Second allogeneic hematopoietic stem cell transplantation for juvenile myelomonocytic leukemia: case report and literature review

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disease in young childhood. Hematopoietic stem cell transplantation (HSCT) is the only way to cure the disease, but relapse after HSCT remains a major cause of treatment failure. A 5-year-old girl with JMML, who had experienced a relapse after the first transplant, did not respond to donor lymphocyte infusion and withdrawal of immune-suppressing agents. She was successfully treated using a second transplant. Detailed reports from the English literature since 1988 relating to a total of 13 JMML patients undergoing a second transplant were reviewed. Seven of the 13 JMML patients (54%) were alive and disease-free, with a median follow-up of 53 months after the second transplant. Within the first 6 months following the initial transplant, 10 JMML patients suffered either autologous recovery (n = 6) or early relapse (n = 4). Seven of the 10 (70%) were alive, with a median survival period of 53 months after the second transplant. Six JMML patients underwent retransplantation within 6 months of the first transplant, with three of these (50%) alive at follow-ups of 24, 57, and 90 months after the second procedure. The authors conclude that a second transplant within 6 months may be worth considering for JMML patients who experience autologous recovery or earlier relapse after the first transplant.     

儿童第二次非血缘供者造血干细胞移植2例

目的探索非血缘造血干细胞移植后复发病例进行第二次移植的可行性。方法患幼年型慢性粒单细胞性白血病(JMML)及重型β-地中海贫血的两例患儿接受非血缘供者造血干细胞移植后分别于移植后的10个月和1个月后原疾病复发,前者给予福达华加环磷酰胺预处理后输注原供者干细胞,降低预防移植物抗宿主病强度;后者给予含TBI预处理,移植另一非血缘供者外周血干细胞。结果两例患者第二次移植后均获得稳定植入,JMML患者并发急慢性移植物抗宿主病,完全缓解至+24月;地中海贫血患者已完全脱离输血状态至+23月。结论对于非血缘造血干细胞移植后复发的患儿,第二次非血缘供者造血干细胞移植是可行的。     

Allogeneic bone marrow transplant improves outcome for juvenile myelomonocytic leukaemia

OBJECTIVE: To correlate clinical presentation and therapeutic outcomes in children with a diagnosis of juvenile myelomonocytic leukaemia. METHODS: The medical records of 14 children who fulfilled the International Juvenile Myelomonocytic Leukaemia Working Group Criteria for a diagnosis of juvenile myelomonocytic leukaemia (JMML) presenting to a single institution were reviewed, and their clinical status at September 2000 was documented. RESULTS: The most common presenting features were hepatosplenomegaly and lymphadenopathy. Fifty per cent of cases presented in the first year of life. Nine of 14 patients initially received chemotherapy otherwise used in the treatment of acute myeloid or lymphoblastic leukaemia with no apparent benefit. All six patients who received conditioning therapy with chemotherapy alone, followed by allogeneic bone marrow transplant (BMT), are in complete remission at a median follow-up duration of 12 months (range 5-91 months). Five of six patients surviving post-allogeneic BMT received marrow from an unrelated donor. Only one of seven patients who did not receive BMT survived long-term. CONCLUSION: Children with a diagnosis of JMML should be treated with allogeneic BMT as soon as a suitable donor is found. The role of anti-leukaemic therapy in this disease, prior to BMT, requires further investigation in the context of a multicentre clinical trial.     

Simultaneous control of third-degree graft-versus-host disease and prevention of recurrence of juvenile myelomonocytic leukemia (JMML) with 6-mercaptopurine following fulminant JMML relapse early after KIR-mismatched bone marrow transplantation

The authors describe a young boy with juvenile myelomonocytic leukemia (JMML) who relapsed 45 days after HLA and killer immunoglobulin-like receptor (KIR) mismatched unrelated donor bone marrow transplant (MMUD-BMT) and subsequently developed life-threatening graft-versus-host disease (GvHD). Treatment with 6-mercaptopurine (6-MP) appeared to control severe GvHD and possibly prevented recurrence of leukemic relapse.     

