Transplantation In Second Remission Research Articles

Pre-Transplant Measurable Residual Disease (MRD) Detection of KMT2A-rearranged Acute Myeloid Leukemia Is Strongly Associated with Inferior Post-Transplant Outcome

Introduction KMT2A-rearranged ( KMT2Ar ) acute myeloid leukemia (AML) is associated with inferior survival and allogeneic hematopoietic cell transplant (HCT) in first remission (CR1) is an important post-remission objective (Issa et al, Blood Cancer Journal 2021). Despite HCT, however, the relapse risk is ~50% (Menghrajani et al, Blood Adv. 2022). Several small cohort studies have described the prognostic utility of pre-HCT MRD assessment using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR), but currently, this is not standard practice (Scholl et al, Haematologica 2005; Huang et al, Med Sci Monitor 2016; Liu et al, Biol Blood Marrow Transplant 2014; Heuser et al, Blood 2021). A significant barrier to widespread implementation of KMT2A::X MRD monitoring is the presence of diverse fusion-partner genes and varied breakpoint regions. The potential to detect and pre-emptively target pre-HCT KMT2A::X MRD has relevance with the development of menin inhibitors, which have been shown to be active in the clinic (Issa et al, Nature 2023). In the current work, we report the prognostic impact of pre-HCT KMT2A::X MRD detection by RT-qPCR and the relationship with post-HCT outcome in adults with KMT2Ar AML. We also describe a novel 3 common primer/probe KMT2A::X reverse transcription digital PCR (RT-dPCR) MRD assay as a simplified dPCR alternative to MRD monitoring. Methods Archived pre-HCT cDNA were available from 54 patients treated in the UK (including UK NCRI AML17 and AML19) and Australia. Samples were analyzed by RT-qPCR using previously described methods in 45 patients (Abildgaard et al, Eur J Haematol. 2013), and RT-dPCR in 9 patients (Ivey, unpublished 2023). The RT-dPCR method, which uses a common 3 primer/probe set to capture breakpoints within KMT2A obviating the need for fusion-gene specific plasmid standards, showed high concordance with RT-qPCR across 20 samples (R 2=0.9915) . Copy numbers were expressed per 100 ABL copies. Assay sensitivity was ~0.001%. Survival outcomes were estimated using the Kaplan-Meier method for relapse-free survival (RFS, date of HCT to relapse or death from any cause) and overall survival (OS, date of HCT to death or last follow-up). Cox proportional hazards was used to assess variables impacting RFS and OS. Categorical variables were calculated using Fisher exact test and continuous variables using Mann-Whitney-U test. The study was approved by human research ethics committees (AUS 21/26; UK 14/WA/1056, NC10.13). Results A total of 54 patients with KMT2Ar AML underwent HCT between 2010-2022. Median age was 43 years (range, 17-70), 63% were female, 94% had de novo AML, all had received prior intensive chemotherapy and 76% were transplanted in CR1, 50% with myeloablative conditioning. KMT2A::X subtypes included t(9;11)/ KMT2A::MLLT3 in 35%, t(6;11)/ KMT2A::AFDN in 26%, t(11;19)/ KMT2A::ELL in 13% and KMT2A::MLLT1 in 5%, t(10;11)/ KMT2A::MLLT10 in 17% and other rare KMT2A::X variants in 4%. Pre-HCT MRD was detected (MRD-pos) in 46% of patients (25 of 54) at a median level of 0.3 copies/100ABL (range, 0.006-35.0394). The frequency of post-HCT relapse was significantly higher in patients with RT-qPCR/RT-dPCR levels ≥0.01% pre-HCT (68% relapsed vs 24% if MRD-neg, p=0.002) (Figure 1). Median time to relapse was 4.7 months (range, 0.8-22.5), with 100% of patients (22 of 22 with available molecular status at relapse) retaining the KMT2A::X variant at relapse. With median follow-up time of 37 months, pre-HCT KMT2A::X MRD-pos was associated with significantly inferior 2-year RFS (19% vs. 63%, p=0.0013) (Figure 2) and 2-year OS (47% vs. 69%, p=0.031). On univariate analysis, variables associated with inferior RFS were pre-HCT MRD-pos status (hazard ratio (HR) 3.2 [95% confidence interval (CI) 1.5-6.9], p=0.002) and transplant in second remission vs. CR1 (HR 2.6 [95% CI 1.2-5.5], p=0.01), however, pre-HCT MRD-pos status was the only variable associated with inferior RFS on multivariate analysis (HR 2.8 [95% CI 1.3-6.1], p=0.01). Conclusions Pre-HCT KMT2A::X MRD detection by RT-qPCR and RT-dPCR is a robust prognostic indicator of post-transplant relapse and inferior survival outcome. Targeting patients with KMT2A::X MRD positive disease pre-HCT using novel menin inhibitors is currently the subject of an enrolling clinical trial (AMLM26 INTERCEPT) (ACTRN12621000439842).

