Vemurafenib combined with cladribine and cytarabine results in durable remission of pediatric BRAF V600E-positive LCH.

Langerhans cell histiocytosis (LCH) is a disorder with a variety of clinical signs. The most severe forms affect risk organs (RO). The established role of the BRAF V600E mutation in LCH led to a targeted approach. However, targeted therapy cannot cure the disease, and cessation leads to quick relapses. Here, we combined cytosine-arabinoside (Ara-C) and 2'-chlorodeoxyadenosine (2-CdA) with targeted therapy to achieve stable remission. Nineteen children were enrolled in the study: 13 were RO-positive (RO+) and 6 RO-negative (RO-). Five patients received the therapy upfront, whereas the other 14 received it as a second or third line. The protocol starts with 28 days of vemurafenib (20 mg/kg), which is followed by 3 courses of Ara-C and 2-CdA (100 mg/m2 every 12 h, 6 mg/m2 per day, days 1-5) with concomitant vemurafenib therapy. After that, vemurafenib therapy was stopped, and 3 courses of mono 2-CdA followed. All patients rapidly responded to vemurafenib: the median disease activity score decreased from 13 to 2 points in the RO+ group and from 4.5 to 0 points in the RO- group on day 28. All patients except 1 received complete protocol treatment, and 15 of them did not have disease progression. The 2-year reactivation/progression-free survival (RFS) for RO+ was 76.9% with a median follow-up of 21 months and 83.3% with a median follow-up of 29 months for RO-. Overall survival is 100%. Importantly, 1 patient experienced secondary myelodysplastic syndrome after 14 months from vemurafenib cessation. Our study demonstrates that combined vemurafenib plus 2-CdA and Ara-C is effective in a cohort of children with LCH, and the toxicity is manageable. This trial is registered at www.clinicaltrials.gov as NCT03585686.

Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia.

We compared the efficacy and safety of eltrombopag (ELTR) combined with immunosuppressive therapy (IST) and IST alone in treatment-naïve children with severe (SAA) and very severe (vSAA) aplastic anemia. Ninety-eight pediatric patients were randomized to receive horse antithymocyte globulin (hATG) and cyclosporin A (CsA) with (n = 49) or without (n = 49) ELTR. The primary endpoint was the overall response rate (ORR) at 4 months. After 4 months, nonresponders were crossed over to the alternative group. In all patients, the ORR in ELTR + IST and IST groups was similar (65% vs 53%; P = .218); however, the complete response (CR) rate was significantly higher in the ELTR + IST group (31% vs 12%; P = .027). In severity subgroups, the ORR was 89% vs 57% (P = .028) in favor of IST + ELTR in SAA, but it did not differ in patients with vSAA (52% vs 50%; P = .902). At 6 months after the crossover, 61% of initial ELTR(-) patients achieved a response compared with 17% of initial ELTR(+) patients (P = .016). No significant difference in ELTR + IST and IST groups was observed in the 3-year overall survival (OS) (89% vs 91%; P = .673) or the 3-year event-free survival (EFS) (53% vs 41%; P = .326). There was no unexpected toxicity related to ELTR. Adding ELTR to standard IST was well tolerated and increased the CR rate. The greatest benefit from ELTR combined with IST was observed in patients with SAA but not in those with vSAA. The second course of IST resulted in a high ORR in initial ELTR(-) patients who added ELTR and had limited efficacy among patients who received ELTR upfront. This trial was registered at Clinicaltrials.gov as #NCT03413306.

Optimized Conformal Total Body Irradiation Among Recipients of TCRαß/CD19-Depleted Grafts in Pediatric Patients With Hematologic Malignancies: Single-Center Experience.

