Posttransplant Cyclophosphamide: A Unique Approach for Prevention of Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation
Ashley Glode, PharmD BCOP Assistant Professor
University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences
Oncology Clinical Pharmacist
University of Colorado Anschutz Medical Campus
Denver,CO
The number of allogeneic hematopoietic stem cell transplants (HSCT) in the United States has steadily increased since the 1990s.1 Allogeneic HSCT is a potentially curative treatment option for various malignant and nonmalignant hematologic conditions. Transplant has expanded as a treatment option for patients because of advancements in conditioning approaches and stem cell sources as well as graft versus-host-disease (GVHD) prevention strategies. Despite these improvements, GVHD remains a major source of posttransplant morbidity and mortality. Specific improvements in GVHD prophylaxis have positively affected acute GVHD, but incidence rates remain in the 20%–60% range.2 Few improvements have been made on the incidence and severity of chronic GVHD, which is reported to occur in up to 80% of patients alive more than 100 days posttransplant. Chronic GVHD is a multisystem disease that can affect a wide variety of tissues. It may involve inflammation and fibrosis of the eyes, oral mucosa, skin, fascia, lungs, liver, gastrointestinal tract, joints, salivary glands, and genitourinary tract. Given all the organ systems potentially involved, it can have a major impact on quality of life. Chronic GVHD management continues to be a significant health-related problem in HSCT survivors because of the increased use of mobilized peripheral blood stem cells as a donor source, which has been associated with higher rates of chronic GVHD compared with bone marrow.2
Calcinuerin inhibitors (CNIs), such as tacrolimus or cyclosporine, combined with methotrexate (MTX) have been employed as GVHD prophylaxis for the past several decades and continue to be the most commonly utilized regimens by transplant centers in the United States. This strategy has resulted in satisfactory prevention rates and survival outcomes but is associated with treatment-related toxicity. Common side effects include nephrotoxicity, hypertension, neurotoxicity, and metabolic abnormalities. Improvements on standard CNI-based regimens for GVHD prophylaxis are needed to decrease GVHD rates and provide alternatives with a better side effect profile.2
The Science Behind Posttransplant Cyclophosphamide
Cyclophosphamide (Cy) has been used for decades as a treatment for several malignancies and is tolerated in a wide range of dosages. It is broken down by the cytochrome P450 system into two metabolites: phosphoramide mustard (the active metabolite) and acrolein. Cy prevents cell growth by crosslinking DNA strands. It is effective throughout the cell cycle but is most effective during the G1 and S phases. Cells rapidly undergoing mitosis are uniquely sensitive to Cy’s mechanism of action because of their reduced ability to replicate the damaged DNA. Aldehyde dehydrogenase is an enzyme required for conversion of phosphoramide mustard to an inactive metabolite, carboxycyclophosphamide. Hematopoietic stem cells possess this enzyme and are therefore resistant to Cy, allowing it to be used after HSCT without impairing engraftment.3
Immune reactions of donor T cells against contrasting host histocompatibility antigens lead to the development of GVHD after allogeneic HSCT. CNI-based GVHD prophylactic strategies weaken alloreactive T cell activation, proliferation, and interleukin-2 (IL-2) production and hinder the apoptosis of alloreactive T cells. The results of these actions cause widespread immunosuppression and delayed induction of transplant tolerance. Of the immunosuppressive agents currently employed, MTX and Cy can induce apoptosis of alloantigen-activated human T cells. Doses of MTX needed for the elimination of alloactivated T cells and tolerance induction cannot safely be given. Fortunately, Cy can be administered in the high doses required for the eradication of alloactivated T cells after allogeneic HSCT.4
Regulatory T cells (Tregs) also play an important role in the establishment of tolerance between the transplant recipient and donor-derived immunity. In animal studies, depletion of Tregs from the stem cell graft resulted in increased GVHD, and an increase in Tregs resulted in GVHD suppression posttransplant. When GVHD occurs in humans, Tregs are at a lower frequency than in patients without GVHD. It is thought that reconstitution of Tregs after HSCT is required to establish a well-balanced immune system that can maintain appropriate levels of tolerance between the transplant recipient and the donor-derived immunity. Studies show that CNIs have negative effects on Treg reconstitution, while mycophenolate mofetil (MMF) and sirolimus may promote posttransplant Treg recovery, making Cy used with either agent an at- tractive GVHD prophylaxis strategy.2
A three-step mechanism to explain the stimulation of early tolerance by posttransplant Cy has been postulated by scientists. In the first step, early proliferating alloreactive donor and recipient T cells are selectively destroyed by the administration of Cy. In the second step, the in-creased Tregs counterbalance the effect of any remaining alloreactive mechanisms. In the final step, the delayed but long-lasting intrathymic clonal removal of antihost T cells maintains long- term tolerance.3
Animal experiments also have shown that the timing of Cy administration is very important.
