5‐Azacitidine Monotherapy Followed by Related Haploidentical Hematopoietic Stem Cell Transplantation Achieves Durable Remission in a Pediatric Patient With Acute Undifferentiated Leukemia Refractory to High‐Dose Chemotherapy

Patients with acute leukemias of undifferentiated lineage (AUL) generally have guarded prognosis. Here, we describe the first reported pediatric patient with AUL refractory to high‐dose chemotherapy who achieved clinical remission with ALL maintenance therapy and 5‐azacitidine. His induction remission was followed by consolidation with reduced toxicity haploidentical hematopoietic stem cell transplant (HSCT). At 9 months post‐HSCT, the patient is alive and in remission. This combination therapy of remission induction with ALL maintenance therapy and 5‐azacitidine and consolidation with reduced toxicity haploidentical HSCT is novel and promising for patients who lack conventional donors and are not candidates for myeloablative therapy.     

Tolerance and effectiveness of nivolumab after pediatric T‐cell replete,haploidentical, bone marrow transplantation: A case report

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22‐year‐old female with multiple‐relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post‐haplo) HSCT. Anti‐PD‐1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft‐versus‐host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD.     

Impact of pretransplant minimal residual disease on the post‐transplant outcome of pediatric acute lymphoblastic leukemia

There are few reports on the clinical significance of MRD before HSCT in pediatric ALL. We retrospectively analyzed the clinical significance of FCM‐based detection of MRD (FCM‐MRD) before allogeneic HSCT in pediatric ALL. Of 38 pediatric patients who underwent allogeneic HSCT for the first time between 1998 and 2014, 33 patients were in CR and five patients were in non‐CR. The CR group was further divided into two groups based on the pretransplant FCM‐MRD level: the MRD^neg (<0.01%; 30 patients) group and the MRD^pos (≥0.01%; three patients) group. There were significant differences in the three‐yr event‐free survival rates between the CR and non‐CR group, and between the MRD^neg and MRD^pos group. The three‐yr cumulative RI in the MRD^neg group were 27.3% ± 8.8%, whereas two of the three patients in the MRD^pos group relapsed within one yr after HSCT. The clinical outcome of the MRD^pos group was as poor as that of the non‐CR group in pediatric ALL. Therefore, an improvement in pretransplant treatment that aims to achieve a more profound remission would contribute to reducing the risk of relapse.     

Low‐dose azacitidine maintenance therapy after allogeneic stem cell transplantation for high‐risk pediatric acute myeloid leukemia

The dismal prognosis of pediatric acute myeloid leukemia (AML) relapsing after hematopoietic stem cell transplantation (HSCT) requires exploration of novel strategies to prevent relapse. Azacitidine (AZA) maintenance therapy could potentially reduce the recurrence rate post HSCT. Here, we presents the cases of three children with high‐risk AML post HSCT who were treated with low‐dose AZA maintenance therapy, demonstrating the feasibility of this therapy. Currently, all three are in complete remission for 13–41 months despite their high‐risk characteristics. Our encouraging data warrant larger prospective studies to assess the efficacy and safety of low‐dose AZA maintenance therapy post HSCT for pediatric patients with high‐risk AML.     

Selective T cell‐depleted haploidentical hematopoietic stem cell transplantation for relapsed/refractory neuroblastoma

Relapsed/refractory NB carries a bleak outcome, warranting novel treatment options. HaploHSCT induces a graft‐versus‐NB effect via natural killer cell alloreactivity. Review of patients with relapsed/refractory NB who underwent haploHSCT with ex vivo T‐cell depletion in our unit from 2013 through 2018. Ten patients were identified (male=5; median age at haploHSCT=6.45 y, range: 3.49‐11.02 y). Indications were relapsed in 7 and refractoriness in 3; disease status at haploHSCT was CR in 2, PR in 6, and PD in 2. All patients received peripheral blood stem cell grafts after ex vivo T‐cell depletion (CD3/CD19‐depletion=1; TCR‐αβ/CD19‐depletion=4; CD3/CD45RA‐depletion=4; and TCR‐αβ/CD45RA‐depletion=1). Conditioning regimens were fludarabine‐based. Neutrophils engrafted on median D + 10 (range: D + 9 to +13), and platelets engrafted (≥20 × 10⁹/L) on median D + 8 (range: D + 5 to D + 14). Early T‐ and NK‐cell recovery were evident. Of the 10 patients, acute rejection developed in 1 (who died of PD despite rescue HSCT), and 1 died of sepsis before engraftment; 8 experienced full donor‐chimerism post‐HSCT. Among the 8, 6 experienced CR, 1 died of PD, and 1 died of pulmonary hypertensive crisis before evaluation. At publication, 4 were in remission (2.8, 7.4, 28.5, and 58.9 months). No significant GvHD occurred. HaploHSCT with selective ex vivo T‐cell depletion may be a safe and useful salvage strategy for relapsed/refractory NB.     