Prognostic Factors in Children with Acute Myeloid Leukemia Receiving the First Hematopoietic Stem Cell Transplantation in Second Remission

Introduction In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) is generally restricted to patients with a high risk of relapse. However, 30-40% of children with AML receiving chemotherapy will eventually relapse; these patients often undergo initial HSCT after achieving second CR (CR2) with re-induction chemotherapy. Previous studies have reported favorable prognostic factors in children with relapsed AML: no prior history of HSCT, longer duration of CR1, and achieving CR2 before HSCT. The identification of prognostic factors in children who received initial HSCT in CR2 may facilitate the refinement of risk stratification in first-line therapy, but they remain largely unknown. In this study, we explored the prognostic factors of pediatric patients with AML who received initial HSCT in CR2. Methods Data from 234 patients were collected from the Transplant Registry Unified Management Program sponsored by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. The patients were selected according to the following criteria: (1) de novo AML, (2) age < 16 years and CR2 at the time of receiving HSCT, (3) no prior HSCT, and (4) HSCT performed between 2000 and 2019. Patients without information on survival and disease recurrence or those with Down syndrome (DS) were excluded. A myeloablative conditioning (MAC) regimen was defined as total-body irradiation (TBI) at > 8 Gy, melphalan > 140 mg/m2, or busulfan ≥ 9 mg/kg. All other regimens were analyzed as reduced-intensity conditioning regimens. High-risk (HR) cytogenetics/genetics were defined as either 7-/7q-, 5q-, complex karyotype (three or more chromosomal abnormalities in the absence of one of the recurring translocations or inversions), t(6;11)(q27;q23), t(6;9)(p23;q34), t(16;21)(p11;q22), t(9:22)(q34;q11.2), or fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD). Results The median age at HSCT was 7 years (range, 1-15), and the median follow-up period for survivors was 7.7 years (range, 0.2-19.2). The 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) rates were 63.5% (95% CI, 56.6-69.5%) and 66.9% (95% CI, 60.0-72.8%), respectively (Figure 1). The 5-year cumulative incidence of relapse was 24.7% (95% CI, 19.2-30.6%), whereas the 5-year cumulative incidence of non-relapse mortality was 11.8% (95% CI, 7.9-16.6%). The 5y-EFS was 72.6% (95% CI, 61.1-81.2%) for patients with core binding factor AML and 100% (95% CI unavailable owing to small patient number) for patients with t(15;17)(q22;q21). Patients with 11q23/KMT2A rearrangement and HR cytogenetics/genetics showed worse outcomes, with 5y-EFS rates of only 43.8% (95% CI, 21.4-64.3%) and 36.4% (95% CI, 17.8-55.3%), respectively. Among the French American British classification subtypes, patients with M7 AML showed inferior outcomes with a 5y-EFS of 18.8% (95% CI, 4.6-40.2%). For the conditioning regimens, aside from "other MAC,” which included only three patients, melphalan-based non-TBI MAC was associated with the most favorable outcomes, with a 5y-EFS of 77.1% (95% CI, 64.2-85.9%). Multivariate analysis identified duration of CR1 > 1 year and melphalan-based non-TBI MAC regimen as independent favorable prognostic factors, while M7 was identified as an independent adverse prognostic factor (hazard ratio 2.62, p = 0.033, Table 1). Conclusion In the present study, approximately two-thirds of children who experienced relapse after chemotherapy remained in remission after HSCT in CR2. Melphalan-based non-TBI MAC is recommended as a conditioning regimen for this select population. Patients with t(15;17)(q22;q21) showed particularly excellent outcomes after initial HSCT in CR2, whereas those with HR cytogenetics/genetics or non-DS M7 were scarcely rescued with HSCT even after attaining CR2. Precise identification of high-risk populations among them with poor early treatment response and/or unfavorable genetic alterations will contribute to refining the risk stratification and indications for HSCT in CR1. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

How I treat adults with relapsed or refractory Philadelphia chromosome–negative acute lymphoblastic leukemia

AbstractThe long-term prognosis of adult patients with relapsed Philadelphia chromosome–negative acute lymphoblastic lymphoma (ALL) is poor. Allogeneic stem cell transplant in second remission is the only curative approach and is the goal when feasible. There is no standard chemotherapy regimen for relapsed disease, although a few agents are approved for use in this setting. The bispecific CD19-directed CD3 T-cell engager, blinatumomab, has recently been granted accelerated approval by the US Food and Drug Administration for relapsed or refractory disease of B-cell lineage. For patients with relapsed T-cell ALL, nelarabine is available. Liposomal vincristine is also approved for relapsed disease. When selecting combination chemotherapy salvage options, evaluation of the prior treatment and timing of relapse informs treatment decisions. Monoclonal and cellular investigational therapies are quite promising and should be explored in the appropriate patient.

