Haploidentical Transplantation Has a Superior Graft-versus-Leukemia Effect Than HLA-Matched Sibling Transplantation for Ph– High-Risk B-Cell Acute Lymphoblastic Leukemia
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for patients with hematological malignancies, particularly for high-risk adult acute lymphoblastic leukemia (ALL) patients. The availability of a suitable donor source often limits its application. However, with the development of haploidentical transplantation, almost all patients can now rapidly access a suitable donor. Haploidentical donor (HID) transplantation has been shown to achieve outcomes comparable to those of human leukocyte antigen (HLA)-matched sibling donor (MSD) or matched unrelated donor (MUD) transplantation. This study aimed to compare the graft-versus-leukemia (GVL) effect between HID and MSD transplantation for Philadelphia-negative (Ph–) high-risk B-cell acute lymphoblastic leukemia (B-ALL).
The study population was derived from two prospective multicenter trials (NCT01883180, NCT02673008). Patients undergoing allo-HSCT between June 2013 and October 2018 were selected if they met the following criteria: aged 14 to 65 years, high-risk B-ALL, HID or MSD as a donor, and undergoing first allo-HSCT. Diagnosis of B-ALL was performed by morphologic analysis of bone marrow (BM) specimens along with flow cytometry immunophenotyping using monoclonal antibodies reactive with B-cell-associated antigens. Patients were classified as high risk if they met one of the following criteria at diagnosis: high white blood cell (WBC) count (≥30 × 10^9/L) at diagnosis, delayed first complete remission (CR1, remission required more than two cycles of induction therapy), refractory or non-remission (NR) at transplantation, or high-risk cytogenetic abnormalities according to the National Comprehensive Cancer Network 2012 guidelines, such as hypodiploidy, t(v;11q23) or MLL rearranged, or complex karyotype (five or more chromosomal abnormalities). Patients with Ph+ B-ALL were excluded from the study.
Patients were assigned to undergo HID or MSD transplantation based on donor availability. MSD (6/6 matching HLA-A, -B, and -DR loci) was the first choice for allo-HSCT. If an MSD could not be obtained, subjects without a suitable MUD (>8 of 10 matching HLA-A, -B, -C, -DR, and -DQ loci) were qualified for HID transplantation. Patients in CR received a myeloablative conditioning regimen of total body irradiation (TBI, 4.5 Gy/days, –5 days, –4 days), cyclophosphamide (CY, 60 mg·kg^−1·day^−1, –3 days, –2 days), and etoposide (VP-16, 15 mg·kg^−1·day^−1, –3 days, –2 days). Patients in NR received an intensified conditioning regimen of fludarabine (Flu, 35 mg·m^−2·day^−1, –10 days to –6 days), cytarabine (Ara-c, 1 g·m^−2·day^−1, –10 days to –6 days), TBI (4.5 Gy/days, –5 days, –4 days), CY (60 mg·kg^−1·day^−1, –3 days, –2 days), and VP-16 (15 mg·kg^−1·day^−1, –3 days, –2 days). Cyclosporin A (CsA) and methotrexate (MTX) were administered in patients undergoing MSD transplantation, and CsA, MTX, mycophenolate, and anti-thymocyte globulin were used in patients undergoing HID transplantation for graft-versus-host disease (GVHD) prophylaxis.
BM samples were analyzed at 1 month, 2 months, 3 months, 4 months, 6 months, 8 months, 10 months, and 12 months within 1-year post-transplantation, then once every 3 months from the 13th to the 36th month, and once every 6 months from the 37th to the 60th month for the monitoring of morphology and measurable residual disease (MRD). If MRD was positive, the test was repeated within a week. Subjects were defined as MRD+ if they had two consecutive positive results. MRD was evaluated by eight-color multi-parameter flow cytometry (MFC). A panel of ten antibody combinations that recognized CD10, CD19, CD20, CD34, CD38, CD45, CD58, CD99, CD123, and cTDT was used for MRD detection, and 0.3 million cells per tube were acquired. For patients with leukemia-associated immuno-phenotype (LAIP) markers at diagnosis, MRD was identified as the detection of at least two LAIP markers identified at diagnosis. For those without LAIP markers at diagnosis, MRD was identified as a cell population showing deviation from the normal patterns of antigen expression seen on specific cell lineages at specific stages of maturation compared with either normal or regenerating marrow. A lower limit of detection of 0.01% was targeted, and the sensitivity of the MFC was 10^−4.