In mice, administering Cy before or on the same day as the stem cell infusion resulted in sup- pressed antibody production but not the development of tolerance. The optimal time to administer Cy was identified as between graft administration and day +4 post-HSCT as evidenced by maximal effect in improving graft survival. The significance of timing has been carried over into clinical trials.3 When patients do not receive immunosuppression for several days after graft infusion, they are at risk for “engraftment syndrome,” especially with increases in human leukocyte antigen (HLA) mismatch. This may present as pulmonary edema, with or without fever, fluid retention, and renal failure.4 It is important to closely monitor patients during this time.
Haploidentical Transplant
The culmination of findings from animal experiments has been translated into GVHD prophylactic strategies performed in the setting of haploidentical HSCT in humans. Haploidentical HSCTs are an important option for patients because they expand the donor pool significantly for patients unable to identify a matched related or unrelated donor. An early fundamental trial conducted at Johns Hopkins University treated patients with high-risk hematologic malignancies with T cell– replete haploidentical bone marrow transplants after receiving nonmyeloablative conditioning regimens (fludarabine 30 mg/m2/day on days-6 to -2 and 2 Gray [Gy; a unit of ionizing radiation] total body irradiation [TBI] on day -1). The GVHD prophylactic strategy included Cy 50 mg/ kg on day +3, MMF 15 mg/ kg orally twice daily on days +4 to +35, and tacrolimus adjusted to achieve a therapeutic level of 5–15 ng/mL on day +4 to at least day +50. Two of the three first patients transplanted developed graft rejection; therefore, Cy 14.5 mg/ kg/day was added on days -6 and -5 for the remainder of patients. With this improved regimen, eight of the following 10 patients transplanted achieved sustained engraftment. Among these patients, the median time to neutrophil recovery was 15 days and 14 days for platelets. Of the 13 patients transplanted utilizing posttransplant Cy, 46% developed acute GVHD at a median of 99 days posttransplant, with one patient developing fatal acute GVHD. Chronic GVHD rates were not captured in this trial.5 The results of this study provided supporting evidence for further investigation of posttransplant Cy in haploidentical HSCT.
This method from Johns Hopkins was refined in a subsequent study attempting to identify the optimal dose of Cy to administer posttransplant. Patients with advanced hematologic malignancies (n = 67) or paroxysmal nocturnal hemoglobinuria (n = 1) received T cell–replete haploidentical bone marrow grafts after conditioning with Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/day on days -6 to -2, and 200 cGy of TBI on day -1. For GVHD prophylaxis, patients were administered one (n = 28) or two doses (n = 40) of Cy 50 mg/ kg/day on day +3 or +3 and +4, respectively. In addition to post- transplant Cy, MMF at 15 mg/ kg orally three times per day and tacrolimus adjusted to achieve a therapeutic level of 5–15 ng/mL were both started the day after completion of posttransplant Cy (day +4 or+5). MMF was continued until day +35 and tacrolimus was tapered off by day +180 unless the patient was experiencing active GVHD. Median time to neutrophil recovery was 15 days and 24 days for platelet recovery. Graft failure occurred in 13% of the evaluable patients (9 of 66). All but one of these patients experienced bone marrow recovery with a median time to neutrophil engraftment of 15 days and platelet engraftment of 28 days. For all patients, the cumulative incidence of treatment-related mortality (TRM) was found to be 15% with a re- lapse rate of 51% at 1 year. The 2-year overall survival (OS) was 36% and event-free survival (EFS) was 26%. The development of acute GVHD occurred in 34% of patients at grades 2–4 with 6% of patients at grades 3–4. The only important difference identified between the different Cy dosing groups was a trend toward decreased development of chronic GVHD in the two-dose Cy group (5% versus 25%;HR = 0.21; 95% CI: 0.04–1.01; p = .05).6 For adult patients with high-risk malignancies, this trial proved haploidentical HSCTs as a viable option with fairly low GVHD rates utilizing posttransplant Cy on days +3 and +4. Further investigation is needed.