Outcome of transplantation for acute lymphoblastic leukemia in children with down syndrome

We report on 27 patients with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) who received allogeneic hematopoietic cell transplantation (HCT) between 2000 and 2009. Seventy-eight percent of patients received myeloablative conditioning and 52% underwent transplantation in second remission. Disease-free survival (DFS) was 24% at a median of 3 years. Post-transplant leukemic relapse was more frequent than expected for children with DS-ALL (54%) than for non-DS ALL. These data suggest leukemic relapse rather than transplant toxicity is the most important cause of treatment failure. Advancements in leukemia control are especially needed for improvement in HCT outcomes for DS-ALL.

If at First You Don't Succeed: Stem-Cell Transplantation for Acute Myeloid Leukemia After First Relapse

Therapy for younger patients with acute myeloid leukemia (AML) is administered with curative intent. After complete remission (CR) is achieved with initial induction therapy, some form of postremission therapy is required to prevent relapse, and the choice is generally between a few courses of high-dose cytarabinebased chemotherapy or one to two courses of chemotherapy followed by allogeneic stem-cell transplantation. The latter comes in a variety of different flavors, most often using fully human leukocyte antigen (HLA) –matched sibling donors, but now with an expanding choice of unrelated, cord blood, or haploidentical donors as well as a range of myeloablative or reduced-intensity pretransplantation conditioning regimens. Randomized trials have failed to show an advantage of autologous transplantation (perhaps because so many of the marrows were contaminated by minimal residual disease that was not detectable with the technology available at that time), and there is no benefit from continued maintenance chemotherapy. It has been difficult to prove that allogeneic transplantation is superior to chemotherapy alone when applied to the broad, biologically heterogeneous population of younger patients with AML. The trials that have been performed are somewhat imperfect in that patients were assigned to transplantation if they had an HLA-matched sibling, rather than being strictly randomly assigned. In addition, many patients declined transplantation, leading to the imaginative so-called donor versus no donor comparisons that were intended to mimic intent-to-treat analyses. A recent meta-analysis of these randomized trials has suggested that allogeneic transplantation in first CR provides the greatest advantage for patients in higher risk groups as defined by cytogenetics and somewhat less benefit for the markedly heterogeneous groups of patients who are characterized as intermediate risk. The relapse rate is lower after allogeneic transplantation because the graft versus leukemia effect makes an important contribution to the overall outcome. This is balanced by higher rates of treatment-related mortality and morbidity, although there have been improvements in transplantation techniques and considerably reduced short-term mortality in recent years. And indeed, even as a card-carrying member of the nontransplanters union, I acknowledge and so inform my patients that the survival after transplantation has never been shown to be worse than with chemotherapy consolidation in the comparative trials. When counseling patients in first remission, most clinicians also mention that the initial decision is only the first part of the calculation, given that patients who relapse can subsequently receive a transplant in second remission. That said, until now, this could only be stated in a general way because there have been virtually no systematic data that address the feasibility and outcome of later transplantation. Problems include the difficulties in achieving a second remission, the development of complications during reinduction that could preclude transplantation, the administrative delays imposed by insurers, delays in identifying unrelated donors if siblings are not available, and an appreciable post-transplantation relapse rate, among others. Hence the importance of the large and unique analysis from the Medical Research Council (MRC) of the United Kingdom that accompanies this editorial. This is a real-world experience in that the MRC enrolls an extraordinarily high fraction of United Kingdom patients with newly diagnosed AML onto clinical trials and has good follow-up of these individuals. The authors focus on 1,271 patients in first relapse, age 16 to 50 years, who had not received an allogeneic transplant in first CR; 19% of these relapsed patients were alive at 5 years after relapse with a major effect of cytogenetic risk category (32% for favorable, 17% for intermediate, and only 7% for high risk). Other salient findings included the following. First, a perhaps higher than expected rate of second CR was achieved in 55% of patients, and the 5-year overall survival of these responders was 34%. The CR rate varied according to risk group and, although it is not stated explicitly, it is likely that the probability of second CR was strongly affected by the duration of first CR. Second, remarkably, 67% of the remitters could receive transplantations in second CR (perhaps because many of these patients had donors who were identified in first CR but chose not to undergo transplantation, and because they were being observed as part of a clinical trial) with a 5-year survival of 44% in those undergoing one of many different types of allogeneic transplantation. It remains to be seen whether such a high fraction of patients could receive transplantations in the United States, but emphasizes the importance of beginning donor searches at the time of diagnosis. Third, chemotherapy alone could have served as salvage treatment for 16% of those achieving second CR who did not undergo JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 10 APRIL 1 2013

Treatment Outcome in T-Cell Lymphoblastic Lymphoma in Adults - a Population-Based Study From the Swedish Lymphoma Registry.

