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Journal of Pediatric Hematology/Oncology:
Clinical And Laboratory Observations

Extramedullary Relapse in the Left Proximal Femur With Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia After Allogeneic Bone Marrow Transplantation

Jaing, Tang-Her M.D.; Hung, Iou-Jih M.D.; Shih, Lee-Yung M.D.; Yang, Chao-Ping M.D.; Hsueh, Chuen M.D.; Lo, Wan-Chak M.D.

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Divisions of Hematology-Oncology, Department of Pediatrics (T.J., I.H. C.Y); Department of Pathology (C.H.); Department of Radiology (W.L.); Chang Gung Children's Hospital, Taoyuan, Taiwan; and Division of Hematology-Oncology, Department of Medicine, Chang Gung Memorial Hospital (L.S.), Taipei, Taiwan.

Submitted for publication October 23, 2001; accepted February 12, 2002.

Address correspondence and reprint requests to Chao-Ping Yang, M.D., Division of Hematology and Oncology, Department of Pediatrics, Chang Gung Children's Hospital. E-mail: ilvlct@adm.cgmh.org.tw.

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Abstract

We describe a rare presentation of extra-medullary relapse in an adolescent boy with Philadelphia chromosome–positive acute lymphoblastic leukemia who had undergone allogeneic bone marrow transplantation after first remission. In spite of enduring bone marrow remission, the patient experienced a local relapse in the left proximal femur within 3 years of the transplant. The findings from radiography, bone scintigraphy, and chimerism analysis with short tandem repeats as well as bone marrow aspirates taken via the iliac crests were indeterminate. Magnetic resonance imaging at the onset of hip pain was characterized by decreased signal intensity of the left proximal femur, a finding characteristic of bone marrow edema. Confirmation of extra-medullary relapse of the proximal femur was delayed until histologic proof of the computed tomography–guided biopsy samples was obtained. Overt bone marrow relapse was identified 14 months later. Reestablishment of normal donor hematopoiesis was achieved with reinduction chemotherapy.

Approximately 25% of children with acute lymphoblastic leukemia (ALL) experience a relapse (1). The most frequent cause of leukemia treatment failure after allogeneic bone marrow transplantation (BMT) is relapse of the underlying host leukemia (2). Extra-medullary relapse (EMR) of the proximal femur is extremely rare, however, and there may be difficulty in making the correct diagnosis despite characteristic features determined from clinical, radiographic, and radionuclide scintigraphic evaluation. We report a case of ALL with local relapse in the proximal femur, and note the significant magnetic resonance imaging (MRI) features.

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CASE REPORT

The 14-year-old male patient initially presented in August 1997 with a 2-week history of fever, weakness, and pain in the lower legs. Initial laboratory studies at presentation included: white blood cells (WBC) count, 5.8 × 109 /L; blasts, 1%; promyelocytes, 3.5%; segmented neutrophils, 2.5%; basophils, 0.5%; monocytes, 11%; lymphocytes, 57.5%; atypical lymphocytes, 1%; abnormal monocytes, 13.5%; hemoglobin (Hb), 91 g/L; and platelets, 180 × 109/L. Immunophenotypic characterization of the bone marrow leukemic cells revealed expression of CD10, CD19, CD34, and TdT. Cytogenetic studies revealed hyperdiploid ALL (50, XY, +18, +20, + der (22), + mar) with the t(9;22)(q34;q11) karyotype demonstrated in all metaphases. These findings were diagnostic of Philadelphia chromosome–positive (Ph+) ALL.

Acute flaccid paralysis was initially suspected. However, subsequent MRI of the lumbosacral spine revealed no abnormal intensity in the visualized cord, and the physeal region of the femoral head appeared normal from MRI of the pelvis (Fig. 1A). The patient was enrolled in the Taiwan Pediatric Oncology Group for very high-risk leukemia (TPOG 97 VHR), which included induction therapy consisting of vincristine, asparginase, prednisolone, idarubicin, and triple intrathecal chemotherapy, followed by consolidation and interim intensification therapy. Although the preexisting leg pain resolved fully after induction chemotherapy, he reached a delayed remission 2 months after the start of chemotherapy. The patient subsequently received a BMT from his HLA-identical sister in April 1998, and was successfully engrafted by day 28. The posttransplant course was complicated by Grade I acute graft versus host disease (GVHD) involving the skin, concomitant with limited GVHD of the gut, which resolved with cyclosporin-A treatment. Cytogenetic studies after BMT confirmed engraftment of the donor marrow with a normal female karyotype.

Fig. 1
Fig. 1
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In March 2000, the patient started to complain of spontaneous-onset left hip pain. The symptom worsened over the next 2 months, particularly during weight-bearing on the affected side. The physical findings were minimal, however, with tenderness over the left gluteal and inguinal regions noted. There were no other signs of inflammation of the left hip joint.

Laboratory studies in May 2000 revealed the following profile: WBC count, 6.6 × 109 /L; segmented neutrophils, 48%; monocytes, 7%; lymphocytes, 44%; atypical lymphocytes, 1%; Hb, 114 g/L; platelets, 197 × 109/L; and normal levels of serum, creatinine, glucose, calcium, phosphorus, and alkaline phosphatase. Analysis of the bone marrow aspirate taken via the bilateral iliac crests confirmed that the marrow was normal.

The hip radiograph was normal, and bone scintigraphy performed in June 2000 revealed high uptake of 99mTc-methylene diphosphonate at the left hip. The follow-up MRI showed decreased signal intensity of the entire left femoral head in T1-weighted images (Fig. 1B), a typical finding for bone marrow edema, which closely corresponded to the findings of earlier scintigraphic studies. Decreased signal intensity, extending to the intertrochanteric line, was demonstrated on coronal MR images (Fig. 2A). EMR of the left proximal femur was thus suspected. Computed tomography (CT)–guided biopsy of the femoral head was conducted, and leukemic cell infiltration subsequently confirmed (Fig. 2B). No immunophenotyping was performed, because of the small size of the sample.

Fig. 2
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Further treatment included local irradiation of the hip as well as donor lymphocyte infusion (DLI). Serial monitoring, with molecular analysis of short tandem repeat (STR) sequences, revealed identical alleles for the blood of the patient and donor, and minor-BCR/ABL was detected from reverse transcriptase -polymerase chain reaction (RT-PCR) using specific 5` oligonucleotide primers in April 2001 (Fig. 3), with overt bone marrow relapse confirmed 1 month later. Flow cytometry for the cell surface markers was positive for CD10, CD19, CD34, cytoplasmic μ-chain and HLA-DR, suggesting the presence of B lineage commitment.

Fig. 3
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Although cytogenetic data were lacking, reinduction therapy, consisting of intravenous etoposide 100 mg/m2 for a period of 60 minutes followed by intravenous ifosfamide 4.0 g/m2 for a period of 90 minutes was administered for 5 consecutive days. Intravenous mesna 400 mg/m2 for a period of 15 minutes was given before and every 2 hours after ifosfamide for 10 doses. The patient developed spiking fever at the WBC nadir after induction chemotherapy. Subsequent CT revealed multiple hepatosplenic abscesses, presumably caused by fungal infection. He was successfully treated with intravenous administration of amphotericin B and other antifungal agents. One course of the remission induction regimen induced CR in July 2001, with STR analysis confirming the presence of donor cells. Although it is unclear whether the patient was actually cured, no Ph+ metaphases were detected in the bone marrow. Morphologic CR was being maintained at 53 months after the initial diagnosis of Ph+ ALL.

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DISCUSSION

The occurrence of EMR of the proximal femur after allogeneic BMT is rare. For the reported case, the mechanism underlying the selective involvement of the proximal femur remains undefined. It may have served as a sanctuary site for preexisting dormant clones of leukemic cells, or perhaps graft-versus-leukemia effect was weaker in the femoral head compared with the marrow.

For symptomatic hips, serial radiographs and bone scintigraphy should be performed to exclude bone or joint disorders, or where disseminated bone disease is suspected. By contrast, bony metastases suggested from bone scintigraphy must be proven histologically because of the high frequency of false-positive results (3). For patients with normal plain bone radiographs and negative localizing findings, precise selection of the bone biopsy site, based on evidence of scintigraphic abnormality, is technically difficult, making further investigation more complex (4). Detection of changes in marrow signal intensity from MRI concurrent with normal random bone marrow studies has clinical implications for diagnosis of EMR in the proximal femur. For this patient, CT-guided bone biopsies of the femoral head helped establish the final diagnosis.

In this case, the “bone marrow edema pattern” of signal intensity changes on MRI (decreased on T1-weighted and increased on T2-weighted images) is a nonspecific finding that may be encountered with several disease entities, including osteomyelitis, osteonecrosis, transient osteoporosis, and infiltrative neoplasm (5). The difficulties in distinguishing between these entities early in the course of the disease, based on imaging studies alone, may create diagnostic pitfalls. Individuals at risk for neoplastic infiltration of the proximal femur should be candidates for MRI and histologic examination of the femoral head.

Of several methods that have been described to evaluate donor and recipient cells after BMT, identification of specific polymorphic markers is the most promising. We implemented an improved method for this donor, with recipient cell analysis post-BMT using STR detection with fluorescent primers. Clearly, this does not exclude local leukemic recurrence. Roberts et al. (6) have reported that molecular signs of residual leukemia may persist up to 35 months after the cessation of chemotherapy in children with ALL in remission, suggesting that eradication of all leukemia cells may not be a prerequisite for cure.

Philadelphia chromosome positivity represents a significant adverse risk factor for childhood ALL that has not been abrogated by intensive chemotherapy (7). For our case, the karyotype of the malignant clone was hyperdiploid and Ph+ with a breakpoint in the minor breakpoint cluster region of the BCR gene, which indicated those originating in a lymphoid committed progenitor cell would be less chemoresistant (8,9). Leukemic patients who relapse after BMT may not necessarily be refractory to additional reinduction chemotherapy (10). It has been reported that EMR is better treated by systemic chemotherapy than by DLI (11,12). Furthermore, the Seattle group has detailed patient outcome after matched or mismatched allogeneic or syngeneic BMT (13). Remissions were more likely to be achieved for patients who relapsed more than 1 year after BMT compared with those who relapsed relatively early (<100 days after BMT; 65% vs. 7%, respectively).

This report provides evidence that extramedullary presentation of the hip may herald systemic leukemic disease. RT-PCR assay can identify the risk-stratifying translocation before overt hematologic relapse, offering a window of opportunity for preemptive therapy of molecular relapse.

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REFERENCES

1. Sarrinen-Pihkala UM, Gustafsson G, Ringden O, et al. No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission. J Clin Oncol 2001; 19:3406–14.

2. Giralt SA, Champlin RE. Leukemia relapse after allogeneic bone marrow transplantation: a review. Blood 1994; 84:3603–12.

3. Robinson LA. Bone localization. Surg Oncol Clin N Am 1999; 8:565–76.

4. Ron IG, Striecker A, Lerman H, et al. Bone scan and bone biopsy in the detection of skeletal metastases. Oncol Rep 1999; 6:185–8.

5. Froberg PK, Braunstein EM, Buckwalter KA, Osteonecrosis, transient osteoporosis, and transient bone marrow edema: current concepts. Radiol Clin North Am 1996; 34:273–91.

6. Roberts WM, Estrov Z, Ouspenskaia MV, et al. Measurement of residual leukemia during remission in childhood acute lymphoblastic leukemia. N Engl J Med 1997; 336:317–23.

7. Uckun FM, Nachman JB, Sather HN, et al. Poor treatment outcome of Philadelphia chromosome-positive pediatric acute lymphoblastic leukemia despite intensive chemotherapy. Leuk Lymphoma 1999; 33:101–6.

8. Kasprzyk A, Harrison CJ, Secker-Walker LM. Investigation of clonal involvement of myeloid cells in Philadelphia-positive and high hyperdiploid acute lymphoblastic leukemia. Leukemia 1999; 13:2000–6.

9. Liang DC, Shih LY, Yang CP, et al. Multiplex RT-PCR assay for the detection of major fusion transcripts in Taiwanese children with B-lineage acute lymphoblastic leukemia. Med Pediatr Oncol 2002; in press.

10. Snyder DS. Management of relapse after bone marrow transplantation. In: Forman SJ, Blume KG, Thomas ED, eds. Bone marrow transplant Oxford: Blackwell Scientific Publications, 1994:548.

11. Chong G, Byrnes G, Szer J, et al. Extramedullary relapse after allogeneic bone marrow transplantation for hematological malignancy. Bone Marrow Transplant 2000; 26:1011–5.

12. Au WY, Kwong YL, Lie AK, et al. Extra-medullary relapse of leukemia following allogeneic bone marrow transplantation. Hematol Oncol 1999; 17:45–52.

13. Mortimer J, Blinder MA, Schulman S, et al. Relapse of acute leukemia after marrow transplantation: natural history and results of subsequent therapy. J Clin Oncol 1989; 7:50–7.

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Keywords:

Extra-medullary relapse; Acute lymphoblastic leukemia; Magnetic resonance imaging; Bone marrow edema; Reverse transcriptase-polymerase chain reaction; Philadelphia chromosome

© 2003 Lippincott Williams & Wilkins, Inc.

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