Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Stage Mycosis Fungoides and Sézary Syndrome

A Concise Review

William T. Johnson; Reetu Mukherji; Saritha Kartan; Neda Nikbakht; Pierluigi Porcu; Onder Alpdogan

Disclosures

Chin Clin Oncol. 2019;8(1) 

In This Article

HSCT: Advancements

High-dose chemoradiotherapy followed by HSCT is a potentially curative modality for a variety of hematologic disorder that are incurable with conventional dose chemotherapy.[12] We consider that using less intensive conditioning regimens, progress in alternative donor transplantation including haploidentical and cord blood stem cell transplantation, development of better T-cell depletion methods including CD34+ cell purification and progress in post-transplant immunosuppressive therapy the major advancements in the last two decades.

Development of Less Intensive Conditioning Regimens

These approaches do not use dose intensity of chemotherapy/radiation therapy to eradicate malignancy. Rather they use immunosuppressive agents, irrespective of their anti-neoplastic properties, to facilitate donor lymphoid and stem cell engraftment. The donor lymphoid elements then destroy the residual normal and malignant lymphohematopoietic elements allowing the transition to complete donor chimerism.[13,14] This type of transplant has been dramatically effective in chronic myeloid leukemia, chronic lymphocytic leukemia, and follicular lymphoma in its original application and may have utility in other diseases as well.[13–16] This approach disproved the earlier dogma in the transplant community that engraftment required the administration of high dose, highly toxic, and lethally ablative conditioning regimens to sufficiently destroy the host immune system to avoid graft rejection. Although used for various patient populations, reduced intensity transplant has broadened the applicability of HSCT to older patients and to patients with comorbidities who otherwise would not tolerate the rigors of a fully myeloablative HSCT.[17,18]

Regimens that are not lethally myeloablative have generated consistent engraftment using immunosuppressive drugs such as fludarabine in combination with other chemotherapeutic agents such as melphalan, busulfan or low dose total body irradiation (TBI).[16–18] Alternative reduced intensity approaches using low dose irradiation and a synergistic immunosuppressive combination of cyclosporine and mycophenolate mofetil have produced comparable results.[19] Although graft-versus-host disease (GVHD) was particularly problematic, this regimen provides proof of principle that reduced intensity HSCT is a promising treatment for older patients and those patients with significant comorbidities.

Approaches to Alternate Donors and Progress in Haploidentical HSCT

A barrier to the application of reduced intensity transplantation in hematologic malignancies is the availability of donors. Only 30% of patients in North America who may benefit from HSCT will have a human leukocyte antigens (HLA)-matched sibling donor.

In the last two decades, new developments in haploidentical HSCT have made it a viable alternative donor option. In selected centers, haploidentical HSCT has produced excellent results in patients with hematological malignancies. Murine and human hematopoietic stem cells are able to decrease alloreactivity of cytotoxic T-cells, which is called "veto cell activity"[20,21] and immune tolerance can be induced by using high doses of stem cells especially in major histocompatibility complex (MHC)-mismatched donor/host combinations.[22] Aversa et al. successfully used a mega-dose of CD34+ stem cells with an enhanced myeloablative and immunosuppressive protocol in haploidentical transplantation, which resulted in high-level engraftment of MHC disparate stem cells.[23] Although almost all patients engrafted well, transplant related mortality still remained high because of increased risks of infection.[24,25] On the other hand, missing MHC class I molecules in recipients of haploidentical HSCT induced donor NK cell activity, which is directly linked to "killer cell immunoglobulin like receptors (KIRs)". Ruggeri et al. showed donor-versus-recipient NK cell activity could eliminate leukemic relapse and graft rejection.[26] Transplantation from NK-alloreactive donors was associated with significantly lower relapse rate and survival in patients with acute myeloblastic leukemia.[27] Using the cytokines during stem cell collection would also improve outcome of the transplant. Huang et al.reported a large group of patients with successful engraftment and relatively low treatment related mortality (TRM) by using granulocyte colony stimulating factor (G-CSF) primed bone marrow and peripheral blood stem cells.[28] The Peking University group recently reported the largest haplo-HSCT study using unmanipulated G-CSF primed bone marrow and peripheral blood stem cells in 756 acute leukemia patients with successful outcomes.[29]

Strategies to Induce Lymphocyte Tolerance in HSCT

The removal of lymphocytes from the donor product has been critical to avoid the lethal GVHD that would occur due to the high degree of HLA disparity in partially-matched related HSCT. If there was a mechanism to add donor lymphocytes to the transplant process without causing significant GVHD, morbidity from graft rejection, infection, and relapse (three significant contributors to morbidity in this type of transplant) would likely decrease. If donor-host tolerance could be established at the time of the transplant, the removal of T- cells would not be necessary. In this scenario, haploidentical HSCT could be infused into the recipient as long as tolerance was established. There is data regarding the immune modulating effects of many drugs, such as cyclophosphamide (CTX) which may be exploited to create immune tolerance and immune modulation of donor lymphocytes in the transplant inoculum.[30–32]

Utilizing CTX

CTX is a well-known alkylating chemotherapeutic medication and is widely used as a part of myeloablative protocols in combination with TBI. Luznik et al. showed in the preclinical murine HSCT experiments that post-transplant CTX (PT-CTX) administration resulted in a durable engraftment in the recipients of MHC-matched and -mismatched donors after non-myeloablative regimens.[32–35] O'Donnell and colleagues reported that partially HLA-mismatched bone marrow could provide rapid and stable engraftment after PT-CTX.[36] Recently, the Bone Marrow Transplant Clinical Trials Network (BMT-CTN) evaluated the efficacy of haploidentical HSCT with PT-CTX and double cord blood transplantation. They found similar efficacy between these alternative donor-transplants.[37] Ciurea et al. with data from the Center for the International Blood and Marrow Transplant (CIBMTR) showed that survival for patients with acute myeloid leukemia after haploidentical transplantation with PT-CTX is comparable with matched unrelated donor transplantation.[38] Grosso et al. modified this approach to give cyclophosphamide after administration of a fixed dose of donor T-cells to induce tolerance prior to stem cell transplantation.[39]

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