Allogeneic Stem Cell Transplantation for the Treatment of Lymphoproliferative Disorders in Patients Affected By Primary Immunodeficiencies: The UK Experience

Malignancies represent a significant morbidity for patients (pts) affected by primary immunodeficiency (PID). 4-25% of pts with PID will develop a malignancy during the course of their life, lymphoproliferative disorders being the most common. Dysfunctional T-cell surveillance, particularly against EBV, and impaired DNA repair mechanisms lie at the basis of this susceptibility. Malignancies in PID pts are difficult to treat as these pts often harbor co-morbidities that increase the risk of treatment-related toxicity. Allogeneic stem cell transplantation (SCT) offers a treatment for both PID and LPD. Data on the outcome of pts referred to SCT for LPD in PID are scant, as PID are rare and sometimes under diagnosed.We retrospectively collected data on pts 0-18 years referred to SCT for LPD in PID in the 12 pediatric SCT centres in the UK from 2000 to 2015. Centralized review for histopathology specimens and radiological imaging was performed to confirm the LPD diagnosis and the disease staging/remission status at SCT. Ethical approval was obtained.

40 patients affected by 13 different PIDs were identified, X-linked lymphoproliferative disease being the most common (15% of the pts).

Median age at LPD diagnosis was 6.1 years (range 0.2-17.2). Pts were diagnosed with a B-cell lymphoma (60%), Hodgkin lymphoma (15%), polymorphic LPD (10%), plasmacytic hyperplasia (7%), T-cell lymphoma (5%) or atypical lymphoid proliferation (3%). 83% of the pts presented with stage III/IV disease, 4% had CNS involvement. LPD proved EBER positive in 66% of the tested samples. Pts received a median of 2 lines of chemo/immunotherapy to treat LPD, which proved resistant to front line treatment in 64% of the pts. 7 pts were referred for SCT but did not receive one due to disease progression (3), donor unavailability (1) or medical decision (3). Among the non-transplanted pts, 1 died from sepsis during chemotherapy, 4 died from disease progression; the OS of this group is 28% at a median follow up of 10 months from LPD diagnosis. For the 33 pts who underwent SCT, median age at SCT was 8.4 yrs (range 0.6-17.7). 58% of the pts had 1 or more comorbidities at SCT (chronic lung disease being most common). Of these, 67% of the pts receiving SCT were in complete remission (CR), 24% in partial remission, and 10% had active disease when starting their conditioning regimen.

7 different types of conditioning regime were used, as per participating center local policies. In 94% of the cases a reduced intensity conditioning (RIC) was used. 74% of treated pts received in vivo T cell depletion with Alemtuzumab (71%) or Anti-Thymocyte Globulin (3%). 27% of the pts received the graft from a matched related, 39% matched unrelated and 33% mismatched donor. Bone marrow and peripheral blood were the most common sources of stem cells (46% and 42% of the cases, respectively).

All pts achieved neutrophil engraftment and secondary graft loss was experienced by 2 pts (6%). 4 pts (12%) died from SCT related toxicity (3 infections, 1 pulmonary VOD/hemorrhage). Acute GVHD grade I-IV developed in 42% of the pts. LPD recurred in 2 cases (1 after secondary graft loss) and was successfully treated with surgery/chemotherapy. With a median follow up of 48 months, 88.0% patients are alive, in CR post SCT. 76% of the evaluable patients exhibited a full donor engraftment at the latest follow up.

Disease stage, histology, underlying PID and remission status at SCT did not impact on the patients´ outcomes. Overall survival was significantly higher in SCT recipients as compared to patients who did not receive SCT (88 vs 28%, p= 0.03). Even among the 3 pts who underwent SCT without achieving LPD remission, OS was 67%, thus underlying that restoring competent immunity might play a role in this context, allowing for LPD control post SCT via the newly grafted T-cells.

This cohort of pts is the largest described of its kind. We conclude that SCT with RIC is safe and efficacious for pts affected by LPD in PID. While larger cohorts of pts are required to confirm these data, our study suggests that remission status at SCT plays a partial role in LPD control. As a consequence, limited pre-SCT chemotherapy might be required and SCT indication might be plausible for pts not achieving CR.