Abstract 2727T-cell lymphoblastic lymphoma (T-LBL) is a rare disease mainly affecting children and young adults. Commonly presenting with a large mass in the anterior mediastinum it represents the lymphoma end of the T-cell acute lymphoblastic leukemia (T-ALL) spectrum and as such has a high risk of CNS involvement. If present, cases with bone marrow infiltration < 25% are classified as T-LBL.The optimal standard treatment for adult T-LBL is not yet defined due to the rarity of the disorder and the consequent lack of randomized prospective trials. Hence, adults that are diagnosed with T-LBL are exposed to a range of chemotherapy regimens, according to a variety of local therapeutic guidelines. Most published data originates from clinical trials in the pediatric population. Here we present the treatment outcome and clinical prognostic factors from a population-based cohort of adult T-LBL patients.Using the Swedish Lymphoma Registry (SLR) all adult T-LBL patients diagnosed between January 2000 and December 2009 were identified in this study. Basic data was collected from the registry and further data was extracted from patient records after obtaining informed consent.Through the SLR 46 cases were identified. Seven cases were re-classified as T-ALL. Median age at diagnosis was 40 years (range 18–77 yrs) with a male:female ratio of 5:3. Bulky disease (>10cm) was present in 67%. Only 2 patients had CNS involvement at diagnosis while 18 (46%) presented with stage IV disease, 10 because of bone marrow involvement and 8 due to extensive extranodal disease. Median follow up for surviving patients was 6.5 years (range 2.0 – 11 yrs). The estimated 5-year OS was 42% for the entire cohort.Of 39 patients 1 declined participation, 1 died after the first cycle and 4 records could not be accessed, leaving 33 patients evaluable for treatment response. FDG-PET was performed in 13 patients after induction treatment. The ORR was 91% (33% CR, 58% PR, 9% SD). In many cases PR was due to PET negative residual masses. Thirty patients (age 18–66 yrs) received intensive ALL-like treatment. For this group treatments used were hyper-CVAD (n=19), LSA2L2 (n=4), VSTB -95 (n=2), NOPHO-ALL-HR (n=2), Euro LB -02 (n=1), GMALL 99/06 (n=1), ABCDV (n=1) resulting in an ORR of 97% (40% CR, 57% PR). No toxic death occurred. Consolidation consisted of radiation therapy against mediastinum followed by maintenance treatment in 3 patients, maintenance treatment in 19 patients, 2 underwent an autologous transplantation and 2 an allogeneic transplantation. Five-year PFS was estimated to 49% with 12 patients experiencing a relapse or progression including 7 patients with normal FDG-PET. Three patients with relapsed/progressive disease had an allogeneic transplant in second remission but subsequently died. Twelve patients died from disease-related causes and 3 from therapy-related causes, including 2 patients that developed secondary hematologic malignancies. Most relapses/progressions occurred in bone marrow, mediastinum or CNS with 3 patients with an isolated CNS relapse/progression. For the 7 patients receiving low intensity treatment (age 69–77 yrs) no patient survived beyond 30 months (median survival was 6.2 months), with 4 available for response evaluation, 2 achieving PR and 2 SD.For the whole cohort, age and female gender were identified as risk factors for shorter OS (HR 1.04, p=0.007 respectively HR 4.67, 0.001). Females were significantly older than males and for patients with intensive treatment, neither female gender nor age were any longer significant risk factors.This study is one of few to provide population-based data on treatment outcome of adult T-LBL. Age as a risk factor is likely to reflect intolerance to intensive treatment since age was not a risk factor for adverse OS or PFS for intensively treated patients. PET scan at time of response evaluation seems to be unreliable as predictor for the risk of relapse. Response rates in this material are comparable with published data while long term OS was slightly inferior, reflecting the population based nature of this data set. Disclosures:No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed.