Total body irradiation (TBI) in combination with chemotherapy is widely used as a conditioning regimen in pediatric and adult hematopoietic stem cell transplantation (HSCT). The combination of TBI with chemotherapy has demonstrated superior survival outcomes in patients with acute lymphoblastic and myeloid leukemia when compared with conditioning regimens based only on chemotherapy. The clinical application of intensity-modulated radiation therapy (IMRT)-based methods (volumetric modulated arc therapy (VMAT) and TomoTherapy) seems to be promising and has been actively used worldwide. The optimized conformal total body irradiation (OC-TBI) method described in this study provides selected dose reduction for organs at risk with respect to the most significant toxicity (lungs, kidneys, lenses). This study included 220 pediatric patients who received OC-TBI with subsequent chemotherapy and allogenic HSCT with TCRαß/CD19 depletion. A group of 151 patients received OC-TBI using TomoTherapy, and 40 patients received OC-TBI using the Elekta Synergy™ linac with an Agility-MLC (Elekta, Crawley, UK) using volumetric modulated arc therapy (VMAT). Twenty-nine patients received OC-TBI with supplemental simultaneous boost to bone marrow-(SIB to BM) up to 15 Gy: 28 patients (pts)-TomoTherapy; one patient-VMAT. The follow-up duration ranged from 0.3 to 6.4 years (median follow-up, 2.8 years). Overall survival (OS) for all the patients was 63% (95% CI: 56-70), and event-free survival (EFS) was 58% (95% CI: 51-65). The cumulative incidence of transplant-related mortality (TRM) was 10.7% (95% CI: 2.2-16) for all patients. The incidence of early TRM (<100 days) was 5.0% (95% CI: 1.5-8.9), and that of late TRM (>100 days) was 5.7 (95% CI: 1.7-10.2). The main causes of death for all the patients were relapse and infection. The concept of OC-TBI using IMRT VMAT and helical treatment delivery on a TomoTherapy treatment unit provides maximum control of the dose distribution in extended targets with simultaneous dose reduction for organs at risk. This method demonstrated a low incidence of severe side effects after radiation therapy and predictable treatment effectiveness. Our initial experience demonstrates that OC-TBI appears to be a promising technique for the treatment of pediatric patients.

αß T Cell-Depleted Haploidentical Hematopoietic Stem Cell Transplantation without Antithymocyte Globulin in Children with Chemorefractory Acute Myelogenous Leukemia.

We evaluated the outcome of αß T cell-depleted haploidentical hematopoietic stem cell transplantation (HSCT) in a cohort of children with chemorefractory acute myelogenous leukemia (AML). Twenty-two patients with either primary refractory (n = 10) or relapsed refractory (n = 12) AML in active disease status received a transplant from haploidentical donors. The preparative regimen included cytoreduction with fludarabine and cytarabine and subsequent myeloablative conditioning with treosulfan and thiotepa. Antithymocyte globulin was substituted with tocilizumab in all patients and also with abatacept in 10 patients. Grafts were peripheral blood stem cells engineered by αß T cell and CD19 depletion. Post-transplantation prophylactic therapy included infusion of donor lymphocytes, composed of a CD45RA-depleted fraction with or without a hypomethylating agent. Complete remission was achieved in 21 patients (95%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 18%, and the cumulative incidence of chronic GVHD was 23%. At 2 years, transplantation-related mortality was 9%, relapse rate was 42%, event-free survival was 49%, and overall survival was 53%. Our data suggest that αß T cell-depleted haploidentical HSCT provides a reasonable chance of long-term survival in a cohort of children with chemorefractory AML and creates a solid basis for further improvement.

[Recurrences of acute promyelocytic leukemia in children: experience with arsenic trioxide therapy and autologous hematopoietic cell transplantation].

AIM: To analyze the specific features of recurrences of acute promyelocytic leukemia (APL) in children after standard therapy with daunorubicin, cytosine arabinoside (Ara-C), all-trans retinoic acid (ATRA) and to develop further programmed treatment policy. SUBJECTS AND METHODS: The study included 9 patients with recurrent APL. The recurrences developed significantly more frequently in a very high-risk group (patients with minimal residual disease being preserved after the intensive therapy phase). Induction used arsenic trioxide (ATO) and/or standard chemotherapy + ATRA; ATO monotherapy was in consolidation. CD34+ cells were mobilized until molecular remission was achieved with high-dose Ara-C and granulocyte colony-stimulating factor. Pretransplantation conditioning involved melfalan as a basic drug in combination with high-dose AraC (5 pts), treosulfan (1 pt) or bisulfan (1 pt). Six patients received gemtusumab ozogamicin, 3-9 mg/m2, at different stages of therapy. RESULTS: Before therapy one patient died; 8 patients achieved the second molecular remission; CD34+ cell mobilization and sampling were effective in 7 cases. Five patients were in long-term molecular remission after autologous hemopoietic stem cell transplantation (autoHSCT). Follow-up was 23-40 months. One patient is being prepared for transplantation. Following autoHSCT, another patient with a developed repeat recurrence died from complications due to related partially compatible transplantation. Visceral, including cardiological, toxicity of therapy was insignificant. In the APL-2003 protocol, overall and event-free survival rates were 93 +/- 3 and 76 +/- 6%, respectively. CONCLUSION; The application of ATO and autoHSCT in recurrent APL makes it possible to achieve and preserve the second molecular remission in case of insignificant extrahematological toxicity. Russian clinics should have access to ATO.

[Results of hematopoietic cell transplantation in the first complete remission in children with acute myeloid leukemia from an intermediate risk group].

AIM: To analyze the results of allogeneic and autologous hemopoietic cell transplantations (allo- and auto-HCT) in children with acute myeloid leukemia (AML) from an intermediate risk group, most of which were performed using lower-intensity conditioning modes. SUBJECTS AND METHODS. The study enrolled 36 children from an intermediate risk group, who had undergone auto-HCT (n = 22) or allo-HCT (n = 14) in December 1994 to December 2008. The patients' age was 0.7 to 16.6 years (median 12.8 years). Chemotherapeutic conditioning regimens were applied to all the patients. Melphalan was a basic myeloablative agent in 83.3% of cases. RESULTS: With a median follow-up of 4.6 years (1.1-13.8 years), three-year relapse-free survival (RFS) was 80.4%; overall survival (OS) was 65.6%. Recurrences were documented only in 6 (16.6%) patients from the auto-HCT. Transplantation-associated mortality (TAM) was 13.8% (five patients died). After allo-HCT versus auto-HCT, RFS, OS, and TAM were 100 and 68.7% (p = 0.03), 93.2 and 55.5% (p = 0.02), and 7.1 and 18.2%, respectively. Acute and chronic graft-versus-host reactions developed in 57.1 and 23.1%, respectively. CONCLUSION: Transplantation of allogeneic hemopoietic cells from a compatible related donor in the intermediate risk group children with AML, by using melphalan-based conditioning regimen, demonstrates a high survival rate with the minimum toxicity.

[Transplantation of the bone marrow from a HLA-compatible unrelated donor after immunoablative conditioning in children with acquired aplastic anemia unresponsive to combined immunosuppressive therapy: preliminary results].

AIM: To analyze the efficiency of transplantation of the bone marrow from a HLA-compatible unrelated donor and continued immunosuppressive therapy (IST) in children with aplastic anemia (AA) unresponsive to 2 courses of IST. SUBJECTS AND METHODS: The study enrolled 14 children aged 2-16 years (median 9 years). A control group comprised 26 patients in whom IST was continued. The median interval between the diagnosis of AA and transplantation was 26 months (9-156 months). The conditioning regimen consisted of thoracoabdominal irradiation in a dose of 2 Gy, fludarabin (Flu) 100-150 mg/m2, cyclophosphamide (Cy) 100-200 mg/kg, antithymocyte globulin (ATG) in 11 patients and Flu, Cy, and ATG in 3. A graft-versus-host reaction was prevented with mycophenolate mefetil in all the patients, tacrolimus in 11, and cyclosporin A in 3. Donors were compatible for high-resolution typing of 10/10 and 9/10 alleles in 8 and 6 patients, respectively; the source of a transplant was bone marrow in 13 patients and granulocyte colony-stimulating factor-mobilized peripheral blood precursors in one case. RESULTS: Thirteen patients achieved primary engraftment after single transplantation; one patient did after repeat transplantation. Grades I to II graft-versus-host reaction (GVHR) developed in 9 patients; postengraftment life-threatening infections in 3, extensive chronic GVHR in 2, circumscribed GVHR in 7. All fourteen hemopoietic cell transplant recipients followed for a median 17.5 months (range 1-71 months) were survivors. CONCLUSION: The likelihood of good survival after unrelated transplantations in AA is much higher than that after continued IST: 100% versus 15 +/- 11%.

