need for monitoring of CBT recipients during this period of highest risk.

While treatment in this series was not standardized, all 10 patients received rituximab 2–18 days after diagnosis. The most effective therapy was corticosteroids at diagnosis combined with rituximab within 2–6 days (patients 7–10). By contrast, serial or staggered therapy (patients 1–6) was less successful. Outcome of AH/ITP patients was good and no patient died of autoimmune cytopenias. Rituximab treatment was well tolerated although transient support with IVIg and/or growth factor may be necessary. However, all 3 patients who underwent splenectomy in this series required ICU transfer.

The incidence of AH/ITP in our analysis is similar to the rates of autoimmune cytopenias published in single center studies after adult donor allograft recipients.(REF 1, 2, 4, 5, 22) For example, a 4.4% cumulative incidence of AH has been reported in adult allogenic transplant recipients at 3 years. Multivariate analysis identified the presence of chronic GVHD, use of unrelated donors, T-cell depletion and concomitant viral infections as risk factors.(REF 3) In contrast to our report in adult CBT recipients, Page et al reported a 52% incidence of autoimmune cytopenia in a small cohort of very young infants at 2 years after CBT. Conversely, Sanz et al has reported a 5.4% incidence of AH and 1.4% incidence of ITP in adult single unit CBT recipients at 3 years post-transplant.(REF 11) In contrast to our report, the majority of AH patients in this analysis had cold agglutinins, concomitant viral infections, and chronic GVHD and this complication was associated with a high mortality.

Overall, the retrospective nature of this series is a limitation of this report and a large prospective randomized controlled trial would be required to define AH/ ITP risk factors and its optimal therapy. However, such studies are unlikely to be performed given the uncommon nature of this complication. In the interim, vigilance for this potentially life-threatening complication with early treatment with combined corticosteroids and rituximab is warranted in patients with severe disease. Our hypothesis is that this combined initial therapy will both speed response as well as ultimately lessen the duration of corticosteroid therapy permitting a more rapid and effective corticosteroid taper. Limitation of corticosteroid exposure as much as possible in this patient population is critical due to their risk of serious viral and fungal infections including cytomegalovirus and mold, as well as other toxicities such as cushingoid facies, steroid myopathy, osteopenia and diabetes. Early rituximab could also potentially avoid the requirement for splenectomy in most patients. While rituximab did not avoid flares in all patients, it is possible that early rituximab with 4 doses could also potentially reduce the likelihood of disease flare upon corticosteroid taper in many. For these reasons, a course of rituximab combined with corticosteroids at diagnosis is now the standard of care for CBT recipients with AH/ITP at our center with rapid corticosteroid taper once CR is achieved.

Acknowledgments

This work was supported in part by the Gabrielle’s Angel Foundation for Cancer Research (J.N.B.), the Society of Memorial Sloan-Kettering Cancer Center (J.N.B. and S.G.), the Memorial Sloan Kettering Cancer Center Translational and Integrative Medicine Research Program (J.N.B.), P01 CA23766 from the National Cancer Institute, National Institutes of Health and the Memorial Sloan-Kettering Cancer Center Support Grant/Core Grant (P30 CA008748).

Footnotes

Conflict of Interest

The authors have no relevant financial conflicts of interest to declare.

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