Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30 % bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (n?=?302). This cohort included 172 patients with >30 % BM blasts; 93 % would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30 % BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48 % in the total cohort and 72 % in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95 % CI 8.53–10.7)?months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1 months), hematologic improvement (HI) (9.7 months), or the combination thereof (18.9 months)), as compared to patients without response and/or without disease stabilization (3.2 months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225 U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30 % BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.     

Bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy for relapsed or refractory multiple myeloma: a multicenter phase 2 study

We previously conducted a phase 1 study of bortezomib, doxorubicin and intermediate-dose dexamethasone (iPAD) therapy and determined the optimal dose of bortezomib to be 1.0 mg/m². We then conducted a multicenter phase 2 study in patients with relapsed or refractory myeloma. Bortezomib 1.0 mg/m² was administered intravenously on days 1, 4, 8 and 11, in combination with intravenous doxorubicin 9 mg/m² on days 1–4, and dexamethasone 20 mg orally on days 1–2, 4–5, 8–9 and 11–12 at a 3-week interval for six cycles. The primary endpoint of this study was the complete remission (CR) rate, and the secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Twenty-seven patients, median age of 63, were enrolled. An overall response rate was 89 % with CR rate of 30 %. The median PFS time was 12.1 months, and the median OS time was not reached. One patient died of pneumonia. Although the incidence of hematological toxicities was high, these were transient and manageable. The most common non-hematological toxicity was sensory neuropathy; grade 3 toxicity was observed in six patients (22 %) and treatment was discontinued in four. We conclude that iPAD therapy is feasible, and shows efficacy by inducing high response rates and long response duration.     

Azacitidine in untreated acute myeloid leukemia: A report on 149 patients

Limited data are available on azacitidine (AZA) treatment and its prognostic factors in acute myeloid leukemia (AML). One hundred and forty‐nine previously untreated AML patients considered ineligible for intensive chemotherapy received AZA in a compassionate patient‐named program. AML diagnosis was de novo, post‐myelodysplastic syndromes (MDS), post‐MPN, and therapy‐related AML in 51, 55, 13, and 30 patients, respectively. Median age was 74 years, median white blood cell count (WBC) was 3.2 × 10⁹/L and 58% of the patients had ≥30% marrow blasts. Cytogenetics was adverse in 60 patients. Patients received AZA for a median of five cycles (range 1–31). Response rate (including complete remission/CR with incomplete recovery/partial remission) was 27.5% after a median of three cycles (initial response), and 33% at any time (best response). Only adverse cytogenetics predicted poorer response. Median overall survival (OS) was 9.4 months. Two‐year OS was 51% in responders and 10% in non‐responders (P<0.0001). Adverse cytogenetics, WBC >15 × 10⁹/L and ECOG‐PS ≥2 predicted poorer OS, while age and marrow blast percentage had no impact. Using MDS IWG 2006 response criteria, among patients with stable disease, those with hematological improvement had no significant survival benefit in a 7 months landmark analysis. Outcomes observed in this high‐risk AML population treated with AZA deserve comparison with those of patients treated intensively in prospective studies. Am. J. Hematol. 89:410–416, 2014. © 2013 Wiley Periodicals, Inc.     

The impact of antimicrobial prophylaxis in morbidity and infections during azacitidine treatment

The clinical consequences of the infectious events in patients receiving azacitidine are poorly documented. Likewise, the role of primary antimicrobial prophylaxis is unknown. In this retrospective, single-center study, we compare the impact of prophylaxis on the incidence of infection and morbidity in all consecutive higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, during the first 4 azacitidine cycles. Seventy-six patients, corresponding to 283 azacitidine cycles, were studied. There were infectious events in 43% of the patients. Development of infections led to more hospital admissions, increased red blood cells and platelet requirements, and a delay in subsequent cycles. Median overall survival was comparable between patients with or without infections. In the multivariate analysis, a neutrophil count below 0.5 × 10⁹/L (OR 12.5 [2.6–50]) and antimicrobial prophylaxis (OR 0.1 [0.02–04]) were independent factors for the development of infection. We conclude that infectious events have a significant impact in the early clinical course of azacitidine-treated patients by increasing hospital admissions and transfusion requirements. Antimicrobial prophylaxis may prevent infections, leading to a decreased need for supportive care in these patients with poor outcome.     

Pilot study on combination of azacitidine and low-dose cytarabine for patients with refractory anemia with excess blast

This study analyzed the outcomes of the combination of azacitidine and low-dose cytarabine in patients newly diagnosed with refractory anemia with excess blast (RAEB). Patients were treated with azacitidine 75 mg/m² for 7 days subcutaneously and cytarabine 20 mg/m² intravenously for 7 days every 28 days. The assigned regimen was repeated for two cycles, then the patients treated with azacytidine alone until progression or allogeneic stem cell transplantation (allo-SCT). Eighteen patients with 5 RAEB-1 and 13 RAEB-2 were enrolled in the current study. After two cycles of the combination therapy, responses were achieved in nine patients (50.0%): four complete response (CR) (22.2%), one partial response (5.6%), two marrow-CR (11.1%), and two hematologic improvement (11.1%). Four patients (22.2%) progressed to acute leukemia during two cycles of the combination therapy. The 1-year overall survival (OS) was 87.5% for the early response group (responses at two cycles) and 0% for the late response group (responses at four cycles, p = 0.042). Plus, the median survival time was 476 days (range, 37–718 days) for the early response group and 221 days (range, 193–249 days) for the late response group. The 1-year OS was 100% for the patients who underwent allo-SCT and 73.4% for those without allo-SCT. In summary, the combination therapy showed promising response rate when compared to treatment with azacitidine alone. However, it was limited in terms of preventing leukemic transformation. Allo-SCT would seem to be the only available treatment that can alter disease progression.     

