Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (MylotargTM CMA-676)

Authors


Francesco Lo Coco, MD, Department of Cellular Biotechnology & Haematology, Via Benevento 6, 00161 Roma, Italy. E-mail: lococo@bce.med.uniroma1.it

Abstract

We report a patient with acute promyelocytic leukaemia (APL) who received two doses of gemtuzumab ozogamicin for advanced disease. Previous treatments included front-line all-trans retinoic acid and anthracyclines, polychemotherapy consolidation, salvage chemotherapy for the first relapse followed by autologous stem cell transplantation (ASCT), arsenic trioxide for the second relapse followed by a second ASCT and then high-dose methotrexate for more advanced systemic disease with central nervous system involvement. The patient achieved prolonged haematological and molecular remission after monotherapy with gemtuzumab ozogamicin given at the time of the third relapse.

The CD33 antigen is a surface adhesion protein present on normal and leukaemic cells but not on earlier normal progenitors (Dinndorf et al, 1986). Recently, monoclonal antibodies targeting CD33 have been developed for clinical use. These include a radionuclide conjugate HuM195 (Caron et al, 1998) and subsequently an engineered human antibody linked with the anti-tumour antibiotic calicheamicin (Zein et al, 1988) called CMA-676 or gemtuzumab ozogamicin (Sievers et al, 1999). The latter has been approved for clinical use in elderly acute myeloid leukaemia (AML). Activity of anti-CD33 antibodies has also been demonstrated in chronic myelogenous leukaemia blast crisis (De Vatten et al, 2000) as well as in acute promyelocytic leukaemia (APL) patients in haematological remission showing persistent minimal residual disease. In particular, Jurcic et al (2000) reported on the use of HuM195 as monotherapy for patients who persistently remained polymerase chain reaction (PCR)-positive for PML/RARα after induction therapy with retinoic acid (RA) with or without chemotherapy. This treatment resulted in molecular remission in 50% of cases, suggesting that CD33-targeted therapy is effective in this leukaemic subset (Jurcic et al, 2000). As for APL patients with advanced disease (first or subsequent haematological relapse), currently, these are treated with additional chemotherapy, arsenic trioxide and/or haematopoietic stem cell transplantation. The role of anti-CD33 has not been investigated. We report a patient with advanced APL (third relapse) who obtained prolonged haematological and molecular remission after two doses of gemtuzumab ozogamicin.

Case report

A 36-year-old woman was admitted in March 1996 with a history of cutaneous and visceral haemorrhages. The blood cell count showed 2·8 × 109/l leucocytes with 34% of blasts and 9 × 109/l platelets. Bone marrow aspirate disclosed leukaemic infiltration by 80% of dysplastic promyelocytes, which stained positive for CD13 and CD33 and negative for human leucocyte antigen (HLA)-DR. Karyotypic and molecular studies showed the presence in leukaemic cells of t(15;17) (q22;q11–21) and PML/RARα rearrangement (BCR1 isoform type), respectively, confirming the diagnosis of acute promyelocytic leukaemia. Multidrug resistance (MDR) efflux was not overexpressed.

The patient was treated according to the AIDA [all-trans retinoic acid (ATRA) and idarubicin] protocol (Mandelli et al, 1997), obtaining haematological remission in April 1996 and molecular remission in May 1996. After 1 month of maintenance treatment with 6-mercaptopurine and methotrexate, the first molecular relapse was documented in two consecutive marrow samples using reverse transcription( RT)-PCR (Lo Coco et al, 1999). The PCR test was persistently positive after salvage treatment with ATRA followed by consolidation with cytarabine 1 g/m2 and mitoxantrone 6 mg/m2, as well as after further chemotherapy with the AAT (amsacrine, cytarabine, thioguanine) chemotherapy scheme and ATRA. Finally, after further treatment with the IEV protocol (ifosfamide, epirubicin, etoposide), a PCR-negative apheresis was collected in spite of the persistence of PCR positivity in the marrow. In August 1997, the patient underwent autologous peripheral blood stem cell transplantation after conditioning treatment with the BAVC scheme [carmustine (BCNU), amsacrine, etoposide, cytarabine]. In December 1997 the patient suffered her second molecular relapse. She then received therapy with interferon and ATRA and persisted in haematological remission until November 1998, although her marrow tested repeatedly PCR-positive. In November 1998, the first haematological relapse was documented. At this time, multidrug resistance (MDR) studies confirmed the absence of rhodamine efflux and overexpression of the P-gp 170 (D-value 0·21).