Expression of CD56 in Acute Myeloid Leukemia (AML) Is Associated with Poor Outcome When Patients Treated with Stem Cell Transplant in Second Remission but Not in the First Remission

Abstract 4880 Background:The CD56 is a neural cell adhesion molecule (N-CAM) expressed in natural killer cells. CD56 expression on the surface of leukemic cells in acute myeloid leukemia (AML) has been reported to correlate with higher rate of relapse and to be associated with poor outcome when patients are treated with conventional intensive chemotherapy. The role of allogeneic hematopoietic stem cell transplantation (HSCT) in improving outcome in this subgroup of AML patients is not known. We investigated whether the outcome of CD56-positive AML patients differ from average AML patients when treated with allogeneic HSCT after intensive chemotherapy and its prognostic relevance in patients transplanted in the first (CR1) or second complete remission (CR2). Methods:Immunophenotyping data of 106 patients with AML who were treated with allogeneic HSCT was reviewed. The expression of the CD56 on the blast population as determined by flow cytometry was correlated with clinical data and outcome. The median age of patients was 24 (range: 14–57) and included 72 patients in the intermediate cytogenetic group and 30 in the adverse cytogenetic group. Of the 106 patients, 71 (67%) were treated with HSCT in their first remission (CR1) and the remaining patients were treated in CR2. Results:Twenty nine (28%) of all studied patients expressed CD56 on the surface of the blasts at diagnosis. When we consider only patients treated with HSCT in CR1, 17 (24%) were CD56 positive. The overall survival (OS) and event free survival (EFS) for patients who were positive for CD56 were not significantly different from the rest of the patients in the CR1 group. In contrast, in the group of patients who were treated with HSCT after relapsing (CR2), patients with CD56 positivity had significantly shorter OS (P=0.03) and DFS (P=0.006). In this group, 11 of the 35 (31%) were CD56+ and their median survival was 8.85 months while the median has not been reached in the CD56 negative patients. Conclusion:Our data suggests that the expression of CD56 in AML is a significant poor prognostic factor if patients are treated with HSCT after relapsing in their second remission. Although this should be confirmed in larger studies, the CD56 expression in AML should be considered as an adverse risk factor and favors treatment with allogeneic HSCT in the first remission and not after relapse in second remission. AML patients with CD56 positive blasts have higher incidence of relapse after chemotherapy and they might lose their opportunity of good outcome if HSCT is delayed and performed only in the second remission. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation for Children with Acute Lymphoblastic Leukemia in Second Complete Remission: Similar Outcomes in Recipients of Unrelated Marrow and Umbilical Cord Blood versus Marrow from HLA Matched Sibling Donors

Transplant decisions for children with acute lymphoblastic leukemia (ALL) in second complete remission (CR2) are often based on the type of available donor. In many cases, allogeneic hematopoietic cell transplantation (HCT) is considered only if a human leukocyte antigen (HLA) matched sibling donor (MSD) is available. The role of unrelated donor (URD) HCT in this patient population is not well established. As advances in supportive care and donor selection have improved, the use of URD HCT in such patients should be reevaluated. We analyzed the outcomes of 87 consecutive children with ALL in CR2 who underwent allogeneic HCT at the University of Minnesota between 1990 and 2007. Donor sources included MSD bone marrow (n = 32), well and partially matched (M, n = 18) and mismatched (MM, n = 16) URD bone marrow and URD umbilical cord blood (UCB, n = 21). Although the incidence of neutrophil recovery was similar in all groups, the overall incidence of grades II-IV acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 37% and 9%, respectively, with a higher incidence of aGVHD in recipients of URD grafts. Leukemia-free survival (LFS) at 5 years was lower in recipients of MM-URD grafts, but was comparable in all other groups. Although relapse at 5 years was highest in recipients of MSD (50%), results were not significantly different compared to recipients of M-URD (17%), MM-URD (6%), and UCB (33%) (P = .17). The development of grades II-IV aGVHD and a first remission >3 years were associated with a lower risk of relapse (relative risk [RR] 0.2, P = .03; RR 0.2. P = .01 respectively). Together, these results support the continued investigation of URD HCT for ALL in CR2, and suggest the timing of HCT in these children should be based primarily on the risk of relapse with conventional chemotherapy and not on the type of donor available.

Successful second allogeneic stem cell transplantation in second remission induced by dasatinib in a child with Philadelphia chromosome positive acute lymphoblastic leukemia

We report on the use of dasatinib, a second-generation bcr-abl kinase inhibitor, in a child in early relapse of Philadelphia chromosome positive acute lymphoblastic leukemia after hematopoietic stem cell transplantation. This patient benefited from the use of dasatinib obtaining of a complete molecular response which allowed a second successful transplant. Moreover, dasatinib was well tolerated in this heavily pretreated patient.