A larger confirmatory trial conducted by Munchel and colleagues studied 210 patients with advanced hematological malignancies who received nonmyeloablative haploidentical HSCTs with posttransplant Cy as GVHD prophylaxis. Patients received the following preparatory regimen: Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/ day on days -6 to -2, and 2 Gy of TBI on day -1. Grafts were bone marrow product with no manipulation to remove T cells. GVHD pro- phylaxis consisted of Cy 50 mg/ kg/day on days +3 and +4, MMF 15 mg/ kg orally three times per day on days +5 to +35, and tacrolimus targeting 5–15 ng/mL from days +5 to +180. Only 204 of the 210 patients included were evaluable for engraftment data. Thirteen percent of patients failed to engraft but nearly all had autologous reconstitution. The median time to neutrophil recovery was 15 days and 24 days for platelets. Acute GVHD occurred in 27% of patients as grade 2–4 and 5% as grade 3–4. The chronic GVHD incidence was low at 13%. The overall incidence of relapse mortality was 55% and nonrelapse mortality (NRM) was 18%. Patients experienced a 3-year OS of 41% and EFS of 32%. An interesting result was discovered with regard to HLA-antigen disparity among donors and recipients. This trial showed a trend toward improved EFS with increasing disparity with a 20% reduction in the risk of an event (death or relapse) for each increment of HLA mismatch (HR = 0.80; 95% CI: 0.66–0.96; p = .02).7 This larger trial provides additional support for the use of posttransplant Cy to prevent GVHD in haploidentical HSCTs.
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted two parallel phase 2 clinical trials to study the reproducibility and applicability of the already published results with the goal of generating future phase 3 randomized controlled trials. BMT CTN 0604 evaluated the efficacy of double umbilical cord blood (dUCB) transplantation, while 0603 studied the efficacy of haploidentical bone marrow transplantation after reduced-intensity conditioning. Patients eligible for either trial needed to have advanced or high- risk leukemia or lymphoma. The conditioning regimen for the dUCB transplants included fludarabine 40 mg/m2/day on days -6 to -2, Cy 50 mg/ kg on day -5, and 2 Gy of TBI on day -1. GVHD prophylaxis included MMF given every 8 hours beginning on day -3 until day +30 or 7 days after engraftment (whichever was later) and cyclosporine dosed to achieve trough levels of 200–400 ng/mL until day +100 in the absence of GVHD. Patients undergoing haploidentical HSCTs received fludarabine 30 mg/m2/day on days -6 to -2, Cy 14.5 mg/ kg on days -6 and -5, and 2 Gy of TBI on day -1. GVHD prophylaxis for this regimen included Cy 50 mg/ kg on days + 3 and +4, MMF three times per day on days +5 to +35, and tacrolimus dosed to achieve a target trough level of 5–10 ng/mL with the goal of discontinuation by day+180. Patients undergoing dUCB transplantation had a median time to neutrophil recovery of 15 days and 38 days for platelet recovery. Ten percent of patients experienced primary graft failure. After haploidentical bone marrow transplant, the median time to neutrophil recovery was 16 days and 26 days to platelet recovery. There was only one case (2%) of primary graft failure in this group. Acute GVHD occurred in 40% of patients at grade 2–4 and 21% of patients at grade 3–4 after dUCB transplant. In the haploidentical transplant group, acute GVHD occurred in 32% of patients at grade 2–4 and 0% of patients at grade 3–4. The cumulative incidence of chronic GVHD in dUCB transplant patients was 25% at 1 year and 13% for haploidentical HSCT patients. The 1-year cumulative incidence of NRM was 24% in dUCB transplant patients and relapse/progression of 31%. The 6-month sur- vival for this group was 74% with a 1-year probability of progression- free survival (PFS) of 46% and OS of 54%. For the haploidentical transplant group the 1-year cumulative incidence of NRM was 7% and relapse/progression was 45%. For this group the 6-month survival was determined to be 84% and 1-year probability of PFS was 48% and OS of 62%.8,9 This trial reproduced results similar to those seen in previous clinical trials. The outcomes of these studies are comparable to high- risk patients transplanted with blood or marrow from matched unrelated donors after reduced intensity conditioning, confirming the utility of alternative donor transplants with unique GVHD prevention strategies. This study led to the development of the BMT CTN Trial 1101 to compare dUCB and haploidentical transplants in a larger phase 3 randomized trial that is still ongoing.9