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B‐cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life‐threatening toxicity. The bispecific T‐cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B‐cell depletion, the safety of its use during severe chemotherapy‐induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy‐associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.     

Persistent Multiyear Control of Relapsed T‐Cell Acute Lymphoblastic Leukemia With Successive Donor Lymphocyte Infusions: A Case Report

There are few therapeutic options for patients with T‐cell acute lymphoblastic leukemia (T‐ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T‐ALL. We present the case of a now 9‐year‐old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life.     

Prophylactic post‐transplant dasatinib administration in a pediatric patient with Philadelphia chromosome‐positive acute lymphoblastic leukemia

Philadelphia chromosome‐positive acute lymphoblastic leukemia has a poor prognosis, even in pediatric patients. Although imatinib‐containing chemotherapy can reportedly improve early event‐free survival, allogeneic hematopoietic stem cell transplantation is still considered to be the main curative treatment option. Dasatinib, a novel abl tyrosine kinase inhibitor, is being used for the treatment of relapsed or refractory Philadelphia chromosome‐positive acute lymphoblastic leukemia and is reported to have excellent efficacy. We used dasatinib after bone marrow transplantation prior to the anticipated relapse for the purpose of prophylaxis against relapse. After discontinuation of dasatinib administration, molecular remission has lasted for 7 months. Although preventive use of dasatinib is as yet uncommon, we consider that dasatinib may eradicate the minimal residual disease and prevent recurrence, and it is feasible to administer and appears to be safe. Further studies are needed to confirm our experience in this case.     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

Myeloid lineage switch following chimeric antigen receptor T‐cell therapy in a patient with TCF3‐ZNF384 fusion‐positive B‐lymphoblastic leukemia

A pediatric patient diagnosed initially with B‐lymphoblastic leukemia (B‐ALL) relapsed with lineage switch to acute myeloid leukemia (AML) after chimeric antigen receptor T‐cell (CAR‐T) therapy and hematopoietic stem cell transplant. A TCF3‐ZNF384 fusion was identified at diagnosis, persisted through B‐ALL relapse, and was also present in the AML relapse cell population. ZNF384‐rearrangements define a molecular subtype of B‐ALL characterized by a pro‐B‐cell immunophenotype; furthermore, ZNF384‐rearrangements are prevalent in mixed‐phenotype acute leukemias. Lineage switch following CAR‐T therapy has been described in patients with KMT2A (mixed lineage leukemia) rearrangements, but not previously in any patient with ZNF384 fusion.     

Detectable minimal residual disease before allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children with acute lymphoblastic leukemia

BACKGROUND: The level of minimal residual disease (MRD) prior to allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to be an independent prognostic factor for outcome of pediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-) quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements have documented the feasibility and practicality of this technique. This approach has also been disputed due to the occurrence of clonal evolution and generally high MRD levels prior to HSCT. PROCEDURE: In our prospective study, MRD before and after HSCT was monitored using quantitative real-time PCR in a cohort of 36 children with ALL consecutively transplanted in our center between VIII/2000 and VII/2004. RESULTS: In 25 of 36 patients, MRD level prior HSCT was assessed. Seventeen patients were classified as MRD-negative and eight were MRD-positive up to 9 x 10(-2). In MRD-positive subgroup, seven events (six relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (event-free survival (EFS) log-rank P < 0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (P < 0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. CONCLUSIONS: We show that MRD quantitation using clonal Ig/TCR rearrangements successfully assesses the risk in pediatric ALL patients undergoing allogeneic HSCT. As our ability to treat detectable MRD levels after HSCT is very limited, alternative strategies for MRD-positive patients prior HSCT are necessary.     