Results of Genoidentical Hemopoietic Stem Cell Transplantation With Reduced Intensity Conditioning for Acute Myelocytic Leukemia: Higher Doses of Stem Cells Infused Benefit Patients Receiving Transplants in Second Remission or Beyond—The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation

Results of Genoidentical Hemopoietic Stem Cell Transplantation With Reduced Intensity Conditioning for Acute Myelocytic Leukemia: Higher Doses of Stem Cells Infused Benefit Patients Receiving Transplants in Second Remission or Beyond—The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation

The Treatment of Delayed Rejection after Boosting of Mononuclear Cells of Her Mother and Chronic Graft Versus Host Disease in Leukemia Recipient Who Underwent Allogeneic Hyplo-Identical Transplantation in Second Remission with Therapeutic Plasma Exchange.

Patient is a Chinese girl of 13 years. She had fever, weakness, headache, and was hospitalized on Feb 20th, 2003. There were 0.89 leukemic monocytes in her bone marrow smear at diagnosis. She was diagnosed acute monoblastic leukemia (M5b) according to FAB classification. The immunophenotyping of bone marrow cells showed CD13 0.579, CD15 0.289, CD33 0.78, cMPO 0.27. After the second remission, she underwent hyplo-identical, ABO-matched combination transplantation of bone marrow and peripheral blood stem cells of her donor mother with T-cell deletion in Aug. 2005. Her hemapoiesis recovered at +10d after transplantation. The while complete blood cell count recovered at +31d when the TCR-PCR DNA gene map was showed the chimera. The rejection appeared at +60d. Her blood picture showed Hb 63g/L, Plt 1.0×109/L, WBC 0.4×109/L. The bone marrow picture showed hypo-cellular as same as in severe aplastic anemia. The TCR-PCR DNA gene map showed the 3/16 locus of recipient. The schedule of treatment of delayed rejection was the combination of Cyclosporin A (CsA), Mycophemolate Mofeil (MMF) and Methylprednisolone (MP). She boosted the G-CSF-primed peripheral mononuclear cells of her mother. The cell dose was 4.3×108/kg without T-deletion. Then she received the stimulation of G-CSF 250 ug daily. One week later, she suffered from Herpes Zoster Virus (HZV) infection. There was characteristic HZV varicella in full right side of head, right face, right eye, and right hand with high fever, malaise. She felt severe postherpetic neuralgia. Only morphine or remain acupuncture can relieve her severe neuralgia. She had also severe pancytopenia, gastrointestinal bleeding. We had to transfuse backed red cell and platelet concentration every week. She received first TPE at +130d and second TPE at +137d after transplantation. Dramatic results were gotten after the two TPE. After TPE she did not need transfusion again. After the third TPE, she was discharged then had treated small dose of CsA for half year. The STR-PCR DNA gene map showed the gene type from her mother. At +311d she suffered from chronic graft versus disease (cGVHD). The skin lesion involved her whole body skin about was about 50% body surface area. The effect had not received after treatment with TPE. The cGVHD had not controlled after the basic treatment with CsA or Sirolimus (FK506), MMF, MP, and Thalidomide 100–400 mg/d. So we added with ultraviolet-B irradiation (UV-B) therapy with dose of narrowbank UV-B, twice a week. The lichenification planum was disappearing. The mechanism of TPE on delayed rejection in ABO-unmatched, allogeneic stem cell transplantation has been clear. But, it is still not clear in ABO-matched and hyplo-identical allogeneic stem cell transplantation. It may be cause humoral rejection as same as ABO-incompatible stem cell or solid organ transplantation. The antibodies have resulted from hyplo-identical allogeneic stem cell of her mother. The mechanism of cGVHD results from donor T-lymphocyte activated and involves skin, liver, gut and so on. It is effective of treatment of cGVHD with immune inhibitor drugs but with TPE. Recently reported ECP is effective because the method result in suppressing the activated T-lymphocyte in recipient.

Results of Genoidentical Hemopoietic Stem Cell Transplantation With Reduced Intensity Conditioning for Acute Myelocytic Leukemia: Higher Doses of Stem Cells Infused Benefit Patients Receiving Transplants in Second Remission or Beyond—The Acute Leukemia Working Party of the European Cooperative Group for Blood and Marrow Transplantation

