ALBERT

Description: Key Points Response to TKIs can be accurately established by measuring the 3-month transcript level. An additional measurement of the transcript level at 6 months adds very little useful clinical information to the 3-month result.

Description: Abstract 4548 High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma (MM). In the face of almost inevitable disease relapse, there is growing evidence for second ASCT as salvage therapy in certain patient groups. However, few published data exist regarding efficacy and safety of third ASCT in relapsed disease. We retrospectively analysed the results of eight patients treated at a single UK institution who each received three separate autologous stem cell transplants for relapsed MM between May 1997 and April 2012. There were four men and four women. Median age at diagnosis was 48 years (range, 25–64 years). Paraprotein isotype was IgA in two patients and IgG in the remaining six patients. At the time of 1st transplant, seven patients were in partial response (PR) and one in complete response (CR). Conditioning melphalan dose was 200mg/m2 in all but two patients who received 140mg/m2. Three patients entered CR following 1st transplant and four patients showed PR. Median time to disease progression was 31 months (range, 11.8–52.9 months). Prior to 2nd transplant, five patients achieved very good partial response (VGPR) and three PR with induction chemotherapy. Melphalan dose was 200mg/m2 in five patients and 140mg/m2 in the remaining three. Median time to disease progression was 22.3 months (range, 10.1– 39.6 months). At the time of 3rd transplant, two patients had achieved VGPR following induction chemotherapy, one showed PR, two stable disease (SD) and three evidence of disease progression. For the 3rd transplant, melphalan dose was reduced in most cases. Median follow up post 3rd transplant was 8.3 months (range 1.1–29.3 months). One patient died of overwhelming sepsis within one month of transplantation (treatment related mortality). At the time of analysis, five patients had relapsed following 3rd ASCT, with median time to disease progression of 10.4 months (range, 2.7–23.7 months). Three of these patients died at 3.5, 17.6 and 27.1 months post 3rd transplant. The remaining two patients are alive with no evidence of disease relapse (progression free survival (PFS) time of 3.3 and 1.3 months). Overall survival (OS) for the group from diagnosis is 62% at 10 years with a median OS from diagnosis of 149 months (range 68.5 – 189.2 months) (Figure 1). Median OS for the group from 3rd transplant is 17.6 months (range, 1.1–29.3 months) (Figure 2). Median PFS is 10.4 months (range 1.1–23.7 months). These results demonstrate that third ASCT is a possible treatment strategy for patients with relapsed MM and may prolong patient survival. Figure 1: Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 1:. Overall survival from diagnosis for patients receiving 3rd autologous stem cell transplantation for relapsed multiple myeloma Figure 2: Overall survival from time of 3rd autologous stem cell transplant Figure 2:. Overall survival from time of 3rd autologous stem cell transplant Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1680 We studied BCR-ABL1 transcript levels in patients with CML in chronic phase at 3, 6 and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival and other outcomes more reliably than serial marrow cytogenetics. We analyzed 282 patients with CML-CP who received imatinib 400 mg/day as first line therapy followed by dasatinib or nilotinib if they failed imatinib. The median age was 46.3 years (range 13–86.4), 157 (55.7%) patients were male. The Sokal risk distribution was: 31.8% low, 40.1% intermediate and 28.1% high. The median follow-up was 69 months (range 17–131). BCR-ABL1 transcripts were analyzed in the peripheral blood at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL internal control and converted to the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts with the ABL1 control 〉40,000 copies (the median ABL control in the CMR samples was 84,000). We employed a ROC curve to identify the cut-offs in transcript levels at 3, 6 and 12 months that would best predict patient outcome. Patients with transcript levels 〉9.84% (n=68) at 3 months had significantly lower 8-year probabilities of overall survival (OS) (56.9% vs 93.3%, p1.67% (n=87) at 6 months and 〉0.53% (n=93) at 12 months identified poor risk patients. However transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with use of the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (RR= 0.207, p

Description: We analyzed a cohort of 26 patients with chronic myeloid leukemia who had failed imatinib and a second tyrosine kinase inhibitor but were still in first chronic phase and identified prognostic factors for response and outcomes. The achievement of a prior cytogenetic response on imatinib or on second-line therapy were the only independent predictors for the achievement of complete cytogenetic responses on third-line therapy. Younger age and the achievement of a cytogenetic response on second line were the only independent predictors for overall survival (OS). At 3 months, the 9 patients who had achieved a cytogenetic response had better 30-month probabilities of complete cytogenetic responses and OS than the patients who had failed to do so. Factors measurable before starting treatment with third line therapy and cytogenetic responses at 3 months can accurately predict subsequent outcome and thus guide clinical decisions.

Description: Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C〉T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or 〉90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p

Description: We analyzed factors having an impact on response to treatment and survival in 78 consecutive patients with chronic myeloid leukemia (CML) in blastic transformation (BT) referred to the Hammersmith Hospital from January 1995 to December 2000. BT was defined as the presence of at least 30% blasts in blood or marrow or extramedullary blastic deposits. Immunophenotyping of blasts showed 57 myeloid, 19 lymphoid, and 2 biphenotypic. The median age of the patients was 39.1 years (range, 11.3-73.4 years), with 55 males and 23 females. The median survival for all patients after onset of BT was 8.2 months (95% CI, 6.4-10). Patients in lymphoid BT survived longer than those in myeloid BT (median, 11.2 months versus 6.9 months, P = .052). Initial treatment varied; 41 patients received cytotoxic drugs, 8 underwent allogeneic or autologous transplantation procedures, 21 received STI571 (imatinib mesylate, Gleevec), 1 received radiotherapy, and 7 received no therapy. Of the 25 (32%) patients who achieved a “second chronic phase” with first therapy, 6 of 21 (29%) were treated with STI571 and 19 of 50 (38%) were treated with chemotherapy, transplantation, or radiotherapy. Patients who achieved a second chronic phase survived longer than those who did not (median time from onset of BT 12.0 months versus 6.3 months, P = .0004). In multivariate analysis the finding of more than 50% blast cells in the blood and the presence of cytogenetic progression were independent adverse prognostic variables for survival. We conclude that survival after onset of BT has improved in recent years but is still unsatisfactory. We speculate that the combined use of STI571 with cytotoxic drugs may offer additional benefit.

Description: Homoharringtonine is a plant alkaloid that inhibits the synthesis of proteins and results in apoptosis. In vitro homoharringtonine shows synergistic or additive effects with imatinib in CML cell lines and in blast cells derived from patients with advanced disease. We undertook a phase I/II study in patients who had achieved a sub-optimal response to imatinib alone to investigate whether the addition of semi-synthetic homoharringtonine (sHHT) (Myelostat®) would reduce the level of residual disease. Patients with CML who had achieved at least 35% Ph-negativity on imatinib were included. All patients were treated with imatinib at ≥ 400mg/day for at least 2 years; and achieved a plateau in BCR-ABL transcripts defined by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. When sHHT was introduced, imatinib was continued at the previous dosage. sHHT was given subcutaneously at a dose of 1.25 mg/m2 twice daily for one day. Courses were repeated every 28 days. The dose of sHHT was escalated by adding one day of treatment every two courses (eg dose level 2: 1.25mg/m2 BD x 2 days) if the ANC was ≥2.5x109/l and the platelet count ≥200x109/l by day +28 of the previous course, or adding half a day if the ANC was ≥1.5x109/l and the platelet count ≥ 100x109/l. Patients were considered to have reached the maximal tolerable dose (MTD) when the sHHT could not be escalated further. Response was assessed by serial monitoring of peripheral blood levels of BCR-ABL transcripts assayed by RT-PCR at the start of each course. Results 10 patients have been enrolled so far. Patients received a median of six courses of sHHT (range 4–8). The MTD has been achieved in all cases (9 cases in account of myelosuppression and in one case in account of grade III asthenia). The median MDT was 2 days (range 1.5–3 days). The transcript level decline in all patients (table 1). In 7 patients the transcript levels declined by 〉0.5 log and in 5 patients by 〉1 log with respect the baseline value. In 2 patients transcripts became undetectable. The combination was relatively well tolerated with the principal toxicities being grade II asthenia (n=9), grade III astenia (n=1), grade III neutropenia (n=3) and grade III thrombocytopenia (n=1). We believe these preliminary clinical observations justify further study of the use of sHHT in patients on imatinib who fail to obtain low levels of minimal residual disease. Table 1 n Time from onset of imatinib to sHHT therapy (months) Median R-PCR over the year preceding sHHT therapy Minimal R-PCR during the year preceding sHHT therapy R-PCR at screening for sHHT R-PCR at last follow up Transcript levels are expressed as a BCR-ABL/ABL percentage 1 27.2 7.3 5.4 16.9 0.6 2 35.9 2.2 0.04 4.5 1.18 3 34.1 0.012 0.01 0.028

