Total Body Irradiation (TBI), Fludarabine (F), Melphalan (M) and Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Pediatric Hematologic Malignancies.

Abstract The FM reduced-intensity preparative regimen has been used successfully in adults for allogeneic HSCT. Its role in pediatric hematologic malignancies is unclear. We studied the engraftment efficacy and the antineoplastic effect of adding TBI to the FM combination. Between July 1998 and January 2004 a total of 29 pediatric (19 males) patients were treated. Twenty-two had acute lymphoblastic leukemia (ALL), 6 had acute myeloid leukemia (AML), and 1 anaplastic large cell lymphoma. Disease status at the time of SCT was: CR2 (19 patients), CR3 (5), CR1 (2, with Ph+ leukemia), and induction failure/relapse (3). Six patients received this regimen for a second HSCT. The donor was unrelated in 21 cases: 1–2 antigen mismatched cord blood (CB) in 20, and peripheral blood stem cells (PBSC) in one. Of the 8 related-donor HSCT, 2 were not genotypically identical. The conditioning regimen was TBI 9Gy (3 fractions on day -7, -6, and -5), F 30 mg/m2 IV daily (days -4 to -1) and M 140 mg/m2 IV on day -1. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. No anti-thymocyte globulin was used. The regimen was well-tolerated, with grade II-III oral mucositis and diarrhea the most common side effects seen. Twenty-seven patients achieved ANC engraftment after a median time of 16 days (range 11–35), and 23 also had platelet engraftment at a median of 42 days (range 14–200). There was one case of primary graft failure and one early death. Six of 27 evaluable patients developed grade III-IV acute GVHD and three chronic GVHD. There were seven deaths in the first 100 days (3 from interstitial pneumonitis, 1 GVHD, 1 renal failure, 1 VOD, 1 graft failure), all in patients with ALL. Nine patients (7 with ALL) relapsed at a median of 8 months post-transplant (range 2–54). With a median follow-up of 54 months (range 7–79), 7 of 22 ALL, 5 of 6 AML, 1 of 1 lymphoma patients are alive and in remission (12 are over two years post HSCT). In conclusion, the addition of TBI to FM leads to successful engraftment of allogeneic HSC (including 1–2 antigen mismatched unrelated cord blood units) in heavily pretreated pediatric patients with hematologic malignancies, without the inclusion of ATG. The regimen was well tolerated and its activity in AML deserves further evaluation.</jats:p

Tacrolimus and Short-Term Methotrexate (mini-MTX) for Graft Versus Host Disease (GVHD) Prophylaxis after Unrelated Single Unit Cord Blood Transplant (CBT) in Pediatric Patients.

Abstract CBT is increasingly used in the management of patients with a variety of hematologic and neoplastic conditions. We investigated the use of Tacrolimus with MTX for the prevention of GVHD. Sixty consecutive pediatric patients (37 males, median age 6.8 years, range 0.4–20 y) underwent 63 single unit CBT. Sixty-two units were mismatched with the patients (1 Antigen mismatch [Ag MM]: 20; 2 Ag MM: 39; 3 Ag MM: 3). Five patients had non-malignant conditions (severe aplastic anemia [SAA] 2, Wiskott-Aldrich 2, Hunter 1). Thirty-one of the 55 patients with malignant diseases (ALL 30, AML 16, CML 2, NHL 2, MDS 2, JMML 2, neuroblastoma 1) had high-risk disease. The conditioning regimen was chemotherapy-only in 34 (Thiotepa, Busulfan[Bu], Cyclophosphamide[Cy] for 28 children younger than 5 years or with prior irradiation; Bu-Cy in the patient with Hunter and a patient with AML and trisomy 21; Fludarabine[Flu], Cy, Lymphoglobulin in one patient with SAA; Bu-Flu:3) transplants. Radiochemotherapy was implemented in 29 patients (Flu, Melphalan[Mel], TBI: 26; Etoposide, Mel, TBI:1; Etoposide, Mel, TBI:1; Flu, Cy, ATG, 200cGy TBI:1 SAA patient). The median pre-cryopreservation total nucleated cell dose was 4.3 x 107 / kg recipient weight (range 1.8–12 x 107/ kg). The combination of Tacrolimus and mini-MTX (5 mg/m2 on days 1, 3 and 6) was used in 60 transplants (Tacrolimus alone in 3). ATG or steroids were not routinely used. Results: Forty-six of the 52 transplants evaluable for acute GVHD did not have severe GVHD (Grade 0:11 patients; I: 10 patients; II: 25 with 22 limited to skin only; III: 3; IV: 3 patients). Eight patients had primary graft failure (2 with persistent disease). There were 3 early deaths. Chronic GVHD was diagnosed in 8/42 evaluable patients. With a median follow-up of 1,757 days (range 512–3,731) 27 patients are alive without disease. Conclusion: Tacrolimus with mini-MTX should be considered for the prevention of GVHD after mismatched unrelated cord blood transplants in pediatric patients with malignant or non-malignant diseases.</jats:p

Pharmacokinetics and individualized dose adjustment of intravenous busulfan in children with advanced hematologic malignancies undergoing allogeneic stem cell transplantation

AbstractWe investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 μmol/L/min per dose (range, 1000–1300 μmol/L/min per dose; SD ±13%) based on the first-dose PK determination. PK studies were repeated on subsequent doses to verify the final AUC. Initial mean IVBU clearance and half-life were 3.96 mL/min/kg and 1.98 hours, respectively. Sixteen (80%) of the 20 patients received dose adjustments: 14 patients required dose escalations, and 2 required dose reductions. Overall, thirteen (72%) of 18 available sample sets at final follow-up PK analysis showed the IVBU exposure to be within the targeted range. IVBU PK was linear, and interpatient variability was much lower than that observed with oral busulfan. IVBU was well tolerated, and no case of hepatic veno-occlusive disease was encountered. Mild and transient hyperbilirubinemia was observed in 7 patients. Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386–1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation