Roberta H. Adams

Tandem High-Dose Therapy in Rapid Sequence for Children With High-Risk Neuroblastoma

PURPOSE Advances in chemotherapy and supportive care have slowly improved survival rates for patients with high-risk neuroblastoma. The focus of many of these chemotherapeutic advances has been dose intensification. In this phase II trial involving children with advanced neuroblastoma, we used a program of induction chemotherapy followed by tandem high-dose, myeloablative treatments (high-dose therapy) with stem-cell rescue (HDT/SCR) in rapid sequence. PATIENTS AND METHODS Patients underwent induction chemotherapy during which peripheral-blood stem and progenitor cells were collected and local control measures undertaken. Patients then received tandem courses of HDT/SCR, 4 to 6 weeks apart. Thirty-nine patients (age 1 to 12 years) were assessable, and 70 cycles of HDT/SCR were completed. RESULTS Pheresis was possible in the case of all patients, despite their young ages, with an average of 7.2 x 10(6) CD34(+) cells/kg available to support each cycle. Engraftment was rapid; median time to neutrophil engraftment was 11 days. Four patients who completed the first HDT course did not complete the second, and there were three deaths due to toxicity. With a median follow-up of 22 months (from diagnosis), 26 of 39 patients remained event-free. The 3-year event-free survival rate for these patients was 58%. CONCLUSION A tandem HDT/SCR regimen for high-risk neuroblastoma is a feasible treatment strategy for children and may improve disease-free survival.

A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: A pediatric blood and marrow transplant consortium study

Summary:Severe mucositis is a common cause of morbidity in hematopoietic stem cell transplant (HSCT) recipients. Glutamine has been shown to reduce mucositis in children receiving chemotherapy. Patients were randomized in a double-blind manner to receive glutamine or glycine at a dose of 2 g/m2/dose (maximum dose 4 g) twice daily until 28 days post transplant or discharge if sooner. Mucositis was graded by use of a modified Walsh scale. A total of 120 children were evaluable: 57 children received glutamine and 63 received glycine. The mean mucositis score was 3.0±0.3 vs 3.9±0.4 (P=0.07) in the glutamine and glycine groups, respectively. The glutamine group demonstrated a reduction in mean number of days of intravenous narcotics use (12.1±1.5 vs 19.3±2.8 in the glycine group, P=0.03) and total parenteral nutrition (17.3±1.7 vs 27.3±3.6 in glycine group, P=0.01). There was no statistically significant difference in toxicity between the two groups. Glutamine appears to be safe and beneficial in reducing the severity of mucositis. Strong consideration should be given to include oral glutamine supplementation as a routine part of supportive care of SCT patients.

Successful Matched Sibling Donor Marrow Transplantation Following Reduced Intensity Conditioning in Children with Hemoglobinopathies

Fifty‐two children with symptomatic sickle cell disease sickle cell disease (SCD) (N = 43) or transfusion‐dependent thalassemia (N = 9) received matched sibling donor marrow (46), marrow and cord product (5), or cord blood (1) allografts following reduced intensity conditioning (RIC) with alemtuzumab, fludarabine, and melphalan between March 2003 and May 2014*. The Kaplan–Meier probabilities of overall and event‐free survival at a median of 3.42 (range, 0.75–11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for SCD, and 100% and 100% for thalassemia, respectively. Treatment‐related mortality (all related to graft versus host disease, GVHD) was noted in three (5.7%) recipients, all 17–18 years of age. Acute and chronic GVHD was noted in 23% and 13%, respectively, with 81% of recipients off immunosuppression by 1 year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at 1 year and beyond; all had discontinued immunosuppression between 4 and 12 months from transplant with no subsequent consequence on GVHD or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond 6 months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of SCD were noted, and pain symptoms subsided within 6 months posttransplant. These findings support using RIC for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.Clinical Trials.gov: NCT00920972, NCT01050855, NCT02435901). Am. J. Hematol. 90:1093–1098, 2015.

Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase

The prognosis for patients with Philadelphia-negative myeloproliferative neoplasms (MPN) who evolve into acute myeloid leukemia (AML) or blast phase (MPN-BP) is extremely poor. Although allogeneic stem cell transplantation (allo-SCT) is considered potentially curative, very few patients have been reported who have undergone allo-SCT for MPN-BP; therefore the success rate remains unknown. In a retrospective review, we identified 13 patients with an MPN transformation to blast phase after a median 9 years (range 5 months to 30 years); 8 (median age 55) continued to allo-SCT within 6 months. Induction chemotherapy cleared blood/marrow blasts in 60% (6/10) (2 declined therapy, 1 had early death). At the time of allo-SCT, 5/8 patients were in complete remission (CR) of their leukemia or had returned to MPN chronic phase (CP), 2 had residual blood blasts and 1 was refractory with >5% marrow blasts. At follow-up (median 20.3 months), 6 patients are alive in CR of both their leukemia/MPN. All 5 patients in CR/CP at pre-allo-SCT remain alive in remission, while 2/3 with persistent blood/marrow blasts relapsed and expired. We conclude that MPN-BP can be cured by allo-SCT in a significant percentage of patients, but that adequate leukemic clearance prior to allo-SCT offers an optimal outcome.

