Andrew Grigg

Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study

Most patients with chronic myeloid leukemia (CML) treated with imatinib will relapse if treatment is withdrawn. We conducted a prospective clinical trial of imatinib withdrawal in 40 chronic-phase CML patients who had sustained undetectable minimal residual disease (UMRD) by conventional quantitative polymerase chain reaction (PCR) on imatinib for at least 2 years. Patients stopped imatinib and were monitored frequently for molecular relapse. At 24 months, the actuarial estimate of stable treatment-free remission was 47.1%. Most relapses occurred within 4 months of stopping imatinib, and no relapses beyond 27 months were seen. In the 21 patients treated with interferon before imatinib, a shorter duration of interferon treatment before imatinib was significantly associated with relapse risk, as was slower achievement of UMRD after switching to imatinib. Highly sensitive patient-specific BCR-ABL DNA PCR showed persistence of the original CML clone in all patients with stable UMRD, even several years after imatinib withdrawal. No patients with molecular relapse after discontinuation have progressed or developed BCR-ABL mutations (median follow-up, 42 months). All patients who relapsed remained sensitive to imatinib re-treatment. These results confirm the safety and efficacy of a trial of imatinib withdrawal in stable UMRD with frequent, sensitive molecular monitoring and early rescue of molecular relapse.

Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR

Around 40–50% of patients with chronic myeloid leukemia (CML) who achieve a stable complete molecular response (CMR; undetectable breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR–ABL1) mRNA) on imatinib can stop therapy and remain in CMR, at least for several years. This raises the possibility that imatinib therapy may not need to be continued indefinitely in some CML patients. Two possible explanations for this observation are (1) CML has been eradicated or (2) residual leukemic cells fail to proliferate despite the absence of ongoing kinase inhibition. We used a highly sensitive patient-specific nested quantitative PCR to look for evidence of genomic BCR–ABL1 DNA in patients who sustained CMR after stopping imatinib therapy. Seven of eight patients who sustained CMR off therapy had BCR–ABL1 DNA detected at least once after stopping imatinib, but none has relapsed (follow-up 12–41 months). BCR–ABL1 DNA levels increased in all of the 10 patients who lost CMR soon after imatinib cessation, whereas serial testing of patients in sustained CMR showed a stable level of BCR–ABL1 DNA. This more sensitive assay for BCR–ABL1 provides evidence that even patients who maintain a CMR after stopping imatinib may harbor residual leukemia. A search for intrinsic or extrinsic (for example, immunological) causes for this drug-free leukemic suppression is now indicated.

A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease

Chronic graft-versus-host disease (cGVHD) is a major limitation of successful hematopoietic cell transplantation. The safety and efficacy of extracorporeal photopheresis (ECP) for 12 to 24 weeks together with standard therapy was compared with standard therapy alone in patients with cutaneous manifestations of cGVHD that could not be adequately controlled by corticosteroid treatment. The primary efficacy end point was a blinded quantitative comparison of percent change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. Ninety-five patients were randomized to either ECP and standard therapy (n = 48) or standard therapy alone (n = 47). The median percentage improvement in TSS at week 12 was 14.5% for the ECP arm and 8.5% for the control arm (P = .48). The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm (P = .04). The nonblinded investigator assessment of skin complete or partial responses revealed a significant improvement in favor of ECP (P < .001). ECP was generally well tolerated. These results suggest that ECP may have a steroid-sparing effect in the treatment of cGVHD. Clinical trials registered at www.ClinicalTrials.gov as NCT00054613.

Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy

We conducted a trial in 103 patients with newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) using imatinib 600 mg/day, with dose escalation to 800 mg/day for suboptimal response. The estimated cumulative incidences of complete cytogenetic response (CCR) by 12 and 24 months were 88% and 90%, and major molecular responses (MMRs) were 47% and 73%. In patients who maintained a daily average of 600 mg of imatinib for the first 6 months (n = 60), MMR rates by 12 and 24 months were 55% and 77% compared with 32% and 53% in patients averaging less than 600 mg (P = .037 and .016, respectively). Dose escalation was indicated for 17 patients before 12 months for failure to achieve, or maintain, major cytogenetic response at 6 months or CCR at 9 months but was only possible in 8 patients (47%). Dose escalation was indicated for 73 patients after 12 months because their BCR-ABL level remained more than 0.01% (international scale) and was possible in 45 of 73 (62%). Superior responses achieved in patients able to tolerate imatinib at 600 mg suggests that early dose intensity may be critical to optimize response in CP-CML. The trial was registered at www.ANZCTR.org.au as #ACTRN12607000614493.

All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4)

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase

We analyzed molecular responses in 55 newly diagnosed chronic-phase chronic myeloid leukemia (CML) patients enrolled in a phase 3 study (the IRIS trial) comparing imatinib to interferon-alfa plus cytarabine (IFN+AraC). BCR-ABL/BCR% levels were measured by real-time quantitative RT-PCR and were significantly lower for the imatinib-treated patients at all time points up to 18 months, P<0.0001. The median levels for imatinib-treated patients continued to decrease and had not reached a plateau by 24 months. A total of 24 IFN+AraC-treated patients crossed over to imatinib. Once imatinib commenced, the median BCR-ABL/BCR% levels in these patients were not significantly different to those on first-line imatinib for the equivalent number of months. The incidence of progression in imatinib-treated patients, defined by hematologic, cytogenetic or quantitative PCR criteria, was significantly higher in the patients who failed to achieve a 1 log reduction by 3 months or a 2 log reduction by 6 months, P=0.002. A total of 49 patients were screened for BCR-ABL kinase domain mutations. Mutations were detected in two imatinib-treated patients who crossed over from IFN+AraC and both lost their imatinib response. In conclusion, first-line imatinib-treated patients had profound reductions in BCR-ABL/BCR%, which significantly exceeded those of IFN+AraC-treated patients and early measurements were predictive of subsequent response.

Mechanisms of Bone Loss Following Allogeneic and Autologous Hemopoietic Stem Cell Transplantation

A significant proportion of patients will be long‐term survivors of bone marrow transplantation (BMT) and little is known about their risk of late bony complications. We therefore evaluated bone mineral density (BMD) prior to BMT, post‐transplantation changes in BMD, and mechanisms of bone loss in long‐term survivors. We performed two analyses. The first was a cross‐sectional study of 83 consecutive BMT patients (38 F, 45 M), examining the relationship between BMD and bone turnover, measured immediately prior to transplantation, and a number of disease and patient variables. The second was a prospective study of 39 patients (19F, 20 M) followed for a median of 30 months (range 5–64 months) following either allogeneic (allo, n = 29) or autologous (auto, n = 10) BMT to determine if bone loss was related to treatment of graft versus host disease (GVHD) with glucocorticoids and cyclosporine A, high bone turnover rates, or hypogonadism. Auto BMT recipients acted as a control group for effects of GVHD therapy on BMD. Prior to BMT, spinal and femoral neck (FN) BMDs were 8.6% and 14% lower in female auto BMT recipients than in female allo BMT recipients, respectively (p = 0.12 and p = 0.003). Urinary bone resorption markers were higher than in normal gender‐ and age‐matched control subjects. Patients treated previously with glucocorticoids also had 8% lower FN BMD. Glucocorticoid‐pretreated women with amenorrhoea had lower lumbar spine (LS) and FN BMDs than eumenorrheic women and women receiving HRT. Post‐allo BMT, patients lost 11.7% of FN BMD compared with a nonsignificant decrease of 1.1% post‐auto BMT (p < 0.001). Spinal BMD and total body bone mineral content (TBBMC) decreased by 3.9% and 3.5%, respectively, post‐allo, compared with an increase (1.5%, p = 0.03) or nonsignificant decrease (−3.7%, p = NS), respectively, post‐auto BMT. Post‐allo BMT bone loss correlated best with the cumulative prednisolone dose at the LS and FN, and with average daily prednisolone dose for TBBMC. At the spine, the rate of bone loss was 4%/10 g of prednisolone, while the rate of bone loss at the FN was greater (9%/10 g of prednisolone). Bone loss was also negatively related to the duration of cyclosporine therapy for GVHD and baseline deoxypyridinoline concentrations. Avascular necrosis of the femoral head occurred in four, and vertebral and rib fractures occurred in one of the allo BMT patients, but in no auto BMT patients. In conclusion, BMT recipients are at risk of osteoporosis secondary to bone loss associated with their underlying illness and/or chemotherapy, particularly in female autograft recipients, and in allograft recipients secondary to GVHD and its treatment.

BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria.

Purpose: In the first years of imatinib treatment, BCR-ABL remained detectable in all but a small minority of patients with chronic myeloid leukemia. We determined whether BCR-ABL continues to decline with longer imatinib exposure and the incidence and consequence of undetectable BCR-ABL. Experimental Design: BCR-ABL levels were measured in a subset of 53 imatinib-treated IRIS trial patients for up to 7 years (29 first-line, 24 second-line). Levels were deemed undetectable using strict PCR sensitivity criteria. Results: By 18 months, the majority achieved a 3-log reduction [major molecular response (MMR)]. BCR-ABL continued to decline but at a slower rate (median time to 4-log reduction and undetectable BCR-ABL of 45 and 66 months for first-line). The probability of undetectable BCR-ABL increased considerably from 36 to 81 months of first-line imatinib {7% [95% confidence interval (95% CI), 0-17%] versus 52% (95% CI, 32-72%)}. Undetectable BCR-ABL was achieved in 18 of 53 patients and none of these 18 lost MMR after a median follow-up of 33 months. Conversely, MMR was lost in 6 of 22 (27%) patients with sustained detectable BCR-ABL and was associated with BCR-ABL mutations in 3 of 6. Loss of MMR was recently defined as suboptimal imatinib response. There was no difference in the probability of achieving molecular responses between first- and second-line patients but first-line had a significantly higher probability of maintaining MMR [P = 0.03; 96% (95% CI, 88-100%) versus 71% (95% CI, 48-93%)]. Conclusions: With prolonged therapy, BCR-ABL continued to decline in most patients and undetectable BCR-ABL was no longer a rare event. Loss of MMR was only observed in patients with sustained detectable BCR-ABL.

Delayed‐onset neutropenia associated with rituximab therapy

Summary. The characteristics of severe neutropenia with a delayed onset following administration of rituximab have been evaluated in 53 consecutively treated patients. All but one patient received rituximab for the treatment of non‐Hodgkins lymphoma. Eight episodes of grade 4 neutropenia were detected between 1 and 5 months after rituximab, when administered alone on five occasions, and on three occasions in combination with chemotherapy, where neutrophil counts had recovered prior to the development of neutropenia. In three episodes, the patients presented with sepsis. Development of neutropenia did not correlate with either the presence of detectable disease or the administration of further treatment. Neutropenia was associated with selective depletion of neutrophil precursors in all but one episode, where it was associated with generalized bone marrow hypoplasia. All episodes developed after a period of either normal or mildly depressed neutrophil counts following treatment with rituximab, and persisted for between several days and several months, before undergoing spontaneous recovery in four instances, and after administration of filgrastim in the remainder. Episodes of neutropenia were associated with disordered immune status manifested by lymphopenia and hypogammaglobulinaemia, raising the possibility that either disturbance of the balance of lymphocyte subsets or an immune dyscrasia induced by rituximab resulted in the development of this type of neutropenia.

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3–80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6–19%) at 12 months, 32% (22–42%) at 24 months and 38% (27–50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20–46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. we conclude that 3–6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD. Bone Marrow Transplantation (2000) 25, 657–664.