Peripheral Blood Stem Cell (PBSC) Haploidentical Transplantation Using a Reduced Intensity Conditioning (RIC), T Cell Replete Approach Proves Both Efficacious and Well Tolerated In a Range of Haematological Malignancies.
Authors: Laurie John , Hodson Andrew , Elston Tamara , Black Carol , Manwaring Ophelia , John Claire , Kazmi Majid A. , Streetly Matthew , Raj Kavita 
Published: October 2019

Abstract 4584

Haploidentical transplantation is an option for patients who do not have a timely identifiable sibling or volunteer unrelated donor (VUD).

Benefits of this stem cell source include donor availability, highly motivated donors and the ability to select the best donor from several relatives taking: age/fitness, cytomegalovirus (CMV) status, ABO group and natural killer cell alloreactivity into account.

Historically the high level of human leukocyte antigen (HLA) disparity led to increased graft failure and high rates of acute and chronic graft versus host disease (GVHD). Luznik et al (Blood 2001) demonstrated that the use of post stem cell return cyclophosphamide in RIC haploidentical transplantation (using bone marrow as a stem cell source) reduced acute and chronic GVHD to acceptable levels, but at the expense of higher relapse rates in their cohort.

We postulated that the use of PBSC's with their inherently higher T cell complement would reduce relapse rates compared to bone marrow, whilst post cell return cyclophosphamide would reduce acute and chronic GVHD.

We present 5 patients treated at our centre using a RIC T cell replete haploidentical transplant protocol utilising PBSC's and post cell return cyclophosphamide.

The patients, (median age 51; range 44–58), were treated for: relapsed follicular non Hodgkin's lymphoma (NHL), secondary acute myeloid leukaemia, Mycosis Fungoides and Adult T-Cell Leukaemia/Lymphoma (ATLL).

Four patients had received 1st line chemotherapy only and remained chemotherapy sensitive, 3 of whom were in complete remission, one in a partial response. None had undergone a previous transplant. The NHL patient was chemotherapy insensitive following 4 previous lines of chemotherapy, a splenectomy and 2 rejected sibling allografts.

Three patients were a major ABO mismatch, the remaining 2 fully matched.

Four patients were CMV +/+ and 1 mismatched.

HLA disparity ranged from 2–5 alleles (2 and 3 patients respectively).

Median CD34+ cell dose returned was 6.98×106 cells/kg (range 4.81–8.00), with a median CD3+ cell dose of 2.36×108 cells/kg (range 1.19–2.97).

The conditioning regime used was that of Luznik et al's (Blood 2001) phase I trial:

Fludarabine 30mg/m2 day -6 to -2, cyclophosphamide 14.5mg/kg day -6 to -5, total body irradiation 2 Gray day -1, post stem cell cyclophosphamide 50mg/kg day +3 to +4, tacrolimus 1mg IV day +5 onwards, mycophenolate mofetil 15mg/kg TDS day +5 to +35.

Outcomes:

Four of 5 (80%) patients were fully donor chimeric by day 28 however graft failure with autologous reconstitution due to previously undetected HLA antibodies occurred in 1 patient. This patient reconstituted autologous neutrophils and platelets at 15 and 26 days respectively.

Median time to neutrophil and platelet engraftment was 16.5 days (range 14–17) and 12 days (range 11–14) respectively.

All 5 patients reactivated CMV (the latest at day 112). With pre-emptive treatment however none developed CMV disease. The incidence of acute GVHD grade II – IV and grade III - IV by day 100 was 40% and 20% respectively. Limited chronic GVHD was seen in 3 patients. 2 were assessed as grade I-II and 1 patient grade III. All cases of acute and chronic GVHD were steroid responsive.

In both ATLL patients a sustained suppression of human T-lymphotropic virus (HTLV) viral loads was observed post transplant.

One patient subsequently died of sepsis at day 113, the patient who had rejected their graft went on to relapse.

The remaining 3 patients continue in CR, performance status 0, currently at day 245, 280 and 438.

This data shows that RIC T cell replete haploidentical transplantation using PBSC's is well tolerated and enables both early engraftment and full donor chimerism. The rates of acute and chronic GVHD (40 and 60%) are comparable to sibling and fully matched unrelated donors.

All of which has resulted in 60% of patients remaining in CR, including both ATLL patients who have gone on to fully suppress their HTLV viral loads.

Disclosures:

No relevant conflicts of interest to declare.