Complete remission following clofarabine treatment in refractory juvenile myelomonocytic leukemia

Juvenile myelomonocytic leukemia (JMML) is the most common myeloproliferative/myelodysplastic disorder seen in children. The treatment of choice, allogeneic stem cell transplantation, provides the only known cure for the disease, but relapse after transplant is common. The authors describe a 5-year-old boy diagnosed at age 34 months with JMML that evolved to acute myeloid leukemia. Initial treatment consisted of fludarabine and cis-retinoic acid therapy, followed by a matched sibling bone marrow transplant. After a relapse, he received a second transplant from the same donor, using peripheral blood stem cells, followed by repeated donor leukocyte infusions. After the second relapse, he received the farnesyltransferase inhibitor R115777 (tipifarnib, Zarnestra), but the leukemia persisted. When bone marrow blasts numbered 60% of the mononuclear cells, he received single-agent clofarabine induction (52 mg/m/d) for 5 days. After three courses, he attained a remission marrow with 5% blasts and disappearance of the 5q- and 9q- cytogenetic abnormalities.     

Successful unmanipulated peripheral blood progenitor cell transplantation from an HLA haploidentical 2-locus-mismatched mother in a thalassemic patient with primary graft failure after transplantation of bone marrow and cord blood from unrelated donors

Abstract:  We report on a boy with β-thalassemia major who developed early graft failure after double-unit unrelated cord blood transplantation, who subsequently received a myeloablative preconditioning regimen using non-T-cell-depleted PBSCT from his HLA-haploidentical 2-loci-mismatched mother. Neutrophil recovery with full donor chimerism was observed at post-transplantation day +11. Furthermore, GVHD was easy to control. The patient was transfusion-independent with complete donor chimerism eight months post-transplant. The result indicated that fetomaternal microchimerism may be an important attribute of a successful transplant. We suggested that a third allo-HSCT may be taken into consideration for patients with transfusion-dependent thalassemia who experience graft failure, even after two previous transplants.     

Survival after recurrence of osteosarcoma: a 20-year experience at a single institution

BACKGROUND: Approximately one-third of patients with osteosarcoma who have a complete response to their initial treatment can be expected to relapse. It is important to define what host, tumor, or treatment characteristics determine outcome after relapse. We present findings in 59 patients treated at our institution from 1974 to 1996 who have relapsed one or more times after their initial response. METHODS: Host and tumor characteristics at diagnosis and relapse, therapeutic interventions and survival outcomes were determined from examination of medical records and a follow-up questionnaire. RESULTS: Of the 59 patients, 37 initially presented with localized disease of the extremity, 11 with localized non-extremity disease, and 11 with metastatic disease. This report focuses on those with localized disease of the extremity. For these patients, median time from original diagnosis to first recurrence was 14 months. Median survival after first recurrence was 31 months. The median post initial relapse survival was the same for patients whose first relapse occurred before or after 14 months from original diagnosis. Seventeen of 29 patients with systemic metastasis at first recurrence had complete removal of their disease and had a median post-op survival of 2.5 years, while the remaining 12 patients with no surgery, had a median survival of 2 years. Of the 37 patients who presented with primary disease only in the extremities and relapsed: 31 died (2 more than 6 years from first recurrence) and 6 are alive from 6 to 24 years from first recurrence (5 without disease and 1 with disease). Three of the five disease-free survivors had three or more relapses. CONCLUSION: With a long follow-up time, we found 15% of patients with relapsed osteosarcoma who originally presented with localized disease in the extremity are alive with no evidence of disease at 10 years from first recurrence (Kaplan-Meier estimate). Even patients with multiple relapses may have long-term disease-free survival after salvage therapy. Chemotherapy and time to first recurrence were unrelated to survival after relapse in this study. Complete surgical removal of metastatic disease may be important for long-term survival.     

