Case report Relapsed chronic myeloid leukemia in ... - Nature

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We report the case of a 44-year-old male who relapsed in accelerated phase chronic myeloid leukemia 10 years after a successful bone marrow transplantation ...
Bone Marrow Transplantation, (1998) 22, 595–597  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt

Case report Relapsed chronic myeloid leukemia in accelerated phase 10 years after allogeneic bone marrow transplantation: full chimera reconversion with donor peripheral blood stem cells infusion A Guimara˜es1, A Machado1, S Carvalho1, H Alaiz1, L Vieira2 and M Abecasis1 1

BMT Unit, Instituto Portugueˆs de Oncologia, Lisbon; and 2Instituto Ricardo Jorge, Lisbon, Portugal

Summary: We report the case of a 44-year-old male who relapsed in accelerated phase chronic myeloid leukemia 10 years after a successful bone marrow transplantation from his HLA-identical brother, and 3 years after 12 months treatment with interferon-alpha (IFN-alpha) for chronic active hepatitis C (CAH). The patient was infused with G-CSF-primed peripheral blood cells (PBSC) from the original bone marrow donor and a full donor reconstitution, with no detectable molecular disease, was obtained within 4 months without clinical aplasia or GVHD, nor help from other forms of chemotherapy or use of biological response modifiers. We speculate that IFN-alpha for CAH delayed the onset of a clinical recurrence of chronic myeloid leukemia and that in advanced disease PBSCs can provide an advantageous alternative to donor lymphocyte infusion (DLI). Keywords: bone marrow transplant; relapse; PBSC; donor lymphocyte infusion; chronic myeloid leukemia; interferon-alpha

Allogeneic BMT is currently the only curative treatment for CML. Other forms of therapy can achieve measurable responses but these are usually not long lasting and blast crisis inevitably ensues. Patients relapsing after allogeneic BMT do so within the first 2 years1 and usually revert to whatever stage in their disease they had been transplanted at, most commonly chronic phase.2,3 Until the early 1990s, relapsed patients with CML were treated with hydroxyurea (Hu) or IFN-alpha with variable responses, but their overall prognosis was far from good and survival was severely curtailed. Fortunately this has changed over the last few years and nowadays patients with molecular, cytogenetic or even hematological relapse are successfully treated with transfusion of lymphocytes from the original donors (DLI), in a technique pioneered by Slavin et al4 and progressively applied by others especially in

Correspondence: Dr A Guimara˜es, UTM, Instituto Portugueˆs de Oncologia, Rua Prof Lima Basto 1093, Lisboa Codex, Portugal Received 2 February 1998; accepted 11 May 1998

CML5 in what has become the most compelling clinical evidence of the graft-versus-leukemia effect. Patients relapsing with advanced disease are usually diagnosed earlier in the post-BMT period and usually, except for very few cases reported in the literature,2,6,7 result from BMT that was performed in stages other than first CP. These patients may require some form of induction with chemotherapy or IFN-alpha, but lasting reconversion to donor hemopoiesis is not often reported. Case report A 34-year-old male was diagnosed with chronic phase CML in 1984 and managed with Hu for 2 years. In 1986, aged 36 and still in first chronic phase, he underwent an allogeneic BMT from his HLA-matched, older brother. He was conditioned with Cy (120 mg/kg) and 10 Gy unfractionated TBI with 8 Gy over the lungs, and received a T cell-replete bone marrow graft containing 2 × 108 nucleated cells/kg. At day +33 he developed grade II acute GVHD which was successfully controlled with methylprednisolone. He had a quick and steady engraftment and no problems were seen until abnormalities in the liver function tests (LFT) were detected within the first 12 months of the course of transplant. Liver biopsy showed a pattern that was compatible with non-A, non-B chronic active hepatitis (CAH) that later proved to be HCV in nature. For this condition, 6 years after BMT, he was treated with IFN-alpha 3 million units i.m. 3 × weekly but, due to lack of improvement in his LFT, this was discontinued after 12 months. He remained well until October 1996 when, 1 month after a routine blood count that showed a normal Hb, WBC with differential as well as platelet count, he developed a temperature and an enlarged spleen, and had an accelerated phase CML relapse diagnosed with a WBC of 50 × 109/l. His blood film showed increased basophils and eosinophils along with increased immature myeloid cells and the bone marrow aspirate showed features compatible with accelerated phase CML with 12% blasts. Cytogenetic studies showed the presence of a complex translocation in all dividing cells t(9;15;22). Fluorescence in situ hybridization (FISH) for the BCR-ABL fusion gene on the bone marrow smear was positive for over 90% of the 250 cells that were