Use of Peripheral Blood Stem Cells as a Donor Source
Recently clinical trials have evaluated the use of peripheral blood stem cells as a graft source instead of bone marrow when utilizing haploidentical HSCTs with posttransplant Cy. The use of peripheral blood stem cells (PBSC) has been linked to a higher incidence of chronic GVHD but a decreased risk of relapse, leading to improved OS and EFS.2 In the study by Solomon and colleagues, patients were deemed to be at high risk for relapse after nonmyeloablative haploidentical HSCT, therefore a myeloablative conditioning regimen was used. Twenty patients with hematologic malignancies were included in the study and received busulfan-based conditioning followed by T cell– replete peripheral blood stem cells from haploidentical donors. The first five patients received fludarabine 30 mg/m2/day on days -7 to -2, IV busulfan 130 mg/m2/day on days -7 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2. This regimen resulted in a notable amount of mucositis requiring dose reductions to the conditioning regimen for the following 15 patients to fludarabine 25 mg/m2/day on days -6 to -2, IV busulfan 110 mg/m2/day on days -7 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2. Posttransplant immunosuppression included Cy 50 mg/ kg/day on days +3 and +4 and, starting on day +5, MMF 15 mg/ kg three times per day, and continued until day +35, and tacrolimus with a goal level of 5–15 ng/mL continued until day +180. All 20 patients on the study experienced donor engraftment with a median time to neutrophil recovery of 16 days and 27 days for platelet recovery. The overall incidence of acute GVHD was 30% for grades 2–4 and 10% for grades 3–4. At a 20-month median follow-up time, the incidence of chronic GVHD was 35% (5% severe). There was 10% NRM at both 100 days and 1 year in this study. The 1-year estimate for OS was 69%, 50% for EFS, and 40% for relapse.10 This study highlights the promising outcomes of utilizing a myeloablative conditioning regimen with PBSC as a donor source.
To further elucidate the impact graft source has on haploidentical HSCT, additional retrospective analyses have been conducted. Ci- urea and colleagues completed a retrospective analysis of 65 consecutive haploidentical HSCTs for patients with hematologic malignancies. Patients received either T cell–replete peripheral blood stem cell transplants (n = 32) or T cell–deplete bone marrow transplants (n= 33), both following the same conditioning regimen. The preparative regimen contained melphalan 140 mg/m2 on day -8, fludarabine 40 mg/m2/day on days -6 to -3, and thiotepa 10 mg/ kg on day -7. For the bone marrow group, GVHD prophylaxis contained rabbit anti-thymocyte globulin (ATG) dosed at 1.5 mg/ kg/day on days -6 to -3. The PBSC group received Cy 50 mg/ kg/day on days +3 and +4, with MMF starting on day +5 to +35 and tacrolimus continuing for at least 4 months posttransplant. For the last 11 patients in the PBSC group, MMF was continued until day +100 as a result of several initial patients developing acute GVHD. Neutrophil engraftment occurred in 94% of the PBSC patients and 81% of the bone marrow patients (p = .10). Within 100 days, the cumulative incidence of acute GVHD grade 2–4 was 20% versus 11% (p = .20) and grade 3–4 5% versus 9% (p = .59) in the T cell–replete arm compared with the T cell–deplete arm, respec- tively. The rate of chronic GVHD was 7% in the T cell–replete arm and 18% in the T cell–deplete arm (p = .03). The 1-year OS rate was 64% versus 30% (p = .02) and PFS rate was 50% versus 21% (p = .02) in the T cell–replete arm compared with the T cell–deplete arm. The 1-year NRM rates were significantly improved in the T cell–replete arm at 16% versus 42% in the deplete arm (p = .02).11