幼年粒单细胞白血病造血干细胞移植疗效初探

目的探讨造血干细胞移植治疗幼年粒单细胞白血病(JMML)的疗效。方法 5例JMML患儿接受无关供者脐血造血干细胞移植治疗。预处理均采用Bu/Cy+Mel+ATG方案:马利兰(0.8～1.0)mg/kg,每6小时1次共用16次(-8d～-5d);环磷酰胺60mg/(kg·d)用2d(-4～-3d);马法兰140mg/m2用1次(-2d):抗胸腺细胞球蛋白2.5mg/(kg·d)连用4d(-4～-1d)。GVHD预防采用CsA+MP±MMF。结果 5例成功植入,3例复发,1例复发后死于卡氏肺囊虫肺炎,1例死于CMV感染相关间质性肺炎,1例长期无病存活。结论 5例JMML移植初步治疗结果不满意,移植失败主要原因为白血病复发。为减少复发,今后需进一步改进移植方法 ,包括选择其他供体、改进GVHD预防方案。     

Hematopoietic stem cell transplantation after first marrow relapse of non-T, non-B acute lymphoblastic leukemia: a pediatric oncology group pilot feasibility study

BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) in children is associated with a poor outcome, especially for those patients whose relapse occurs during the first 36 months after diagnosis. The best therapy for these patients is not known. This study was designed to evaluate the feasibility of enrolling children with recurrent ALL in a standardized treatment protocol that included receipt of a hematopoietic stem cell transplant (HSCT). PROCEDURE: Eligible patients with a bone marrow relapse of non-T, non-B ALL underwent a common induction and consolidation followed by receipt of either an allogeneic HSCT from a human leukocyte antigen (HLA)-identical sibling or an autologous HSCT purged with B-4 blocked ricin. A common conditioning regimen was used for all patients. RESULTS: Twenty-eight patients from eight institutions were enrolled. Fourteen patients did not receive a transplant during the study, because of toxicity (4), relapse (1), inadequate purging (1), and parental or physician preference for an alternative donor transplant (8). Six patients received allogeneic HSCTs. Five of them have remained in remission for a median of 78 months. Eight patients received autologous HSCTs purged with B4-blocked ricin. Four have remained in remission for a median of 94 months. Of the nine patients who received alternative donor transplants, only two remain in remission. CONCLUSION: We conclude that well designed and controlled prospective studies are necessary to define the role of HSCTs in children with recurrent ALL. In order to be successful, such studies must have the full support of participating centers. Autologous HSC transplantation may have a role in the treatment of relapsed ALL, but further studies are needed.     

Relapse in childhood acute lymphoblastic leukemia after elective cessation of initial treatment: Failure of subsequent treatment with cyclophosphamide,cytosine arabinoside,vincristine and prednisone (COAP)

Although the majority of children with acute lymphoblastic leukemia (ALL) can electively stop treatment after 21/2–5 years of continuous disease-free remission, 20–25% of those patients relapse after discontinuation of therapy. We treated 15 patients whose disease recurred after stopping treatment. Fourteen of them attained complete remission, but the median duration of disease-free survival was only 11 months. In this population, the site of initial relapse, bone marrow or testicle, did not influence subsequent outcome. Patients who relapsed within six months of stopping initial therapy had shorter second remissions than those who relapsed after six months. We conclude that the combination chemotherapy utilized in this study was inadequte for the control of relapsed ALL. Future programs will have to use different drug combinations or bone marrow transplantation.     

Bone marrow relapse occurring as first relapse in children with acute lymphoblastic leukemia

In a retrospective review which covered the whole Dutch childhood population of approximately 3 million children we studied the prognosis in 164 children with acute lymphoblastic leukemia (ALL) who were initially treated between 1973 and 1983, and who had an isolated bone marrow relapse occurring as first relapse. Until their first relapse, the patients were initially treated according to standard protocols, while treatment for relapse was heterogeneous, and not intensive. Second complete remission (CR) was attained by 78% of the patients. The median duration of second CR was 9 months, the median survival 13 months. Multivariate analysis showed that the duration of the first CR was the most significant variable with regard to prognosis. None of the patients who developed their bone marrow relapse during initial treatment, i.e., within 24 months from diagnosis, survived. Among the 73 patients who relapsed after cessation of the initial treatment there were 19 long-term disease-free survivors, 14 of whom had not developed subsequent relapses after 48+-125+ months. From this study we conclude that treatment in children with first bone marrow relapse has to be intensified.     

