Same Sibling Marrow following Cord Allogeneic Transplantation as Therapy for Second Relapse Acute Promyelocytic Leukemia in a Pediatric Patient

Abstract

Background

Optimal therapy for relapsed acute promyelocytic leukemia (APL) in pediatric patients is controversial. Allogeneic hematopoietic stem cell transplantation is an alternative, with event-free survival of 70–75%.

Observations

We report a pediatric patient with APL who relapsed 28 months after cord blood transplantation from her sibling and then was treated with bone marrow transplantation from the same donor. Bone marrow was selected for higher cell dose, donor availability and partial donor chimerism. Persistent molecular remission was achieved, currently at 65 months post bone marrow transplantation.

Conclusions

This case suggests the potential role of graft-versus-leukemia activity in APL and illustrates the use of different cell sources from the same donor in allogeneic transplantation for pediatric patients.

Introduction

Acute promyelocytic leukemia (APL) in the US constitutes about 4–8% of acute myeloid leukemias (AML) in the pediatric population, with patients achieving remission rates of 90–96%, 5-year event-free survival of 76–80% and 5-year overall survival of 89–90%.(1–4) Once considered fatal, relapsed APL, that occurs in 15–25% of the cases, has been successfully treated with chemotherapy only,(5, 6) autologous or allogeneic hematopoietic stem cell transplantation (HSCT),(7–9) with the standard of care still controversial. More recently, a few publications have suggested that HSCT may be a more effective consolidation for refractory or relapsed APL. (10, 11)

Second HSCT for relapsed AML have been attempted based on responses achieved by donor lymphocyte infusions (DLI) (12–14) and evidence of strong graft-versus-leukemia (GVL) effect against AML,(15) including cases with bone marrow and peripheral blood stem cell grafts from the same donor.(14, 16)

We report for the first time a pediatric patient with relapsed APL who was successfully treated with a bone marrow transplant from her HLA-matched sibling after relapsing 28 months post cord blood transplant from the same donor.

Case Report

A female Caucasian child was diagnosed with hypergranular APL at 22 months of age with history of one month of fatigue, bruising, gum bleeding and upper respiratory tract infection. Peripheral blood examination showed anemia, thrombocytopenia and normal leukocyte count with myeloid blasts; bone marrow (BM) aspirate documented hypercellularity with blasts presenting translocations t(2;9) and t(15;17). Cerebrospinal fluid (CSF) was negative for blasts. Induction chemotherapy consisted of ATRA, cytarabine and daunorubicin, and complications were disseminated intravascular coagulation and febrile neutropenia, without need of mechanical ventilation or surgical procedures other than central venous catheter placement. Consolidation with doxorubicin and ATRA was then administered, without complications.

After four months of therapy, bone marrow relapse was diagnosed at presentation of fever and bruising, with similar morphology and cytogenetics. Reinduction chemotherapy was instituted with high-dose cytarabine and ATRA, and consolidation chemotherapy was instituted with arsenic trioxide (ATO) 0.15mg/kg × 5days/week for two months to bridge transition during gestation of a male sibling. A fully matched cord blood from the sibling was transplanted (CBT) with the patient in morphological remission (Table 1, Figure 1) using myeloablative conditioning with busulfan 4mg/kg/day × 4days and cyclophosphamide 60mg/kg/day × 4days, and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Both recipient and donor were cytomegalovirus (CMV) negative, with mismatched blood type recipient O+ and donor A+. Cell dose was 7.7×10⁸ total nucleated cells (TNC), 5.88×10⁷ TNC/kg or 3×10⁵ CD34+ cells/kg of recipient weight.

Table 1.

Patient description and graft characteristics: Patient characteristics described at the moment of the UCBT and BMT, along with the grafts used.

	patient at UCBT	umbilical cord blood	patient at BMT	10/10 matched sibling donor
		TNC dose 7.7 × 108		TNC dose 46.7 × 108
		TNC/kg 5.8 × 107 CD34+/kg 3.0 × 105		TNC/kg 2.8 × 108 CD34+/kg 4.1 × 106
Age	2y 6mo		5y 2mo	2y 9mo
CMV status	negative	negative	negative	negative
HSV status	negative	negative	negative	negative
Blood type	O +	A +	A +	A +

UCBT: umbilical cord blood transplant; BMT: bone marrow transplant; TNC: total nucleated cell; CMV: cytomegalovirus; HSV: Herpes simplex virus; y: year(s); mo: month(s).

Figure 1. Therapy, laboratory results and engraftment timeline.

Timeline of the patent’s clinical course between first transplant and 6 years of follow up. Disease detection and donor chimerism as determined by FISH (A), therapeutic interventions (B), skin (C) and gut (D) GVHD grade, and aminotransferase levels (E) are plotted over time. CBT: umbilical cord blood transplant, BMT: bone marrow transplant, ATO: arsenic trioxide, CSA: cyclosporine, Pr: prednisone, FK: tacrolimus, MMF: mycophenolate mofetil.

With neutrophil engraftment on day+22, discharge was possible on day+28. Day+26 BM showed 77% of female cells and 23% of male cells by fluorescence in situ hybridization (FISH). Cyclosporine wean was started on day+109, discontinued on day+151, without active GVHD. Day+165 BM showed 76.9% of male cells and cytogenetic remission. Normal immunological reconstitution was documented with lymphocyte subset counts and proliferation assays, and inactivated immunizations were given.