Castagna also conducted a study comparing PBSC (n = 23) and bone marrow (n = 46) donor products for haploidentical HSCT, yet this time both products were T cell replete. Patients underwent a non- myeloablative conditioning regimen including Cy 14.5 mg/ kg/day on days -6 to -5, fludarabine 30 mg/m2/day on days -6 to -2, and 2 Gy of TBI on day -1. The GVHD prophylactic regimen administered was Cy 50 mg/ kg/day on days +3 and +4 and, starting on day +5, MMF at 15 mg/ kg three times per day until day +35 and tacrolimus adjusted to maintain trough levels 10–20 ng/mL or cyclosporine adjusted to maintain levels between 100–200 ng/mL tapered by day +180. Patients re- ceiving PBSC were given prophylaxis with cyclosporine, and patients receiving bone marrow were administered either tacrolimus (n = 34) or cyclosporine (n = 12). For the entire study population, the median time to neutrophil recovery was 20 days and 29 days for platelet recovery. Grade 2–4 acute GVHD occurred in 25% of patients receiving bone marrow (BM) and 33% of those receiving PBSC (p = .43). The cumulative incidence of grades 3–4 acute GVHD was 14% and 3% in the PBSC and BM arms, respectively (p = .10). The incidence of chronic GVHD was 13% regardless of stem cell source (p = .21). The 2-year OS estimate was 68% and PFS was 62%. The 2-year overall NRM was 18%; 22% for BM source and 12% for PBSC source (p = .96).12 Several studies have analyzed the use of PBSC as a source for haploidentical HSCTs, showing that it is an alternative to bone marrow product.
Matched Related and Unrelated Transplant
With the role of posttransplant Cy established in haploidentical HSCT with either PBSC or BM as a source, the use of Cy in the post- transplant setting was further evaluated in matched related and unrelated HSCTs. Patients with advanced hematologic malignancies who received matched related (n = 78) or unrelated (n = 39) donor trans- plants were included in this analysis by Lunzik and colleagues. The conditioning regimen utilized was myeloablative with busulfan 4 mg/ kg/day orally or 3.2 mg/ kg/day IV given in four daily divided doses for 4 consecutive days, followed by admistering Cy 50 mg/ kg IV for 2 days. Busulfan doses were adjusted to achieve a target area under the curve (AUC) of 800–1400 µmol/ L x min. Grafts were T cell–replete bone marrow product. GVHD prophylaxis was single-agent Cy given at a dose of 50 mg/ kg/day on days +3 and +4 after trans- plant. Neutrophils recovered in a time of 23 days for related grafts and 25 days for unrelated grafts. Platelet recovery occurred in a median of 31 days for related donors and 34 days for unrelated donors. At 100 days posttransplant the cumulative incidence of grade 2–4 acute GVHD was 43% and of grade 3–4 was 10%. There was not a significant difference in grade 2–4 acute GVHD between related and unrelated donors (42% versus 46%; HR = 0.87; 95% CI: 0.50–1.54; p = .64). The cumulative incidence of chronic GVHD for all patients was 10% with a median follow-up time of 26.3 months. The cumulative incidence of chronic GVHD at 2 years was not significantly different be- tween related and unrelated donors (9% versus 11%; HR = 0.83; 95% CI: 0.25–2.88; p = .79). The 2-year cumulative incidence of relapse was 44%. This was not significantly different when analyzed by donor type (HR = 1.4; 95% CI: 0.78–2.60; p = .25). For related donor grafts the median follow-up on trial was 29 months and 24 months for unrelated donor grafts for surviving recipients. The OS and EFS also did not significantly differ by donor type (OS HR = 0.85; 95% CI: 0.49–1.50; p= .58; EFS HR = 1.12; 95% CI: 0.68–1.86; p = .65). The OS was found to be 36% at 1 year and 55% at 2 years. The 1-year EFS was 48% and at 2 years was 39%.13 This trial revealed promising results for posttransplant Cy use in matched related and unrelated donors.