Differentiating juvenile myelomonocytic leukemia from chronic myeloid leukemia in childhood

Juvenile myelomonocytic leukemia (JMML) is a rare clonal myeloproliferative disease of early childhood. To determine the diagnostic features, appropriate treatment, and overall patient survival pertaining to JMML for children, the authors reviewed the clinical data of 16 children with JMML admitted to the National Taiwan University Hospital between 1978 and 2001. Median age at diagnosis was 2.5 years. Fever was the most common symptom at diagnosis. At initial presentation, the mean white blood count and absolute monocyte count were 30 x 10(9)/L and 4.5 x 10(9)/L, respectively. Cytogenetic analysis was performed in 14 patients, and 2 patients (14%) had monosomy 7. Another patient, with normal karyotype at diagnosis, had deletion of 7q22 at the follow-up chromosome study. Forty-seven chronic myeloid leukemia (CML) patients were also diagnosed and followed at the same hospital during the same interval period. The age, leukocyte counts, platelet counts, basophil counts, monocyte percentages on peripheral blood smears, and median survival rate showed significant differences between JMML and CML patients (P < 0.05). The median survival was 10 months and the probability of 10-month survival was 0.38 by Kaplan-Meier analysis for 12 of the 16 JMML patients who did not receive hematopoietic stem cell transplantation (HSCT). Among three patients receiving HSCT, one patient relapsed 9 months after the first HSCT and was treated successfully by a second HSCT from the same sibling donor.     

Successful hematopoietic stem cell transplantation from an HLA‐mismatched parent for engraftment failure after unrelated cord blood transplantation in patients with juvenile myelomonocytic leukemia: Report of two cases

JMML is an aggressive hematopoietic malignancy of early childhood, and allogeneic HSCT is the only curative treatment for this disease. Umbilical cord blood is one of donor sources for HSCT in JMML patients who do not have an HLA‐compatible relative, but engraftment failure remains a major problem. Here, we report two cases of JMML who were successfully rescued by HSCT from an HLA‐mismatched parent after development of primary engraftment failure following unrelated CBT. Both patients had severe splenomegaly and underwent unrelated CBT from an HLA‐mismatched donor. Immediately after diagnosis of engraftment failure, both patients underwent HSCT from their parent. For the second HSCT, we used RIC regimens consisting of FLU, CY, and a low dose of rabbit ATG with or without TBI and additionally administered ETP considering their persistent severe splenomegaly. Both patients achieved engraftment without severe treatment‐related adverse effects. After engraftment of second HSCT, their splenomegaly was rapidly regressed, and both patients showed no sign of relapse for over 4 years. These observations demonstrate that HSCT from an HLA‐mismatched parent could be a feasible salvage treatment for primary engraftment failure in JMML patients.     

The timing of autologous stem cell transplantation and the prognostic factors affecting the prognosis in children with relapsed hodgkin lymphoma

Although ASCT is used as a standard treatment following second remission for adults in oncology practice, data are lacking for relapsed childhood HL. Therefore, we evaluated the exact timing of the ASCT treatment, as well as factors affecting the prognosis in children with relapsed HL who underwent ASCT. Patients were divided into two groups (Group 1: ASCT after second remission [n = 6], Group 2: ASCT after >2 remissions [n = 3]). Overall, DFS rate was 64.8% at 24 months after ASCT. In Group 1, post‐transplant DFS and OS were 83.3% and 75%, respectively, and the post‐transplant response without event rate was 5/6 (83.3%). However, in Group 2 this was 1/3 (33.3%). Nonetheless, the timing of ASCT was not a significant prognostic factor for DFS and OS in univariate analyses (p = 0.21 and p = 0.73, respectively). Median follow‐up time was 21 months after transplant, and DFS and OS were 62.5% and 75% in early relapse group (n = 6) at 24 months. DFS and OS were both 66.7% in late relapse (n = 3). In addition, response rates of ASCT without event were 66.7% for both early and late relapse groups. Relapse types (early: 3–12 months, late: >12 months) was not a significant prognostic factor for DFS and OS in univariate analyses (p = 0.96 and p = 0.92). While we found ASCT to be a useful treatment following second remission, it does not demonstrate better success in early relapse cases, when compared to late relapse cases. Therefore, after second remission for relapsed HL, ASCT is advisable regardless of the time of relapse.     

