Acute central serous chorioretinopathy — an uncommon complication of imatinib mesylate (imatinib) therapy in chronic myelogenous leukaemia

Abstract The prognosis of patients (pts) with chronic myelogenous leukaemia (CML) in blast crisis (BC) remains poor. Despite better result with imatinib mesylate (IM), overall hematologic response rates with IM alone are about 50% including 13% of pts reaching complete hematologic remission (CHR). Response duration is short and median survival is 6 to 7 months. Daunorubicin and cytarabine are 2 major drugs for acute myeloblastic leukaemia and have additive or synergistic in vitro effects with IM, depending of the cell line studied. We therefore planned a dose escalating study in an attempt to assess the safety and the efficacy of IM associated with chemotherapy. We combined fixed doses of IM (600 mg daily started 3 days before chemotherapy) and cytarabine (100 mg/m² per day as a continuous IV infusion D1 to D7) with increasing dosages of daunorubicin (cohort 1: no daunorubicin, cohorts 2, 3 and 4 : 15, 30 and 45 mg/m²/day D1 to D3 respectively). G-CSF was administered from D9 until haematological recovery. No PK analysis were performed in this study. Unacceptable toxicities were defined as aplasia duration ≥ 45 days and/or unusual grade 3/4 toxicities. Lowest Toxic Dose was defined as the occurence of unacceptable toxicities in ≥2/6 pts per cohort. Maximum Tolerated Dose defined the recommended dose i.e dose level at which 1 or less than 1 unacceptable toxicity occured in 6 pts. Pts aged ≥18 years with CML myeloid BC were eligible if not previously exposed to IM (n=6 pts evaluable for toxicity in each cohort). 20 pts (median age 55 range 29–74) have been enrolled, 19 pts being evaluable (1 pt with lymphoid BC was excluded). Median follow up is 9 months. Grade 3 to 4 non haematological toxicities were hepatitis not related to IM (n=1, dose level 1), spleen pain (n=1, dose level 2), hyperbilirubinemia (n=1, dose level 2) and skin rash (n=1, dose level 3). All responding pts had a neutrophil recovery before D45 (median duration of neutropenia 16 days, range 1–44); one pt in cohort 3 experienced a thrombocytopenia (< 100 G/l) for longer than 45 days leading to recommend the 30 mg/sq dosage of daunorubicin for the further pts included in the study. CHR was achieved in 45% (n=9) of cases, including 5 pts in complete cytogenetic response(CCR). Median CHR duration was 5 months (range 0,5–16+ months). 1 pt received allogenic bone marrow transplantation in CR. During this first part of the trial 10 deaths were recorded with a 12 months estimated survival of 52% (95%CI: 26–77): 2 deaths were due to disease progression; 3 occurred early in the course of the disease ( 2 CNS haemorrhage and 1 after splenectomy ); 3 after achieving initial hematologic response ( 1 relapse, 1 septic shock, 1 hepatitis) 2 because of refractory relapse after achieving initial CCR. Imatinib combined with the classical 3 + 7 induction protocol produce a high rate of haematological remissions in myeloid BC pts. Daunorubicin dosage should be tapered to 30 mg/m² per day to avoid excessive toxicity. Additional pts are currently under treatment with this dosage in order to confirm this recommendation. An update of this trial will be presented.

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Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukaemia in Complete Molecular Remission for More Than Two Years.

Blood ◽

10.1182/blood.v106.11.1101.1101 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1101-1101 ◽

Cited By ~ 5

Author(s):

Philippe Rousselot ◽

Françoise Huguet ◽

Jean Michel Cayuela ◽

Odile Maarek ◽

Gérald Marit ◽

...

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukaemia ◽

Residual Disease ◽

Kinase Domain ◽

Myelogenous Leukaemia ◽

Molecular Response ◽

Molecular Remission ◽

Kinase Domain Mutation ◽

Minimum Residual ◽

Ph Chromosome

Abstract Background. Imatinib mesylate (IM, Gleevec®) induces cytogenetic remission (CCR) defined as the disappearance of Philadelphia (Ph) chromosome-positive metaphases in more than 85% of patients with chronic myelogenous leukaemia (CML). However, less than 10% achieve a complete molecular response which may be defined by a minimum residual disease undetectable using polymerase chain reaction (PCR). Virtually all patients in CCR will relapse after IM interruption because of detectable residual disease. In the present study, we have discontinuated IM in patients with undetectable residual disease for more than 2 years. Patients and method. We prospectively collected the results from 8 CML patients (median age 62 years; 41 years to 82 years) treated with IM (400 mg/day). Residual disease was quantified by RTQ-PCR and expressed as the BCR-ABL/BCR ratio. PCR negativity was controlled independently by two molecular laboratories every 4 months and patients were included in the study if they have been PCR negative during at least 2 years under IM therapy. After IM discontinuation, RTQ-PCR was monitored every month. Results. According to Sokal’s classification, 4 patients were considered low risk, 3 intermediate risk and one high risk. All patients except one received interferon (treatment duration 3 to 72 months). One of them received an autologous stem cell transplantation for interferon failure. Median duration of IM therapy was 37 months (34 months to 40 months) and median time from CML diagnosis to IM discontinuation was 104 months (43 months to 152 months). RTQ-PCR negativity was observed during 30 months in median (24 months to 46 months) as required for the inclusion in the study. Four patients presented a molecular relapse with a detectable BCR-ABL transcript rising from 0,001% to 0,01% confirmed at least two times after 2 months (2 patients), 3 months and 4 months of IM discontinuation without detectable BCR-ABL kinase domain mutation. IM was then restarted and lead to a novel molecular remission in 2 patients and to a major molecular response in the 2 others. Four other patients are still negative with a follow up of 8, 9, 12 and 13 months after IM discontinuation. Of note, all these patients received interferon before IM therapy and one patient still have detectable serum antinuclear antibodies. Conclusion. As we have previously reported with interferon, it is possible to stop IM in patients with CML who achieve a molecular remission as we have strictly defined. Early molecular relapses are sensitive to IM re-challenge. Interestingly, we did not observed late relapses at this point. As our patients in persistent molecular remission were previously exposed to interferon, it is possible that IM therapy combined with immune response modifiers could be responsible for a putative cure of the disease.

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