Transplant‐related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25‐year retrospective review

Background

Over the last 25 years, donor source, conditioning, graft‐versus‐host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high‐risk patients in first and subsequent remission. There is a large burden of infectious and pre‐HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.

Procedure

A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8‐year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009).

Results

Despite a significant increase in unrelated donor HSCT, event‐free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time.

Conclusion

EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post‐HSCT are unchanged, and remain the focus for improvement. Pediatr Blood Cancer 2013;160:1520–1527. © 2013 Wiley Periodicals, Inc.     

Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement

Blinatumomab is a bispecific T‐cell engaging αCD19 antibody used in refractory or relapsed B‐cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again. During this treatment, the leukemia lost CD19 expression as well as nearly all other B‐cell markers, while still harboring the initial minimal residual disease marker, and switched to a myeloid phenotype.     

Toxic epidermal necrolysis in a child 6 months post‐hematopoietic stem cell transplantation

TEN is a rare and critical disease mostly caused by drugs. It is mediated by activated CD8+ T cells that cause keratinocyte apoptosis with the assistance of cytokines/chemokines. We herein report a pediatric case of TEN after allogeneic HSCT with precursor B‐cell acute lymphoblastic leukemia (pre‐B‐ALL) in second complete remission. Although we did not evaluate the T‐cell subpopulation in blood or skin lesion of the patient, an imbalanced immune reconstitution after HSCT might additively contribute to the development of TEN.     

Allogeneic bone marrow transplantation in first remission rescues children with Philadelphia chromosome-positive acute lymphoblastic leukemia: Tokyo Children's Cancer Study Group (TCCSG) studies L89-12 and L92-13.

BACKGROUND: The prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) is generally poor and reports from large studies are scarce. We evaluated the efficacy of allogeneic bone marrow transplantation (allo-BMT) for children with this type of leukemia. PROCEDURE: The chemotherapy regimens consisted of an induction phase and very intensive consolidation followed by a reinduction phase and late intensification treatment. The selection of treatment modalities such as chemotherapy, allo-BMT, or autologous transplantation was made by each institute. The principal endpoint was the outcome of children with Ph(+) ALL according to the treatment options. RESULTS: Thirty-two patients (4.3%) were diagnosed as Ph(+) ALL out of the 741 cases of ALL consecutively enrolled in two protocols of the Tokyo Children's Cancer Study Group (TCCSG) from 1989 to 1994. Thirty patients (93.8%) were induced into complete remission (CR). Of these 30 patients, eight children electively received allo-BMT in the first CR. Six of these patients are in continuous remission at a median follow-up of 58 (range 48-105) months after the diagnosis. One patient died following recurrence and another patient died of graft vs. host disease. Three patients treated with autologous BMT or peripheral blood stem cell transplantation in the first CR experienced a subsequent relapse. In the remaining 19 patients, 13 patients were treated with very high-risk chemotherapy alone and all relapsed within 28 months. One patient was excluded from the analysis because he was treated with standard-risk chemotherapy until relapse. The other five patients were also excluded from the analysis because Philadelphia chromosome was not detected until they relapsed. None of the relapsed patients survived in spite of treatment including allo-BMT. In multivariate analysis, only allo-BMT remained as an independent factor for good prognosis. CONCLUSIONS: The only way to cure children with Ph(+) ALL was allo-BMT in this study and its outcome seemed promising.     

Blinatumomab activity in a patient with Down syndrome B‐precursor acute lymphoblastic leukemia

Persistent minimal residual disease (MRD) after consolidation may indicate chemotherapy insensitivity in B‐precursor acute lymphoblastic leukemia (BP‐ALL). Given the strong association of MRD and outcome in non‐Down syndrome (non‐DS) BP‐ALL, it is likely that MRD levels are also of prognostic significance in DS BP‐ALL. We report here the successful use of blinatumomab, a bispecific T‐cell engager antibody construct, in a patient with DS BP‐ALL and persistent MRD at the end of consolidation. Blinatumomab has been shown to have excellent results in patients with relapsed/refractory BP‐ALL. This patient had no significant toxicity and achieved MRD negativity after only one cycle of blinatumomab.     