PART II. SURVIVAL AFTER RELAPSE DURING UNMAINTAINED REMISSION AND AFTER SECOND CESSATION OF THERAPY

Nygaard, R. and Moe, P. J. (Department of Paediatrics, University Hospital, Trondheim, Norway). Outcome after cessation of therapy in childhood leukemia. A population-based Nordic study of 986 patients. II. Survival after relapse during unmaintained remission and after second cessation of therapy. Acta Paediatr Scand Suppl 354: 20, 1989.
This is the second part of a population-based investigation of 986 patients after discontinuation of therapy for childhood leukemia. Patients who had their first relapse after cessation of therapy ( n =206) were studied for subsequent outcome in terms of survival after relapse. The patients with ALL ( n =191) were also analyzed according to patient variables with possible influence on survival. Fifty-one (26.7%) of the patients with relapse of ALL electively stopped therapy once more, and for them subsequent survival in remission was evaluated.
The overall estimated proportion alive at five years after relapse in unmaintained remission was 0.37 and at ten years 0.28. There was no significant difference in survival after relapse for males vs. females, and this could be attributed to the fact that isolated testicular relapses carried a better chance of subsequent survival than did relapses in other sites. Age at relapse did not have any influence on survival. However, time from cessation of therapy to first relapse was of prognostic value: Patients who relapsed within 6 months had a signifcantly lower survival than did those with relapse after longer periods in unmaintained remission.
Five-year DFS was 0.57 after second cessation of therapy in patients with ALL. Our study confirms that there may be more than one chance of cure.     

Allogeneic hematopoietic cell transplant following crizotinib monotherapy for relapsed/refractory anaplastic large cell lymphoma

Relapsed ALK‐positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow‐up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced‐toxicity conditioning regimen containing fludarabine, alemtuzumab, and low‐dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant‐related complications were experienced. One patient developed chronic renal disease secondary to transplant‐associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients’ post‐CRZ monotherapy, and further studies may be warranted.     

Isolated CNS relapse following stem cell transplantation for juvenile myelomonocytic leukemia

A 1-year-old girl with juvenile myelomonocytic leukemia (JMML) underwent allogeneic bone marrow transplantation (BMT) from her HLA-matched brother. A few months after BMT she experienced a bone marrow relapse that did not respond to withdrawal of immunosuppression. To enhance the graft-versus-leukemia (GVL) effect, she underwent peripheral stem cell transplantation (PSCT) from the same donor, using a nonmyeloablative conditioning regimen. She achieved clinical remission and developed chronic graft-versus-host disease (GVHD), which was treated with prednisone and cyclosporine A. One year after PSCT she experienced an isolated central nervous system (CNS) relapse. She was treated with intrathecal Ara-C followed by craniospinal irradiation and achieved a third clinical remission. While extramedullary relapses have been described in JMML, this is the first report of a CNS relapse. Based on this case and others in the literature, the authors suggest that newer therapies are changing the natural history of JMML. By manipulating the GVL effect it is possible to achieve a prolonged bone marrow remission, but only at the expense of unmasking the risk of late extramedullary relapse.     

Relapse after first cessation of therapy in childhood acute lymphoblastic leukemia: A 10-year follow-up study