The strategies for preventing leukemia relapse included immunosuppressant withdrawal and prophylactic or preemptive therapy with donor lymphocyte infusion (DLI). For patients in NR pre-transplantation, immunosuppressant was withdrawn by 10%/week in patients without acute GVHD (aGVHD) by day +30 post-transplantation, and prophylactic DLI was administered on day +90 post-transplantation if patients had no active GVHD and available donor lymphocytes. Pre-emptive DLI was administered in patients with post-MRD+ from day +60 when patients had no active GVHD and available donor lymphocytes, and it was given monthly until MRD became negative or GVHD occurred or for a total of four times. Donor lymphocytes were all obtained from granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells. The CD3+ T-cell count for each prophylactic or pre-emptive DLI was 3.0 × 10^7/kg of the recipient weight. Short-term immunosuppressant was used for the prevention of GVHD after DLI.
Infection prophylaxis was administered as previously described. Oral sulfamethoxazole and norfloxacin were used in all patients. Antifungal agents were administered 5 days pre-transplantation. For patients without a history of invasive fungal infection (IFI), oral fluconazole was used until day +60 post-transplantation. Otherwise, for patients with a history of IFI, antifungal agents for secondary prevention based on response to the initial antifungal therapy were used until day +90 post-transplantation. Patients with Epstein-Barr virus (EBV) or cytomegalovirus (CMV) DNA-emia received pre-emptive therapy.
The primary endpoint was the incidence of post-MRD+. Secondary endpoints included hematopoietic engraftment, GVHD, infections, non-relapse mortality (NRM), relapse, overall survival (OS), leukemia-free survival (LFS), and GVHD-free/relapse-free survival (GRFS). Relapse was defined as the reappearance of leukemic blasts in the peripheral blood or ≥5% blasts in the BM aspirate or biopsy not attributable to any other cause or the reappearance or new appearance of extramedullary leukemia. CR was defined as <5% blasts in the BM and no persistence of extramedullary disease. NR was defined as a failure to obtain CR. NRM was defined as death from any cause not subsequent to relapse. OS was defined as the time from transplantation until death from any cause. LFS was defined as the time from transplantation until relapse or death from any cause. GRFS events were defined as grade III-IV aGVHD, chronic GVHD (cGVHD) requiring systemic immunosuppressive therapy, leukemia relapse, or death from any cause during follow-up after allo-HSCT. Neutrophil engraftment was defined as the first of three consecutive days with an absolute neutrophil count exceeding 0.5 × 10^9/L. Platelet engraftment was defined as the first of 3 days with an absolute platelet count exceeding 20 × 10^9/L without transfusion support. aGVHD and cGVHD were graded according to the literature. Prophylactic and pre-emptive therapies were defined as interventions for MRD-negative and MRD-positive patients without hematologic relapse, respectively.
A total of 335 patients with Ph– high-risk B-ALL were enrolled, including 145 in the HID group and 190 in the MSD group. The median age was 28 (range, 14–59) years. There were 116 patients in CR and 29 in NR at transplantation in the HID group, whereas 148 in CR and 42 in NR in the MSD group. Baseline factors were well balanced between the two groups.
All patients achieved neutrophil engraftment except for two patients who died of infections (one in the HID and one in the MSD group) and two who died of hepatic veno-occlusive disease (HVOD) in the MSD group. Of the 331 evaluable patients, the median time of neutrophil engraftment was 12 (range, 9–24) days and 11 (range, 9–21) days in the HID and MSD groups, respectively. The 28-day cumulative incidence of neutrophil engraftment was 99.3% and 98.4% in the HID and MSD groups, respectively. The median time of platelet engraftment was 14 (range, 9–108) days and 12 (range, 8–85) days, respectively, in the HID and MSD groups. The 100-day cumulative incidence of platelet engraftment was similar between HID and MSD groups (94.5% vs. 97.4%). All the patients achieved CR on day +30 post-transplantation, except four patients who died before neutrophil engraftment.
Up to the last follow-up date, MRD+ was observed in 120 patients after transplantation, including 39 patients in the HID and 81 in the MSD groups. The 3-year cumulative incidence of post-MRD+ was 27.2% and 42.6% in the HID and MSD groups, respectively. The median time from allo-HSCT to post-MRD+ was 150 (range, 30–733) days and 103 (range, 30–615) days in the two groups, respectively. Multivariable analysis revealed that HID was a protective factor for post-MRD+; NR status pre-transplant was a risk factor for post-MRD+.
According to the DLI strategy, a total of 156 patients received DLI for relapse prevention at a median time of 125 (range, 60–610) days post-transplantation, including 60 (41.4%) patients in the HID and 96 (50.5%) in the MSD groups. Forty-two patients received prophylactic DLI (HID, n = 18; MSD, n = 24) and 114 pre-emptive DLI (HID, n = 42; MSD, n = 72). The median number of DLI was 1 (range, 1–4) per patient, with no difference between the two groups.