PBSC infusion for late CML relapse after BMT A Guimara˜es et al

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studied. Molecular studies in the relapse marrow proved the patient to be a mixed chimera with less than 10% donor DNA and revealed a b3a2 junction BCR-ABL mRNA. Clinically the patient developed a persistent unremitting fever accompanied by progressive red cell and platelet cytopenia, ascites and increasing spleen size. His peripheral WBC did not respond to Hu. After appropriate consent from the donor and approval from the Ethical Board, as part of a protocol for cell therapy for relapsed leukemia, the patient was transfused with G-CSF-primed peripheral blood cells (PBSC) from the original bone marrow donor at a cell dose of 7.39 × 108 nucleated cells/kg with 5.76 × 106 CD34+/kg and 18.47 × 107 CD3+/kg. These were obtained from a high volume apheresis after a 4-day mobilization with 10 ␮g/kg G-CSF, as normally performed for PBSC collection at our center.8 No acute GVHD was recorded and the patient continued showing unremitting fever of 39– 40°C needing regular antipyretics, which did not change for the following 4 weeks. At 4 weeks, the patient’s temperature started to decline and he finally became apyrexic at week 9 which was simultaneous with the lowest recorded WBC and platelet counts of 2.8 × 109/l, and 37 × 109/l, respectively. After day +65, the peripheral blood picture gradually improved until a normal count was reached at day +78. The lowest recorded neutrophil count (0.5 × 109/l ) was recorded at day +65 and lasted until day +67. Molecular detection of the BCR-ABL fusion mRNA using a two-step procedure that gives a sensitivity of 1/105 cells was still positive at day +30 but became negative at day +79 and has remained negative at 12 months follow-up. The patient’s clinical condition improved dramatically and he has now increased 6 kg in weight, the ascites have disappeared and the spleen is no longer clinically assessable. His liver function tests remain unchanged if compared with his pre-PBSC infusion levels. He is now leading a normal life and has gone back to work 6 months after the procedure. Discussion DLI is now an established approach for leukemia relapse after BMT, particularly in CML where the response rate is extremely high. The response rate is surprisingly constant in the two most recent series that do not overlap patients. Collins et al9 reported a 75% response rate in evaluable patients (n = 37) with cytogenetic or chronic phase relapsed CML and in another series Kolb et al10 describe a 74% response on 53 evaluable patients with hematologic relapse and 76% for 19 patients with cytogenetic relapse. In spite of these excellent results, the response rate is still more prompt, more durable and generates fewer side-effects the earlier the procedure takes place in the course of leukemic relapse.5,6,11 The most serious side-effects reported in the two largest published series have been GVHD and pancytopenia. Pancytopenia was observed in 20% of patients in one series including 56 patients with CML, which together with GVHD or on its own resulted in death in seven patients.10 In another series of 112 patients with CML,9 myelosuppression was seen in 31% of patients (which included transient

neutropenia and thrombocytopenia, as seen in our patient), was the sole cause of death in six patients and together with GVHD contributed to death in another two patients. GVHD ranged between 61% and 75% in both series and was the sole cause of death in five and eight patients, respectively. Relapse rate after CML seems to have an early peak with more than 50% of patients relapsing within the first 2 years. The longest described disease-free interval between BMT and CML relapse has been 6.5 years in the EBMT series. Late relapses, after 5 years, also occur more often in a male-to-male transplant than any other combination.1 Although the pre-emptive use of PBSC with lymphocytes did not prevent myelosuppression in one study,12 other groups have used G-CSF-mobilized donor cells and found that it might reduce the pancytopenia-related complications of DLI.13 In our own series we have used this method in five patients with CML and no severe myelosuppression was detected, no patient developed neutropenia below 0.5 × 109/l or had to be admitted for antibiotics after the procedure, neither was there any need for transfusion support (Bone Marrow Transplant, in press). In the two published series by Kolb et al10 from the EBMT group and by Collins et al,9 reporting the results from 100 American centers, only six cases out of 28 with CML that relapsed in AP have been successfully treated with DLI. In the European series, only two out of 14 similar patients had some form of response: one died in aplasia during the first 30 days and the other obtained a CR with the introduction of other forms of immunotherapy after DLI . In the American series, four of 14 patients had a full chimera reconversion but it is not known whether other forms of immunotherapy have been simultaneously used or whether the full chimera status has been investigated at molecular or simply at chromosomal level. In a smaller series Mackinnon et al14 have used DLI to treat relapsed CML patients. Among these patients there were four patients in AP relapse of which two did not respond, one died in aplasia within the first month and only one patient responded. IFN-alpha was frequently used to treat relapsed CML after BMT before the advent of DLI. In patients with cytogenetic relapse the use of IFN-alpha significantly delayed progression to hematological relapse,3 in some cases lasting cytogenetic remissions were achieved and in one case a molecular remission up to 17 months has been documented.15 The unusual situation about this patient is the extremely prolonged interval (10 years) between the first procedure and the relapse and the fact that the patient had been transplanted in CP and relapsed suddenly in AP 1 month after a full blood count with a normal differential had shown a complete normal blood picture. There is a fragile balance between GVL and BCR-ABL disease in the complex immunologic setting of the post-BMT period. The use of IFN-alpha for 12 months for HCV-dependent CAH, might have tipped the balance at the right time prolonging a phase of minimal residual disease in an environment that would have otherwise progressively favored BCR/ABL hemopoiesis and led to the inevitable progression to hematologic relapse. It is conceivable that in this setting, the use of IFNalpha might have delayed the onset of a full CML relapse, which was most certainly present at the time when IFN-

PBSC infusion for late CML relapse after BMT A Guimara˜es et al

alpha was started, at molecular or even at cytogenetic level. This would probably explain the late disease relapse – 3.5 years later than the latest described relapse. This patient was not managed with any other form of therapy other than PBSC infusion and in spite of a florid AP, a full chimera was obtained without any GVHD or clinically relevant aplasia. The total absence of GVHD might be related to the pre-DLI state of mixed chimerism of the patient, as well as with the late relapse and the subsequent temporal distance from the cytokine storm. Another interesting feature is the prompt molecular response at week 12 which is 25 weeks earlier than the only evaluable responder of the Mackinnon series. We conclude that in settings such as this, PBSC can provide an advantageous alternative to DLI with an added indication in advanced disease.

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Acknowledgements 10 We thank Dr A Botelho de Sousa for the timely referral of this patient to our center.

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References

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