Coccidioidomycosis in hematopoietic stem cell transplant recipients.

Coccidioidomycosis is an endemic fungal infection of the desert southwestern United States that can cause devastating disseminated infection in immunocompromised persons. Clinical coccidioidomycosis, which is caused by Coccidioides species, has been well characterized in patients who have had solid organ transplants, but it has rarely been described in patients who have received a hematopoietic stem cell transplant (HSCT). We report the experience of 121 consecutive HSCT recipients at a single tertiary care institution in an endemic area. One patient had fatal disseminated coccidioidomycosis after receiving an allogeneic transplant, and 2 patients had pulmonary infection before successful autologous HSCT; 1 of these 2 had a reactivation of coccidioidal infection after HSCT but was treated and survived. Coccidioidomycosis was not commonly identified in HSCT recipients, even in the endemic area. A prospective evaluation is required to address the optimal use of coccidioidal serologic tests, antifungal protocols, and secondary prophylaxis in these patients.

Rapid-sequence tandem transplant for children with high-risk neuroblastoma.

Background The majority of patients with high risk neuroblastoma (NB) still relapse. Procedure We designed a Phase II trial for children with advanced NB utilizing a program of induction chemotherapy followed by tandem high-dose chemoradiotherapy with stem cell rescue (HDC/SCR) in rapid sequence. Fifty-five patients were evaluable, ages 1–14 years, and 97 cycles of HDC/SCR have been completed to date. Pheresis was possible for every patient, despite their young age, with an average of 7.2 × 106 CD34+ cells/kg available to support each HDC/SCR cycle. Results Engraftment was rapid, with median time to neutrophil engraftment of 11 days. Five patients who completed the first HDC course did not complete the second and there were four toxic deaths. With a median follow-up of 24 months from diagnosis, 38 of 55 patients (3-year EFS 59%) remain event-free. A subset of the patients received stem cells purged by CD34 selection. The engraftment and EFS of these patients are similar to the overall group. Conclusion This work demonstrates that a tandem transplant regimen for high-risk NB is a feasible treatment strategy in children and may improve disease-free survival. Med. Pediatr. Oncol. 35:696–700, 2000.

Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study

BACKGROUND The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts. METHODS In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417. FINDINGS 96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively. INTERPRETATION Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies. FUNDING US National Heart, Lung, and Blood Institute and National Cancer Institute.

Myeloablative therapy with autologous stem cell rescue for patients with Ewing sarcoma.

The aim of this study was to identify risk factors associated with PFS in patients with Ewing sarcoma undergoing ASCT; 116 patients underwent ASCT in 1989–2000 and reported to the Center for International Blood and Marrow Transplant Research. Eighty patients (69%) received ASCT as first-line therapy and 36 (31%), for recurrent disease. Risk factors affecting ASCT were analyzed with use of the Cox regression method. Metastatic disease at diagnosis, recurrence prior to ASCT and performance score <90 were associated with higher rates of disease recurrence/progression. Five-year probabilities of PFS in patients with localized and metastatic disease at diagnosis who received ASCT as first-line therapy were 49% (95% CI 30–69) and 34% (95% CI 22–47) respectively. The 5-year probability of PFS in patients with localized disease at diagnosis, and received ASCT after recurrence was 14% (95% CI 3–30). PFS rates after ASCT are comparable to published rates in patients with similar disease characteristics treated with conventional chemotherapy, surgery and irradiation suggesting a limited role for ASCT in these patients. Therefore, ASCT if considered should be for high-risk patients in the setting of carefully controlled clinical trials.

Successful treatment of JMML relapsed after unrelated allogeneic transplant with cytoreduction followed by DLI and interferon-alpha: evidence for a graft-versus-leukemia effect in non-monosomy-7 JMML

Summary:Relapse is the major cause of treatment failure after allogeneic transplantation of children with juvenile myelomonocytic leukemia (JMML), and the role of post-transplant immunomodulation is poorly understood. We report a 12-month-old child with JMML relapsed after unrelated marrow transplantation who received cytoreduction followed by donor lymphocyte infusion (DLI) with improvement, and after addition of interferon-alpha (IFN) achieved complete donor chimerism. He was weaned from IFN and has maintained complete remission for 19 months. This is the first published report of a patient with non-monosomy-7 JMML responding to post-transplant immunomodulation and suggests a role for DLI plus IFN in these patients.

Persistent human rhinovirus type C infection of the lower respiratory tract in a pediatric cord blood transplant recipient.

Persistent human rhinovirus type C infection of the lower respiratory tract in a pediatric cord blood transplant recipient