Lineage Switch in MLL‐Rearranged Infant Leukemia Following CD19‐Directed Therapy

Rearrangements of the mixed lineage leukemia (MLL) gene occur frequently in infants with both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Conversions of leukemia cell lineage are rare, but occur most commonly in the setting of MLL‐rearrangement. Blinatumomab is a bidirectional antibody targeting CD19 with significant activity in relapsed B‐precursor ALL. We report an infant with ALL with t(4;11)(q21;q23) refractory to cytotoxic chemotherapy who was treated with blinatumomab. Following rapid initial clearance of peripheral lymphoblasts, bone marrow evaluation demonstrated a leukemic lineage switch to CD19‐negative monoblastic AML. Complete remission was achieved with myeloid‐directed chemotherapy.     

Successful treatment with daratumumab for post‐HSCT refractory hemolytic anemia

Autoimmune cytopenias (AIC) following allogeneic hematopoietic stem cell transplantation (HSCT) may cause significant morbidity and mortality and are often challenging to treat. We present a case of a pediatric patient with primary myelofibrosis of infancy caused by VPS45 protein deficiency, who developed severe refractory hemolytic anemia and immune‐mediated thrombocytopenia 3.5 months following HSCT. After the failure of several treatments, he received daratumumab, an anti‐CD38 specific antibody, and demonstrated fast and sustained response. The only side effect was delayed recovery of humoral immunity. Daratumumab, by targeting antibody‐producing plasma cells, may be a valid treatment option for refractory post‐HSCT AIC.     

A medication diary‐book for pediatric patients with acute lymphoblastic leukemia in Indonesia

Background

Event‐free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary‐book on the treatment outcome of childhood ALL.

Procedure

A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary‐book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event‐free survival estimate (EFS) at 3 years was assessed.

Results

Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS‐estimate at 3 years of the intervention group was significantly higher than the EFS‐estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low‐educated mothers, no significant difference was found in the EFS‐estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86).

Conclusions

We conclude that a medication diary‐book might be useful to improve the survival of pediatric patients with ALL in resource‐limited settings, particularly in patients with highly educated mothers. Pediatr Blood Cancer 2013;60:1593–1597. © 2013 Wiley Periodicals, Inc.     

Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission

Schechter T, Ishaqi KM, Rojas M, Irina Z, Doyle JJ, Gassas A. Outcome of hematopoietic stem cell transplantation of children with very high risk acute lymphoblastic leukemia in first complete remission.
Pediatr Transplantation 2010:14: 377–382. © 2009 John Wiley & Sons A/S. Abstract: Approximately 10% of children with ALL present at diagnosis with VHR for relapse if treated with chemotherapy alone. They may benefit from allogeneic HSCT in CR1. We have reviewed the outcome of this population in our institution. Forty‐three patients (median age: 8.9 yr) with VHR ALL in CR1 underwent HSCT from October 1994 to April 2006. VHR features included Philadelphia chromosome (n = 17), induction failure (n = 9), hypodiploidy (n = 6), MLL gene rearrangement (n = 5), and others (n = 6). All patients received TBI (1200 cGy) with either CY and/or etoposide. Stem cell source was unrelated (n = 24) and related (n = 19). Incidence of grade III‐IV acute GVHD and chronic extensive GVHD were 25% and 16%, respectively. Twelve patients relapsed (eight received related HSCT). Eleven patients died due to transplant‐related mortality (eight received unrelated HSCT). For a median follow up of 39 months (range 11–110), the event free survival and OS were 0.49 (95% CI: 0.31–0.67) and 0.53 (CI: 0.44–0.71), respectively. Outcomes of children with VHR ALL receiving HSCT in CR1 remain unsatisfactory. Relapse, mainly after related HSCT, and TRM, mainly after unrelated HSCT, continue to be major problems.