The outcome of 171 children with ALL who relapsed for the first time after elective cessation of therapy (1–86 mo) and followed over 10 years (median 60 mo; range 1–232 mo) has been evaluated. One hundred and three patients relapsed in the bone marrow (BM), 29 in the testis (T), 21 in the central nervous system (CNS), 14 in the BM plus another site and 4 in other sites. Second remission was achieved in 97% of patients (97% BM, 100% T, 90% CNS, respectively) with reinduction schedules including three or more drugs. All but 4 out of 100 patients who relapsed in the BM received cranial reprophylaxis with intrathecal CT alone or CT plus radiotherapy. Seven patients in second CR underwent allogeneic bone marrow transplantation from an HLA matched sibling. The overall survival was 34% and disease-free survival (DFS) probability at 100 years was 22%. A second relapse was observed in 73% of patients. Forty children are alive in second continuous remission and 24 are alive after a second or subsequent relapse. Patients with isolated T relapse showed a significant better outcome than those with BM or CNS involvement. Most patients (62%) with isolated BM relapse showed a further disease recurrence in BM, and DFS was shorter when relapse occurred within 12 months from off-therapy. Eighty-two patients in second CR stopped the treatment a second time and showed a survival and DFS probabilities, respectively, of 69% and 43%. Thus, children with ALL who relapse after cessation of therapy still have a high risk of further late relapses and should be treated with intensive chemotherapy and CNS reprophylaxis. BMT must be considered for all patients relapsing in the BM within 12 months from off-therapy. © 1995 Wiley-Liss, Inc.     

Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma

BACKGROUND: Survival after relapse in patients with Ewing sarcoma is very poor and this retrospective study attempts to identify of prognostic factors predicting survival after relapse. PROCEDURE: A total of 191 patients with localised Ewing sarcoma were registered in the ET-2 trial of the United Kingdom Children's Cancer Study Group (UKCCSG). All patients received standardised primary treatment with chemotherapy and surgery and or radiotherapy as local modality treatment. Sixty-four patients who relapsed are included in this report. Treatment at relapse was variable and included chemotherapy, surgery, radiotherapy and high dose therapy (HDT) or megatherapy with peripheral stem cell transplantation (PBSCT) or autologous bone marrow transplantation (ABMT) in various combinations. A subgroup of patients had only non-specific symptomatic treatment at relapse. Both univariate and multivariate methods were used to investigate variables affecting survival after relapse. RESULTS: The overall actuarial median survival from relapse for all patients was 14 months (95% CI 11-16 months). Univariate analysis showed that males had a longer survival (median, 16 months vs. 11 months); patients who relapsed while on treatment did worse (median, 3 months vs. 16 months) and patients who had a longer disease-free interval (DFI) prior to relapse had a better outcome (DFI <1 year, median survival = 3 months; DFI 1-2 years, survival = 8 months; DFI > 2 years, median survival = 24 months, P < 0.001). Multivariate analysis confirmed that duration of first remission was the only factor associated with longer survival after relapse. CONCLUSIONS: These data suggest that although aggressive therapy may delay disease progression after relapse for some children, the course of the disease after relapse is usually fatal. International co-operative studies are needed to evaluate new strategies.     

The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long-term outcomes

Nishikawa T, Inagaki J, Nagatoshi Y, Fukano R, Nakashima K, Ito N, Sawa D, Kawano Y, Okamura J. The second therapeutic trial for children with hematological malignancies who relapsed after their first allogeneic SCT: Long‐term outcomes. Abstract: The impact of a second all‐SCT on the long‐term outcomes of children who relapse after allo‐SCT has been unclear. We retrospectively analyzed the long‐term outcomes of different salvage treatments for such children. Sixty‐six children with hematological malignancies (40 ALL, 22 AML, three MDS, and one CML) who relapsed after a first allo‐SCT received either a second allo‐SCT (n = 16) or CTx and/or DLI (n = 50). The median follow‐up for all children was 9.1 yr. The five‐yr OS after relapse was significantly better in patients who underwent a second allo‐SCT (42.9%) than in patients treated with CTx and/or DLI (11.8%) (p < 0.05). However, this advantage diminished with increasing time. The eight‐yr OS for these groups of patients were 21.4% and 11.8%, respectively (p = n.s.). Among the 16 patients who received a second allo‐SCT, two died more than five yr after the second allo‐SCT. A second allo‐SCT can therefore lead to a prolonged OS in patients who relapse after allo‐SCT. However, a second allo‐SCT should be selected carefully. This is because the mortality rate is still high, even when there is an extensive duration of time following the second allo‐SCT.