Description: Second generation tyrosine kinase inhibitors (2G-TKI) have displaced allogeneic stem cell transplant as the preferred therapy for patients with CML in chronic phase (CP) who fail imatinib. However a significant proportion of patients still fail to respond to 2G-TKI and may benefit from alternative therapy (including stem cell transplant). We have performed univariate and multivariate analyses in our cohort of 80 patients treated with dasatinib (n=67) or nilotinib (n=13) while still in first CP after imatinib failure in order to identify those patients who will benefit most with these therapies. The median age was 50 years and 46% were male; 72 patients were resistant to imatinib (2 primary haematological resistance, 40 primary cytogenetic, 32 secondary cytogenetic and 25 developed secondary hematologic resistance) and 8 were intolerant. 20 had developed kinase domain mutations while on imatinib therapy. 31 and 29 patients received maximal doses of imatinib 600 and 800 mg per day respectively. The median follow up was 28.3 months (range 6–42). The 3-year cumulative incidence of CCyR was 52.6%. The multivariate analysis identified four pre-2G-TKI independent predictive factors for CCyR, namely low Sokal risk score at diagnosis, the best cytogenetic response obtained on imatinib, G-CSF requirement during imatinib therapy and time from detection of imatinib failure (as defined by European LeukemiaNet criteria) to onset of second 2G-TKI therapy. Using these factors we devised a scoring system that could be used to predict the probability of achieving CCyR on 2G-TKI therapy. The score was calculated by allocating one point when any one of the following four features was present: (1) intermediate or high Sokal risk group, (2) need of G-CSF support during imatinib therapy, (3) institution of 2G-TKI more than 18 months after imatinib failure, and (4) failure to achieve a cytogenetic response on imatinib (≥95% Ph-pos). The 3-year cumulative incidence of CCyR for patients with 0–1 points was 95.6%, with 2 points 50% and with 3–4 points 18.7% (p15% had a survival of 77.4% (p=0.003, Figure 2). We performed a multivariate analysis including all relevant variables defined at the start of 2G-TKI and the 3-month transcript level. The 3-month transcript level was the only independent predictor for survival. Similarly we performed a 6-month landmark analysis where we explored the relationship between cytogenetic response and outcome. Patients who had achieved a McyR (n=38) or a CCyR (n=32) had a significantly better survival than those with lower levels of cytogenetic response (100% vs. 79.2% (p=0.006) and 100% vs 82.6 (p=0.02)) respectively. We also performed a multivariate analysis including the variables defined at the initiation of therapy, the 3-month transcript levels and the cytogenetic response at 6 months. Interestingly the 3-month molecular response was the only independent variable predicting for survival. Similar results were found for progression-free survival (data not shown). We conclude that factors measureable before starting treatment with 2G-TKI may be valuable for predicting response; molecular responses at 3-months and cytogenetic responses at 6 months provide further information about the value of continuing treatment with 2G-TKI. Figure 1 Figure 1. Figure 2 Figure 2.

Description: Abstract 2274 Patients with CML in chronic phase who have failed imatinib therapy are commonly treated with dasatinib or nilotinib, but a significant proportion fail to respond or relapse in which case they are often treated with the other tyrosine kinase inhibitor (TKI) that they had not yet received. We report here the largest series of CML patients in CP treated with a third line TKI after failing both imatinib and another TKI. We enrolled 26 patients. The median age was 64 years and 54% were male. 20 patients had received dasatinib and 6 nilotinib as second line therapy. All patients were still in first CP at the moment of commencing third line therapy, and none was harboring a T315I mutation. Failure to second line therapy was defined as no CHR at 3 months, no major cytogenetic response (MCyR) at 12 months or loss of a hematological or cytogenetic response. Patients who were unable to continue therapy on account of toxicity were also considered as having failed therapy. The median follow up for the surviving patients after starting third line therapy was 21.5 months (range, 6 – 46.5 months). The 2.5 years (30 months) cumulative incidences of MCyR, CCyR and MMR were 48.2%, 32.4%, 21.1% respectively. Multivariate analysis showed that the achievement of at least MiCyR (

Description: Abstract 3414 We have previously shown that adherence to imatinib therapy is the single most important factor determining the degree of molecular response achieved by CML patients (Marin et al, JCO 2010). We now study the relation between adherence to imatinib and the probabilities of losing CCyR and of imatinib failure in patients receiving long term therapy. We measured the adherence to imatinib in 87 consecutive chronic phase CML patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment, all of whom were in complete cytogenetic response (CCyR). Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS, see below) and patients were followed subsequently for a median of 15 months. Data from the patients were censored in March 2010, when our previous work was published, to ensure that the results of this study were not influenced by possible changes in a patient's behavior. MEMS is an electronic device fitted into the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of kinase domain mutations and the following factors assessed at diagnosis: demographic data, hemoglobin, leukocytes, Sokal risk group, BCR-ABL1 transcript type, hOCT1 transcript levels, and the presence of the 1236C〉T polymorphism in ABCB1. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. Adherence was defined as the quantity of imatinib actually taken divided by the amount prescribed expressed at a percentage. The median adherence was 97.6% range 24–100%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). During the follow up 7 (8%) patients lost their CCyR, and 12 (13.8%) discontinued the imatinib therapy (7 because of loss of CCyR, 2 because of failure to achieve MMR and 3 because of side effects). In multivariate analysis the adherence rate was the only independent predictor for loss of cytogenetic response (RR=0.95, p=0.0001) and discontinuation of imatinib therapy (RR= 0.97, p=0.009). When we categorized the adherence rate as (≤90% or 〉90%) we found that at 18 months the 23 patients with an adherence rate ≤90% had a higher probability of losing the CCyR (26.8% vs 1.5%, p=0.0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, p=0.006) than the 64 patients with an adherence rate 〉90% (Figure). In summary we have shown that poor adherence to imatinib is the principal factor contributing to the loss of cytogenetic responses and treatment failure in Patients on long term therapy. Figure Figure. Disclosures: Marin: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.