Nucleated cell dose is an important and modifiable factor in hematopoietic stem cell transplantation (HSCT), however its association with outcomes in the context of reduced intensity conditioning regimen (RIC) HSCT for adults with acute myelocytic leukemia (AML) is not known. From 1998 to 2003, 253 patients with de novo AML, received transplants with RIC and peripheral blood from a genoidentical donor. Median age was 55 years (range, 18 to 72) and the median follow-up was 17 months (range, 2 to 67). One hundred forty one patients received transplants in first remission (CR1), 47 received transplants in second remission (CR2), and 65 patients received transplants in a more advanced phase. Fludarabin-based RIC was used in 91% of patients and low-dose (< 4 Gy) total-body radiation in 23% of patients. The median nucleated and CD34 cell dose infused were 9.1x 10(8)/kg and 5.8x 10(6)/kg, respectively. Overall, 2-year leukemia-free survival (LFS) was 41% +/- 4% and it was 46% +/- 5% for patients receiving a higher cell dose (> 9.1x 10(8)/kg) and 37% +/- 5% for the remainders (P = .03). Higher cell doses exclusively benefited patients who received transplantations in CR2 or beyond, with LFS of 47 +/- 8 versus 20 +/- 8, with no detectable effect for patients who received transplants in CR1. In a multivariate analysis of the overall patient population, higher nucleated cell dose cells were associated with higher LFS (P = .04), higher incidence of chronic graft-versus-host disease (P = .01), and there was a trend towards a lower relapse incidence (P = .06). Interestingly, CD34+ cell dose was not associated with any outcomes. Nucleated cell dose is an important factor that can be modified to improve results of RIC for patients with AML transplanted later than in CR1.

Late thyroid toxicity in 153 long-term survivors of allogeneic bone marrow transplantation for acute lymphoblastic leukaemia

The purpose of this study was to identify risk factors for hypothyroidism after bone marrow transplantation (BMT) for high-risk or relapsed acute lymphoblastic leukaemia (ALL) in children. In all, 388 children with acute lymphoblastic leukaemia underwent allogeneic bone marrow transplantation between 1984 and 1994. Overall 5-year survival was 54.6%. Thyroid function was assessed in the 153 patients with more than 5 years of follow-up. In total, 16 patients developed uncompensated hypothyroidism (UH) and 46 compensated hypothyroidism (CH) a median of 2.9 and 2.7 years, respectively, after BMT. Thyroid dysfunction-free survival rates were 73.2% after 5 years and 59.2% after 10 years. Three factors were significantly associated with the onset of hypothyroidism, namely age, bone marrow transplantation in second remission, and single-dose total body irradiation (TBI). Ultrasonography of the thyroid showed nodules in 10 of 35 patients. The median time from BMT to nodule detection was 7.8 years. Cytology (n=5) and surgery (n=4) showed no evidence of thyroid cancer. Four of the 14 patients who received cytoreduction without TBI but with busulphan and cyclophosphamide developed UH (n=2) or CH (n=2). We concluded that children who undergo BMT for ALL are at a high risk of subsequent thyroid dysfunction.

Allogeneic bone marrow transplantation in second remission of childhood acute lymphoblastic leukemia: a population-based case control study from the Nordic countries.

This study compares allogeneic BMT with conventional chemotherapy for childhood ALL in second remission. Seventy-five children were transplanted between July 1981 and December 1995. For each patient two control patients matching the following criteria were selected from the Nordic database of ALL: (1) time of diagnosis, (2) T vs. non-T ALL, (3) site of relapse, (4) initial risk group, (5) sex and (6) relapse < or > or =6 months after cessation of therapy. The minimal time of follow-up was 24 months. Mortality rate in CR2, leukemic relapse rate and the proportion in continued second remission were 16/75 (21%), 22/75 (29%) and 37/75 (50%), respectively. P2.-EFS for the BMT group was significantly better than that for the control group (0.40 vs. 0.23, P = 0.02). Children transplanted for bone marrow relapses in particular had a higher P2.-EFS (0.35 vs. 0.15 for the control group, P<0.01). Also, children grafted for early BM relapses had a higher P2.-EFS (0.32 vs. 0.11 for the control group P = 0.01). The outcome was similar when children were transplanted after early or late relapse. Also, there was no difference in outcome between the BMT and the chemotherapy group for children with late relapses. We conclude that allogeneic BMT with an HLA-identical sibling donor or other family donor should be performed in children relapsing in bone marrow during therapy or within 6 months of discontinuing therapy.

Bone marrow transplantation versus chemotherapy for maintenance of second remission of childhood acute lymphoblastic leukemia: A study of the children's cancer group (CCG‐1884)