An additional multi-institutional trial utilized a myeloablative conditioning regimen of IV busulfan targeted to AUC and fludarabine at 40 mg/m2/day on days -5 to -2 in patients with high-risk hematologic malignancies undergoing HLA-matched related and unrelated BM transplants. GVHD prophylaxis consisted of single-agent posttransplant Cy given on days +3 and +4 at a dose of 50 mg/ kg/day. A total of 92 patients were transplanted during this analysis with 45 patients receiving related donor grafts and 47 patients receiving unrelated do- nor grafts. The median time to neutrophil engraftment was 21 days and platelet engraftment was 24 days. Grade 2–4 acute GVHD occurred in 51% of patients, with grade 3–4 in 15%. The cumulative incidence of chronic GVHD was 14% at 2 years. Approximately one-third of all patients (35%) never required additional immunosuppressive medication. NRM was 9% at day 100 and 16% at 1 year. OS was 67% at 2 years, and EFS was 62%.14 This study also supports the efficacy of posttransplant Cy for myeloablative related and unrelated matched donor transplant.
A clinical trial in matched sibling and unrelated donor transplants compared posttransplant Cy with tacrolimus and minidose methotrexate as GVHD prevention. Patients on the study arm (n = 49) received reduced-intensity conditioning with fludarabine at 40 mg/m2 followed by IV busulfan targeting an AUC of 4,000 µmol/ L x min on days -6 to -3. Patients receiving an unrelated donor graft also were given ATG on days -3 to -1 (total dose 4 mg/ kg). Posttransplant Cy was given at a dose of 50 mg/ kg/day on days +3 and +4. In the control arm (n = 133) patients received the same reduced-intensity conditioning regimen of fludarabine with melphalan. GVHD prophylaxis for this arm included tacrolimus plus mini-MTX (10 mg/m2 on day +1, then 5 mg/m2 on days +3, +6, +11). Unrelated donor transplants also received anti-thymocyte globulin (ATG) in the control arm. A computer- generated algorithm identified matched controls for 37 of the study patients. More than half (59%) of patients in both arms had unrelated donors and required additional immunosuppression during conditioning with ATG. More patients in the posttransplant Cy arm received bone marrow product than in the control arm (70% versus 48%). The cumulative incidence of acute GVHD grade 2–4 occurred in 46% of the posttransplant Cy arm and 19% in the control arm (HR, 2.8; 95% CI, 1.1-6.7; p = .02). The incidence of acute GVHD grades 3–4 was 14% in the study arm and 0% in the control arm (p = .02). For chronic GVHD, the cumulative incidence was 14% versus 21% in the study arm compared with the control arm, respectively (HR = 0.8; 95% CI: 0.2-2.6; p = .7). The OS, PFS, and NRM at 2 years were not significantly different between the groups with results of 26% versus 46% (HR = 1.8; 95% CI: 0.9-3.3; p = .08), 22% vs 33% (HR = 1.3; 95% CI: 0.7–2.3; p = .4), and 36% versus 16% (HR = 2.4; 95% CI: 0.8–6.7; p = .1) for the posttransplant Cy arm compared with the control arm, respectively.15
Building on the results of the data for single-agent Cy posttransplant in matched related and unrelated donors, a trial by Solomon and col- leagues evaluated a CNI-free GVHD prevention strategy. Patients were given a reduced-intensity conditioning regimen consisting of fludarabine 30 mg/m2/day on days -9 to -6, IV busulfan 130 mg/m2/ day on days -5 to -4, and Cy 14.5 mg/ kg/day on days -3 and -2 fol- lowed by administration of an unmanipulated peripheral blood stem cell graft on day 0. Immunosuppression consisted of Cy 50 mg/ kg/ day on days +3 and +4, then sirolimus began on day +5 and was discontinued day +90 to +100 without tapering in the absence of GVHD. Twenty-six patients with high-risk hematologic malignancies were treated in this trial. Seventeen patients had matched sibling donors, and the remaining nine patients had matched unrelated donors. All patients engrafted with a median time for neutrophil recovery of 15 days and 30 days for platelets. Acute GVHD grades 2–4 occurred in 46% of patients and 15% in grades 3–4. Thirty-one percent of patients experienced chronic GVHD. The 1-year cumulative incidence of NRM was 4%. Two-year estimated OS was 71%, EFS 64%, relapse 32%, and NRM 13% at a 20-month median follow-up period for surviving patients.16
The results of this trial are promising, with a very low rate of NRM and an impressive 2-year OS.