[Long-term results of combined treatment of acute promyelocytic leukemia in children and adolescents with gene therapy].

AIM: To analyse the results of treatment of children and adolescents with acute promyelocytic leukemia (APL) including polychemotherapy and ATRA (protocols APL 93, 98 and 2003). MATERIAL AND METHODS: The course of the disease, modification of the treatment protocols with reduction of anthracyclines and ATRA doses, results of molecular monitoring of PML/RARalpha transcript have been analysed for 107 APL patients. RESULTS: For prognosis of the disease important are initial characteristics of the patient and the time of the tumor regress assessed by molecular methods--establishment of molecular remission and molecular recurrence. CONCLUSIONS: In APL it is necessary to conduct molecular monitoring especially in patients at high risk and with poor prognosis in a decrease of treatment intensity for toxicity relief. Detection of molecular recurrence is indication for treatment. To raise efficacy of APL recurrence therapy it is necessary to design a special updated protocol.

[Clinico-laboratory variants of the course and results of therapy of hepatitis-associated aplastic anemias in children].

AIM: To study clinical and laboratory characteristics of hepatitides and evaluate efficacy of immunosuppressive therapy and transplantation of the bone marrow in hepatitis-associated aplastic anemia (HAAA). MATERIAL AND METHODS: A retrospective analysis of case histories of children with HAAA was made. For all the patients standard tests for detection of aquired aplastic anemia and hepatitis were conducted. Transplantation of hemopoietic stem cells (THSC) from HLA-identical donors was made in 4 patients, 25 patients were treated with combined immunosuppressive therapy (antithymocytic globulin--ATG plus cyclosporin A -CsA), one patients received monotherapy with CsA, two--prednisolone and a short course of CsA, one child was untreated. RESULTS: Of 260 children admitted to hospital from April 1989 to July 2005 for aquired aplastic anemia, 33 (12.7%) met diagnostic criteria of HAAA. Boys to girls ratio was 267. Hepatitides were severe: median of alaninaminotransferase concentration was 1215 IU/l, aspartataminotransferase--789 IU/l, bilirubin--152.5 mcmol/l. Median of the interval from hepatitis symptoms to documentation of pancytopenia was 66 days (0-204 days). All four patients after THSC are alive for 30-72 months. Probability of complete remission after the first course of ATG+CsA is 0.72 +/- 0.09, probability of survival 0.81 +/- 0.07, median of the interval to transfusion independence--50 days. CONCLUSION: HAAA prognosis is good only in administration of up-to-date therapy. After seronegative hepatitis it is necessary to control hemogram parameters and in the presence of minimal cytopenia patients should be directed to hematological hospital.

[Time course changes in the count of peripheral granulocytes in children with acquired aplastic anemias treated with antithymocyte globulin, cyclosporin A and granulocytic colony stimulating factor]. / Dinamika kolichestva granulotsitov v perifericheskoi krovi u detei s priobretennymi aplasticheskimi anemiiami, poluchivshikh lechenie antitimotsitarnym globulinom, tsiklosporinom A i granulotsitarnym koloniestimuliruiushchim faktorom.

AIM: To examine the pattern of changes in the count of peripheral granulocytes in children with aplastic anemias (AA), receiving a combined immunosuppressive therapy with antithymocytic globulin (ATG) and cyclosporin A in combination with granulocytic colony-stimulating factor (G-CSF). MATERIALS AND METHODS: 31 children (17 boys and 14 girls) aged 2-15 years (median 9 years) with newly diagnosed severe and very severe acquired AA took a combined immunosuppressive therapy with ATG and cyclosporin A in combination with G-CSF in an initial dose of 10 micrograms/kg a day. RESULTS: A three-linear and response was recorded in 19 (61%) children, an isolated granulocytic response was in 26 (84%). The interval median before the recovery of granulocytes to 1.5 x 10(9)/l and 5 x 10(9)/l was 19 and 38 days, respectively. CONCLUSION: Use of G-CSF may increase the count of granulocytes in the vast majority of patients with AA, without dramatic influence on the frequency of a three-linear response. Intermittent use of G-CSF may maintain the count of granulocytes long at the safe level and reduce the cost of treatment.