The overall cumulative incidence of grade II-IV aGVHD was 46.2% and 47.9%, and that of grade III-IV aGVHD was 11.7% and 14.7% in the HID and MSD groups, respectively. Of the 156 patients undergoing DLI, 70 (44.9%) patients developed grade II-IV aGVHD after DLI, including 23 (38.3%) in the HID and 47 (49.0%) in the MSD groups. After ruling out the effects of DLI, the incidence of grade II-IV aGVHD by day +100 post-transplantation was 31.8% and 23.2%, and that of grade III-IV aGVHD was 10.3% and 8.9% in the HID and MSD groups, respectively. Seven patients died of severe aGVHD, including three in the HID and four in the MSD groups.
The 3-year cumulative incidence of overall cGVHD was 46.3% and 52.1%, and extensive cGVHD was 13.1% and 19.5% in the HID and MSD groups, respectively. Sixty-five (41.7%) patients developed cGVHD after DLI, including 21 (35.0%) in the HID and 44 (45.8%) in the MSD groups. After ruling out the effects of DLI, the cumulative incidence of cGVHD was 33.7% and 31.5%, and extensive cGVHD was 9.8% and 9.7% in the HID and MSD groups, respectively. Five patients died of extensive cGVHD, including one in the HID and four in the MSD groups.
With a median follow-up of 37.5 (range, 0.1–88.2) months post-transplantation, 27 and 50 patients relapsed in the HID and MSD groups, respectively. The median time of relapse was 5.9 (range, 1.7–19.9) months and 6.1 (range, 2.2–52.4) months post-transplantation in the HID and MSD groups, respectively. The 3-year cumulative incidence of relapse post-transplantation was 18.6% and 25.9%, respectively, in the HID and MSD groups. Of the 77 relapsed patients, 15 patients abandoned treatment and 62 received salvage treatment, including 38 patients receiving DLI combined with chemotherapy, 17 receiving chemotherapy alone, 4 receiving chimeric antigen receptor T-cell immunotherapy, and 3 receiving second allo-HSCT. Of the 62 patients undergoing salvage treatment, 40 patients achieved CR and 13 were still alive. The multivariable analysis revealed that cGVHD was a protective factor for relapse; post-MRD+ was a risk factor for relapse.
The 1-year cumulative incidence of EBV-DNAemia was 33.2% and 18.6% in the HID and MSD groups, respectively. The 2-year cumulative incidence of EBV-associated diseases was 9.5% and 5.6% in the two groups, respectively. Two patients died of EBV-associated diseases in the HID group, whereas none died in the MSD group. The 1-year cumulative incidence of CMV-DNAemia was 61.0% and 42.1% in the HID and MSD groups, respectively. The 2-year cumulative incidence of CMV-associated diseases was 7.3% and 7.0% in the two groups, respectively. Five patients died of CMV-associated diseases, including two in the HID and three in the MSD groups. In total, 43 patients died of infections, including 21 in the HID and 22 in the MSD groups. The 3-year infection-related mortality was 14.5% and 12.3% in the HID and MSD groups, respectively.
At the last follow-up, 215 patients survived, and 120 patients died (47 in the HID and 73 in the MSD groups). Causes of death included relapse (n = 54), infections (n = 43), GVHD (n = 12), intracranial hemorrhage (n = 4), heart failure (n = 2), thrombotic microangiopathy (n = 2), HVOD (n = 2), and CsA-related neurotoxicity (n = 1). The 3-year NRM was 18.0% and 15.9%, respectively, in the HID and MSD groups. The 3-year OS was 67.4% and 61.6%, in the HID and MSD groups, respectively. The 3-year LFS was 63.4% and 58.2%, respectively, in the HID and MSD groups. The 3-year GRFS was 51.7% and 37.8%, respectively, in the two groups.
Multivariable analysis revealed that cGVHD was the only protective factor for OS and LFS; post-MRD+, NR status pre-transplant, and grade II-IV aGVHD were risk factors for OS; post-MRD+ was a risk factor for LFS.
In conclusion, HID transplantation has a lower incidence of post-MRD+ than MSD transplantation, suggesting that HID transplantation might have a superior GVL effect than MSD transplantation for Ph– high-risk B-ALL patients. HID transplantation should be recommended as one of the optimal choices for Ph– high-risk B-ALL patients.
doi.org/10.1097/CM9.0000000000001852
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