Conclusion
Posttransplant Cy is a safe and effective alternative to standard immunosuppression strategies. Cy administered early after HSCT leads to suppression of GVHD and graft rejection without compromising immune reconstitution. It has been utilized as a GVHD prevention strategy in HSCTs from bone marrow or peripheral blood as well as with vari- ous conditioning regimens and donor sources. Patients included in these studies had related, unrelated, matched, and mismatched donors, high- lighting the versatility of posttransplant Cy. The BMT-CTN continues to explore this method of immunosuppression and has an ongoing trial, BMT CTN 1203, that is comparing novel approaches for GVHD prevention to contemporary controls in patients undergoing related or un- related reduced-intensity conditioning transplants. In one arm of this tri- al, patients will receive posttransplant Cy at 50 mg/kg on days +3 and +4 followed by tacrolimus and MMF.9 The results of this large multicenter trial are anticipated to confirm the data from the completed studies on using posttransplant Cy. Posttransplant Cy should continue to be evaluated as an immunosuppression option given its comparably low rates of acute and chronic GVHD and minimal side effects.
References
1. Pasquini MC, Wang Z. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2013. www.cibmtr.org. Accessed January 15, 2015.
2. Rezvani AR, Storb RF. Prevention of graft-vs.-host disease. Expert Opin Pharmacother. 2012;13(12):1737-1750.
3. Al-Homsi AS, Roy TS, Cole K, Feng Y, Duffner U. Post- transplant high-dose cyclophosphamide for the prevention of graft-versus-host disease. Biol Blood Marrow Transplant. 2014:1-8.
4. Luznik L, Jones RJ, Fuchs EJ. High-dose cyclophosphamide for graft-versus-host disease prevention. Curr Opin Hematol.
2010;17(6):493-499.
5. O’Donnell PV, Luznik L, Jones RJ, et al. Nonmyeloablative bone marrow transplantation from partially HLA-mismatched related donors using posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2002;8:377-386.
6. Luznik L, O’Donnell PV, Symons H, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14:641-650.
7. Munchel A, Kesserwan C, Symons HJ, et al. Nonmyeloablative, HLA-haploidentical bone marrow transplantation with high dose, post-transplantation cyclophosphamide. Pediatr Rep. 2011;3(s2) e15:43-47.
8. Brunstein CG, Fuchs EJ, Carter SL. Alternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts. Blood. 2011;18(2):282-288.
9. Blood and Marrow Transplant Clinical Trials Network. BMT CTN Protocol Listing. https://web.emmes.com/study/ bmt2/public/ NewProtocol.html. Accessed December 15, 2014.
10. Solomon SR, Sizemore CA, Sanacore M, et al. Haploidentical transplantation using T cell replete peripheral blood stem
cells and myeloablative conditioning in patients with high-risk hematologic malignancies who lack conventional donors is well tolerated and produces excellent relapse-free survival: results of a prospective phase II trial. Biol Blood Marrow Transplant. 2012;18:1859-1866.
11. Ciurea SO, Mulanovich V, Saliba RM, et al. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1835-1844.
12. Castagna L, Crocchiolo R, Furst S, et al. Bone marrow compared with peripheral blood stem cells for haploidentical transplantation with a nonmyeloablative conditioning regimen and post- transplantation cyclophosphamide. Biol Blood Marrow Transplant. 2014;20:724-729.
13. Luznik L, Bolanos-Meade J, Zahurak M, et al. High-dose cyclophosphamide as single-agent, short course prophylaxis of graft-versus-host disease. Blood. 2010;115(16):3224-3230.
14. Kanakry CG, O’Donnell P, Furlong T, et al. Multi-institutional study of post-transplantation cyclophosphamide as single- agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol. 2014;32(31):3497-3505.
15. Alousi AM, Saliba RM, Chen J, et al. A matched controlled analysis of post-transplant cyclophosphamide (CY) versus tacrolimus and mini-dose methotrexate in matched sibling and unrelated donor transplant recipients receiving reduced-intensity conditioning: post-transplant CY is associated with higher rates of GVHD. Blood. 2012;120:4200.
16. Solomon SR, Sanacore M, Zhang X, et al. Calcineurin inhibitor-free graft-versus-host disease prophylaxis with post- transplantation cyclophosphamide and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1828-1834.