Reinduction therapy was started with arsenic trioxide 0·15 mg/kg for two cycles, which resulted in the second haematological remission and the third molecular remission (January 1999). In June 1999, while still in molecular remission, the patient underwent autologous bone marrow transplantation (ABMT) after conditioning with melphalan. The PCR tests, always performed in bone marrow specimens, persisted negative until November 1999, when the third molecular relapse was documented. In January 2000, the patient reported the occurrence of episodic syncope, headache and right hearing loss. A bone marrow aspirate showed the presence of 5% leukaemic promyelocytes. Lumbar puncture showed central nervous system (CNS) infiltration with promyelocytic blasts. Magnetic resonance of the right ear was consistent with leukaemic infiltration of the mastoid bone. No biopsy specimen was taken to confirm disease infiltration in this site. She received intrathecal therapy consisting of four infusions of methotrexate, cytarabine and 6-methylprednisolone, as well as systemic therapy with high doses of intravenous (i.v.) methotrexate (5·4 g total dose). A bone marrow aspirate, performed on d +10, after the administration of methotrexate, showed progressive disease with 40% infiltration with promyelocytic blasts (second haematological relapse). At this time, after informed consent she was given therapy on a compassionate basis with a total of two doses of gemtuzumab ozogamicin, 9 mg/m2 with an interval of 15 d.

One month after the start of gemtuzumab ozogamicin, morphological examination of bone marrow aspirate documented the occurrence of the third haematological remission (March 2000) with thrombocytopenia. No relevant systemic toxicity was recorded during this therapy. In May 2000, the fourth molecular remission was observed. The patient was then treated with craniospinal radiotherapy and received no further systemic treatment. She remained healthy and in the third haematological and fourth molecular remission for 11 months (three consecutive negative PCR tests were obtained during this period) and relapsed again at the molecular level in April 2001. Longitudinal blood cell counts revealed during this period persistent thrombocytopenia with platelet counts ranging from 20 to 60 × 109/l. At present, the patient remains healthy in the third haematological remission and is receiving oral ATRA for the fourth molecular relapse. Figure 1 summarizes the patient's clinical course together with the results of longitudinal molecular follow-up and treatments received in distinct phases of the disease.

Figure 1.

 Schematic diagram showing the patient's clinical course along with the results of longitudinal molecular follow-up and treatments received in distinct phases of the disease. ●, PCR-positive tests for PML/RARα (sensitivity 10−4); ○, negative tests; ▪ haematological relapse. Dx, diagnosis. Acronyms: AIDA, all-trans retinoic acid (ATRA) plus idarubicin; MTZ, mitoxantrone; Ara-C, cytarabine; AuSCT, autologous stem cell transplantation; AAT, amsacrine, cytarabine, thioguanine; IEV, ifosfamide, epirubicin, etoposide; IFN, alpha-2b interferon; As2O3, arsenic trioxide; MTX, metotrexate; CMA-676, gemtuzumab ozogamicin. The asterisk below AuSCT indicates that a PCR-negative apheresis was obtained, despite persistence of PCR-positivity in the marrow after treatment with IEV and used for AuSCT. With the only exception of the circle marked by an asterisk, all circles symbolize bone marrow PCR tests.

Discussion

This report suggests that gemtuzumab ozogamicin has potent therapeutic efficacy in advanced, multirelapsed APL. Before receiving such treatment, our patient was in her third molecular relapse and second haematological relapse, and had disseminated disease including CNS infiltration. All therapeutic approaches known to be effective against APL, had been used before with limited effect in this case, including front-line ATRA and anthracyclines, polychemotherapy consolidation, salvage chemotherapy followed by stem cell transplantation after the first relapse and finally arsenic trioxide for more advanced disease. Although high-dose methotrexate had been used in an attempt to counteract both systemic disease and CNS infiltration, 10 d after the initiation of such treatment the patient showed a progressive increase of blast infiltration in the marrow, indicating that methotrexate was not very effective in controlling leukaemic progression. Significantly, gemtuzumab ozogamicin was administered as monotherapy and, thereafter, the patient received no further treatment, obtaining a sustained haematological and molecular remission. To the best of our knowledge, this case represents the first example of successful monoclonal antibody-targeted therapy by gemtuzumab ozogamicin in advanced APL. In fact, previous experience concerns APL patients treated for minimal residual disease who in addition were given a different compound, i.e. the radionuclide conjugate HuM195 (Jurcic et al, 2000).

The reasons underlying the efficacy of gemtuzumab ozogamicin in APL are not clear, although several issues might be considered to explain these results. First, the APL immunophenotypic profile including committed and relatively mature blasts population (commonly staining negative for CD34) with highly expressed surface CD33 in the totality of the neoplastic clone appear per se, a favourable condition for successful use of this approach. Second, it may be important to observe that the gemtuzumab ozogamicin conjugate contains a drug, calicheamicin, that belongs to a family of intercalating drugs, anthracyclines, known to be highly effective in APL (Bernstein, 2000). Further, APL cells usually do not overexpress MDR at diagnosis (Takeshita and Ohno, 1996), whereas they may convert to MDR-positive at relapse (Michieli et al, 2000). Interestingly, our case, which showed discordant phenotypic/functional MDR expression at the time of the first relapse, responded subsequently to gemtuzumab ozogamicin. Finally, we noted that this approach was not associated with extramedullary toxicity in our patient. This last issue appears particularly relevant in view of the fact that heavily pre-treated individuals with advanced APL might be ineligible for other intensive therapies. Treatment of more patients with advanced APL is currently being carried out to better elucidate the activity of gemtuzumab ozogamicin in this subset.

Acknowledgments

This work was supported by ROMAIL, AIRC and MURST Cofin-70%.

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