Background Maintenance of second remission of childhood acute lymphoblastic leukemia (ALL) with intensive chemotherapy is often unsuccessful. The major cause of treatment failure is relapse. Materials and Methods Of 96 children with ALL who relapsed in the marrow while on or within 1 year of completing initial therapy, 62 achieved a second remission. Nineteen patients underwent bone marrow transplantation in second remission, 11 from a human leukocyte antigen (HLA)-matched related donor, seven using autologous marrow, and one from a matched unrelated donor. The event-free survival (EFS) of transplanted patients was compared to that of patients treated with intensive chemotherapy using high-dose cytarabine, vincristine, escalating dose methotrexate, L-asparaginase, and an anthracycline (daunorubicin or idarubicin). Only those patients treated with chemotherapy who survived in second remission up to the mean time that patients were transplanted (135 days) were included in the control group (33 of 43 patients who achieved second remission). Results The actuarial 2-year event-free survival of transplanted patients is 37 ± 22% (95% C.I.) compared to 18 ± 13% for chemotherapy-treated patients (P = 0.017). EFS for allo-transplant recipients was similar to that for auto-transplant recipients. Duration of initial remission was a strong predictor of the outcome of retrieval therapy. Patients whose initial remission was greater than 3 years had better EFS after achieving second remission (five of 11 still in remission, compared to four of 41 patients whose initial remission was less than 3 years). Adjustment in the multivariate analysis for duration of initial remission did not diminish the benefit of transplant over chemotherapy. Conclusions While there remains considerable possibility for further improvement in EFS after achieving second remission of childhood ALL, bone marrow transplant is superior to chemotherapy in maintaining second remission. Med. Pediatr. Oncol. 29:534–540, 1997. © 1997 Wiley-Liss, Inc.

Bone Marrow Transplantation for Pediatric Leukemia

The ability to deliver high-dose chemotherapy with or without radiotherapy followed by marrow rescue has made marrow transplantation the treatment of choice for children with AML in first remission, juvenile CML, and adult-type CML in chronic phase. For patients with ALL or NHL who relapse, transplantation in second remission represents a reasonable therapeutic option. The role of marrow transplantation for patients in the advanced stages of their disease will continue to be explored to develop promising new therapies, which may improve results of transplantation earlier in the disease course. Development of transplant preparative regimens that have the same or improved therapeutic efficacy with less late effects is especially important for growing and developing children. In the meantime, all children who have received a marrow transplant must be followed for development of delayed effects, which may not appear until years after the transplant procedure. Children who are cured of their leukemia continue to occasionally visit the pediatric hematologist/oncologist, but they do so less often with increasing time after curative therapy. Thus, it is necessary for the primary care pediatrician to be familiar with the details regarding the child's previous therapy in order to anticipate and to be prepared to treat the delayed effects. Attention to school performance is of particular importance for early identification of those children who may need special educational attention. Advances in the treatment of children with leukemia continue to be made both with chemotherapy and with marrow transplantation that should result in greater numbers of children being cured.(ABSTRACT TRUNCATED AT 250 WORDS)

A Unique Case of Three Autografts for Acute Myelogenous Leukaemia with Subsequent Long Term Survival in Second Remission

We report here a patient with acute mycloid leukaemia who relapsed 20 months after undergoing a double autograft procedure in first remission. He was reinduced and subsequently underwent a third autologous bone marrow transplantation in second remission using bone marrow harvested in second remission and a Busulphan and Cyclophosphamide conditioning regimen. Although the engraftment was very slow, he has remained in second remission for 34+ months. This case demonstrates that durable disease-free survival can be attained by a second preparative therapy, even in second remission, for patients relapsed after autologous bone marrow transplantation.

Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission.

Bone-marrow transplantation has been used in patients with acute lymphoblastic leukaemia (ALL) thought to be at high risk of relapse if managed with chemotherapy. Data from 444 ALL patients with one or more high-risk features at diagnosis were analysed to evaluate outcome after HLA-identical bone-marrow transplantation during first or during second remission. The 4-year actuarial probability of leukaemia-free survival was 45% (95% confidence interval 36-54%) for transplants in first remission compared with 22% (15-29%) for those in second remission (p less than 0.0002). The 4-year probabilities of relapse were 26% (14-38%) and 56% (45-67%) respectively (p less than 0.0001). For high-risk ALL, transplantation in first remission had clearly superior results to transplantation in second remission. Further studies are needed to determine whether patients with high-risk ALL should receive transplants during first remission or should initially receive chemotherapy, with transplantation being reserved for patients who relapse.

Speed of relapse in children with acute lymphoblastic leukaemia.

16 children with acute lymphoblastic leukaemia (ALL) who relapsed on maintenance treatment between September 1978 and December 1981 were studied. Their previous bone marrow aspirates were reviewed to determine the first evidence for marrow relapse and the subsequent rate of evolution of the disease. 60% of children had bone marrow evidence of unsuspected relapse at 8 wk, and 40% had evidence at 12 wk before clinical or peripheral blood relapse occurred. Early detection of relapse will prevent continued use of ineffective maintenance chemotherapy and may also reduce morbidity during subsequent induction therapy. Regular 8-weekly marrow aspirates are therefore recommended during first remission of ALL in children with a histocompatible sibling who would be eligible for bone marrow transplantation in second remission.