Clinical Case of the Month – Thrombocytopenia Post-Haploidentical SCT in an Adolescent Patient

August 2024 Clinical Case of the Month

Title: Thrombocytopenia Post-Haploidentical Stem Cell Transplantation in an Adolescent Patient.

Physicians' expert perspective: Prof Estelle Verburgh, Haematology Department, University of Cape Town Groote Schuur Academic Hospital, Cape Town, South Africa

A 15-year-old adolescent male received a peripheral blood haploidentical stem cell transplant (haploSCT) from his younger male sibling (11 years old) for a new diagnosis of severe aplastic anaemia. The transplant was complicated by a major ABO mismatch (recipient: B positive, donor: AB positive) but did not require pre-transplant manipulation due to low antibody titers. He received 5 red cell units and 1 apheresis platelet unit prior to transplant. There were no donor specific HLA-antibodies and both recipient and donor were CMV IgG positive. The conditioning regimen followed a modified Baltimore protocol, including post-transplant cyclophosphamide (50 mg/kg), ciclosporin, and mycophenolate mofetil as graft versus host disease (GVHD) prophylaxis.

Pre-engraftment complications included Carbapenem Resistant Enterobacteriaceae (CRE) colonization and neutropenic fever with Extended Spectrum Beta-Lactamase Klebsiella pneumoniae bacteremia. Platelet engraftment occurred on day +16 and neutrophil engraftment occurred on day +22, with a mixed peripheral blood chimerism of 92% on day +30, 91% on day +60, and 94% on day +90. The patient did not develop Graft versus Host Disease (GVHD) and achieved robust peripheral blood counts. Consideration was given to switch the patient from valaciclovir to ganciclovir for a fluctuating low level CMV viraemia (CMVVL) but this did not progress beyond 1-2 log IU/mL. The patient continued on ciclosporin as per aplastic anaemia transplantation guidelines, and on valaciclovir for CMV prophylaxis.[1]

In the fifth month post SCT he developed severe neutropenia. The recurrent episodes of neutropenia coincided with high normal ciclosporin levels and in absence of other causative drugs, the patient was switched from ciclosporin to tacrolimus with recovery of neutropenia. A lack of compliance regarding the administration of fluconazole and tacrolimus, resulted in severely high tacrolimus levels of 29 ng/mL and transient renal impairment, and an abrupt fall in platelet count from 330, to 5 x 10*9 platelets.. A thrombotic microangiopathy was ruled out, and drug toxicity triggering an immune thrombocytopenia was considered the most likely cause. The platelet count failed to recover on withdrawal of tacrolimus and did not respond to a short course of high dose steroid therapy, as well as high dose intravenous immunoglobulin therapy. One week later, treatment with a thrombopoietin mimetic was commenced. The severe thrombocytopenia persisted and was further complicated by epistaxis and increasing platelet refractoriness even to HLA-matched platelets. In this period the bone marrow examination confirmed normal cellularity. Full donor chimerism >95% was also documented.

The thrombocytopenia that developed six months after haploSCT in this patient can best be defined as:

A. Prolonged isolated thrombocytopenia (PIT) following allogeneic SCT 
B. Immune thrombocytopenia not related to SCT
C. Tacrolimus bone marrow toxicity
D. Secondary failure of platelet recovery (SFPR) post SCT
E. Immune thrombocytopenia post SCT

Expert perspective by Estelle Verburgh:

Thrombocytopenia occurring in the period following an allogeneic SCT is a common occurrence with multifactorial etiology.[2] When thrombocytopenia occurs persistently, or develops suddenly, it is significantly associated with increased morbidity and mortality. This patient had a stable and favorable course post haploSCT, until day +181 when there was a sudden occurrence of a severe thrombocytopenia that proved refractory to therapy.  Initially the thrombocytopenia was clearly related to the development of tacrolimus toxicity. Nevertheless, this occurrence exerted a multifactorial domino effect in which a wide range of etiologies had to be considered, ruled out, and where possible, treated.[2]

There are various definitions for the thrombocytopenia occurring in different settings post SCT. Prolonged isolated thrombocytopenia (PIT) is defined as recovery of other cell counts with continuous dependence on platelet transfusions for greater than 90 days after SCT.[3] This patient clearly did not fit this category, an ominous one related either to the increased platelet turnover of GVHD, sinusoidal obstruction syndrome, thrombotic microangiopathy and various infections, or to the impaired platelet production of a poorly functioning graft, stem cell /stromal microenvironment failure, drug toxicity, and disease recurrence. Another important category with related etiology is secondary failure of platelet recovery (SFPR) defined as a decline of platelet counts below 20,000/μL for 7 consecutive days or requiring transfusion support after achieving sustained unsupported platelet counts ≥50,000/μL for 7 consecutive days post SCT.[4] These two conditions are respectively described to occur in approximately 5% and 20% of SCT patients, and confers a considerable mortality risk. In this patient, the late occurrence of extremely low platelet counts in the post-SCT course, made the diagnosis of SFBR less likely.

There are other causes of post SCT thrombocytopenia. In this patient the treatment of the immune thrombocytopenia had to be carefully considered, and attention given to other potential causes of morbidity. There is the prolonged dysregulated immunity of a haploSCT, and the prolonged treatment with calcineurin inhibitors in a patient transplanted for aplastic anaemia who exhibited early mixed chimerism.[1] Apart from steroid and immunoglobulin therapy, the value of thrombopoietin mimetics have been described in post SCT thrombocytopenia.[5, 6] However, the immune thrombocytopenia proved refractory after three weeks’ treatment duration.

Conclusion and further course:

Not unexpectedly, after the steroid treatment the patient developed an increase in the CMVVL to 2132 IU/mL and was admitted for intravenous ganciclovir. The CMVVL had already spontaneously decreased to 700 IU/mL on the day of ganciclovir initiation – making the virus a less likely etiological factor contributing to the thrombocytopenia. A new finding of an EBV viraemia 4 log IU/mL, coincided with the decision to administer rituximab for the refractory immune thrombocytopenia, and a response is awaited two days post administration.

Correct Answer: E

References:

1. Iftikhar, R., et al., Allogeneic hematopoietic stem cell transplantation in aplastic anemia: current indications and transplant strategies. Blood Rev, 2021. 47: p. 100772.
2. Bento, L., et al., Thrombocytopenia and Therapeutic Strategies after Allogeneic Hematopoietic Stem Cell Transplantation. J Clin Med, 2022. 11(5).
3. Bielski, M., et al., Prolonged isolated thrombocytopenia after hematopoietic stem cell transplantation: morphologic correlation. Bone Marrow Transplant, 1998. 22(11): p. 1071-6.
4. Bruno, B., et al., Secondary failure of platelet recovery after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 2001. 7(3): p. 154-62.
5. Kilic Gunes, E., et al., Eltrombopag treatment in thrombocytopenia following hematopoietic stem cell transplantation: A multicenter real-world experience. Leuk Res, 2024. 140: p. 107484.
6. Peffault de Latour, R., et al., Romiplostim in patients undergoing hematopoietic stem cell transplantation: results of a phase 1/2 multicenter trial. Blood, 2020. 135(3): p. 227-229.

Future Clinical Case of the Month

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