Twenty-eight months after CBT the patient developed fatigue, fever, weight loss, pallor and bone pain, and BM aspirate showed 31.7% of APL blasts. CSF was again negative. Reinduction therapy was started with intravenous ATO 0.15mg/kg × 5days/week for 4 weeks. Follow-up BM after one month of reinduction documented 16.7% of blasts. A second cycle of ATO was administered, achieving complete BM morphological remission, which had 95% male cells and 1.3% of residual t(15:17) by FISH. During the second cycle the patient developed a right atrial thrombus associated to a central venous catheter, for which she received enoxaparin therapy for six months.

Bone marrow transplant (BMT) from the same matched sibling was performed 32 months post-CBT, when the patient was 61 months of age and still CMV negative, using myeloablative conditioning with total body irradiation (TBI) 12 Gy over 4days, cytarabine 500mg/m2/dose × 4doses and cyclophosphamide 60mg/kg/day × 2days, and low-level cyclosporine prophylaxis (target level of 200–300 ng/mL). At BM harvest, the donor was 34 months of age, with up-to-date immunizations, and CMV negative. TNC dose was 46.7 × 10⁸, equivalent to 2.8 × 10⁸ TNC/kg and 4.1×10⁶ CD34+ cells/kg of recipient weight. To induce GVL, cyclosporine wean was started immediately after engraftment and stopped on day+54, when the patient presented with only mild skin erythema (acute skin GVHD stage 1). On day+82 oral prednisone was started at 1mg/kg/day due to worsening of the acute skin GVHD to stage 2 and elevated liver enzymes (Figure 1), with total bilirubin less than 2 mg/dL (acute liver GVHD stage 1, Glucksberg grade II). On day+109 with new worsening of the GVHD with skin erythema (stage 2) and persistently elevated liver enzymes (score 3 of chronic GVHD), cyclosporine was restarted at immunosuppressive doses, resulting in resolution of skin and liver GVHD and allowing partial prednisone wean. A new attempt to discontinue cyclosporine around day+260 was followed by new recrudescence of skin erythema (chronic skin GVHD score 2) and elevated liver enzymes (chronic liver GVHD score 3), and oral tacrolimus 0.05mg/kg q12h was started in place of cyclosporine (Figure 1). Mycophenolate mofetil (MMF) was added on day+672 for progressive sclerotic-type chronic GVHD limiting range of motion of arms and trunk, characterizing mild-to-moderate chronic GVHD. As the skin erythema and liver function tests became normal, tacrolimus was discontinued on day+887. The patient never had respiratory symptoms or severe infections, and responded well to MMF and physical therapy, with resolution of the scleroderma and normal range of motion of hands and arms, allowing MMF discontinuation by day+1130.

This child currently attends regular school and does not present with developmental delay, with persistent molecular remission at 65 months post-BMT and chronic GVHD score 1 for skin and performance, more than 8 years from diagnosis.

Discussion

Despite very high complete remission rates in patients with APL, relapses still occur in 15–25% of patients. A second complete remission is achievable for most patients,(1, 2, 5) and alternatives for consolidation therapy include chemotherapy only, autologous or allogeneic HSCT.(11)

Favorable post-HSCT outcomes of patients with AML are generally attributed to GVL.(15) Immune responses against AML have been demonstrated by the role of NK cytotoxicity and antigen-specific antibodies and T-cell clones.(17, 18) Considering the importance of the allo-response for GVL, the use of a different stem cell source for the second HSCT is usually preferred, but no evidence has been published to support that assumption.(19, 20)

In this patient, the malignancy was responsive to chemotherapy, cytogenetic remission was achieved more than once with standard therapy, even at a late relapse post CBT, increasing the chances of successful consolidation with HSCT. Her good clinical condition leading to BMT, young age (5 years-old), good organ function and absence of infections allowed myeloablative conditioning regimen with addition of TBI and decreased immunosuppression to allow mild GHVD, fundamental modifications in the second transplantation. The BM chimerism showed good donor cell engraftment from the CBT with residual leukemia and recipient’s cells, ensuring the presence of functional donor-derived antigen presenting cells to favor a better GVL response. Considering that APL is a well-known target for GVL [7–10] with easy and sensitive determination of minimal residual disease, and the fact that this patient had limited disease burden at the second relapse, which happened late post-CBT (28 months), we have decided to perform a BMT from the same donor. The BMT graft would favor engraftment due to higher stem cell dose, allowing the TBI-containing full-myeloablative conditioning regimen. In comparison to the CBT graft, the BMT graft contains higher numbers of mature CD45-RO+ T-cells and promotes faster immune reconstitution of T and B cell compartments, favoring significant immunity against leukemia and infections(21–23). Finally, in the absence of any other siblings, the same donor was healthy and readily available, with the additional possibility of sequential DLI if necessary.

The management post-BMT was focused on allowing mild GVHD to optimize GVL. As standard practice in our institution, single drug cyclosporine was used for GVHD prophylaxis for a matched sibling HSCT. Lower target levels were maintained, and evidence of mild skin erythema during intensive follow-up was surrogate for therapy titration during the first 100 days post-BMT. Despite mild liver GVHD and the development of scleroderma that required increased and prolonged immunosuppression, physical and occupational therapies, the child is currently thriving well with no developmental delay, no scleroderma and no immunosuppressive therapy.

This case demonstrates the role of GVL in APL and the complexity of balancing the development of GVL and GVHD. Our case also illustrates how different stem cell sources from same donor in allogeneic transplantation for pediatric patients can be used to induce a GVL effect.