Therapeutic decision-making in elderly patients with acute myeloid leukemia: conventional intensive chemotherapy versus hypomethylating agent therapy

Standards of care for elderly acute myeloid leukemia (AML) patients unfit for intensive chemotherapy remain undefined. We aimed to compare outcomes of hypomethylating agent (HMA) therapy and intensive chemotherapy (IC) in elderly AML patients and identify the subgroup of patients who are eligible for HMA therapy. We reviewed data on the outcomes of 86 AML patients aged ≥ 65 years, who had undergone treatment between 2010 and 2015. These treatments included IC (25 patients, 29.1%) or therapy using HMA including azacitidine or decitabine (61 patients, 70.9%). The overall response rates were 32 and 19.7%, respectively. Median overall survival (OS) (8 vs. 8 months) and progression-free survival (PFS) (6 vs. 7 months) durations were similar in the two groups. Patients in the HMA group with less than 10% peripheral blood (PB) blasts achieved significantly better OS duration than patients in the IC group (P = 0.043). Patients in the IC group with PB blasts and bone marrow blast of ≥ 10 and ≥ 50%, respectively, achieved better PFS durations than the corresponding patients in the HMA group (P = 0.038). Multivariate analysis identified the hematologic improvement-platelet (HI-P) as an independent prognostic factor for survival in the HMA group (P = 0.005). Our results showed that HMA therapy and IC were associated with similar survival duration in elderly AML patients. This study was noteworthy because it assessed prognostic factors that would help to select elderly patients who could expect actual benefits from undergoing the different therapeutic options available, especially HMA therapy.     

Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML)

The hypomethylating agents (HAs), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with acute myeloid leukemia (AML). Little is known about how AML responds to hypomethylating agents after standard therapy, and the activity of these agents in a real-world setting is not well studied. We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002 to 2011 treated with HAs either as first-line (n?=?34), salvage (n?=?28), or consolidation (n?=?13) therapy. We collected data on age, gender, race, Charlson comorbidity index (CCI), cytogenetics, type of treatment, complete remission (CR), complete remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan–Meier estimates and Cox proportional hazards models. Frontline response rate (CR + CRi) was 26.5 %, and median overall survival (OS) was 3.4 months (95 % CI 1.3–7.4), with 18 % alive at 1 year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6 versus 26.5 %, p?=?0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 months (CI 4.8–10.3). In the consolidation cohort, OS was 13.8 months (CI 8.0–21.6) with one patient in remission more than 30 months from diagnosis. These data suggest that prior cytotoxic therapy decreases marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over 1 year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.     

Predictive value of pretreatment risk group and baseline LDH levels in MDS patients receiving azacitidine treatment

This study analyzed the outcomes of myelodysplastic syndrome patients treated with azacitidine. Between August 2006 and June 2008, a total of 126 patients were treated with azacitidine at a dose of 75 mg/m²/day subcutaneously for 7 days, which was repeated every 28 days. The median age of the patients was 64 (range, 20–82)?years. Forty-three patients (33.4%) were classified as intermediate-2 and high risk according to International Prognostic Scoring System (IPSS), while 61 patients (47.3%) were classified as high and very high risk according to WHO Prognostic Scoring System (WPSS). Sixty patients (47.6%) exhibited a response at the median of 3 (range, 1–5)?cycles. A complete response was observed in 21 patients (16.7%), a partial response in six patients (4.8%), and total hematologic improvement in 61 patients (48.4%). For the IPSS risk group, the median survival for the patients with intermediate-1 was 20.0 months, for intermediate-2 was 14.9 months, and for high risk was 6.3 months (p?=?0.008). For the WPSS risk group, the median survival duration was 21.3 months for the very low and low risk patients, 16.5 months for intermediate risk patients, and 14.9 months for the high and very high risk patients (p?=?0.003). The patients with higher than normal lactate dehydrogenase (LDH) levels at the time of diagnosis showed a poor survival (p?=?0.003). The median survival duration for the patients with high LDH levels was 13.9 months, while that for the patients with normal LDH levels was 20.6 months. The multivariate analyses revealed that high LDH levels [hazard ratio (HR) 4.384, p?<?0.001] and high and very high WPSS risk group (HR 3.855, p?=?0.014) were significantly associated with a worse survival, whereas a response to azacitidine was identified as a good prognostic factor for survival (HR 0.224, p?=?0.019). In conclusion, while the pretreatment risk group and initial LDH levels were both confirmed as important prognostic factors to predict the outcomes for patients treated with azacitidine, more effective therapies are still needed to prevent disease progression.     

Platelet doubling after the first azacitidine cycle is a promising predictor for response in myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) patients in the Dutch azacitidine compassionate named patient programme

The efficacy of azacitidine in the treatment of high‐risk myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML) and acute myeloid leukaemia (AML) (20–30% blasts) has been demonstrated. To investigate the efficacy of azacitidine in daily clinical practice and to identify predictors for response, we analysed a cohort of 90 MDS, CMML and AML patients who have been treated in a Dutch compassionate named patient programme. Patients received azacitidine for a median of five cycles (range 1–19). The overall response rate (complete/partial/haematological improvement) was 57% in low risk MDS, 53% in high risk MDS, 50% in CMML, and 39% in AML patients. Median overall survival (OS) was 13·0 (9·8–16·2) months. Multivariate analysis confirmed circulating blasts [Hazard Ratio (HR) 0·48, 95% confidence interval (CI) 0·24–0·99; P = 0·05] and poor risk cytogenetics (HR 0·45, 95% CI 0·22–0·91; P = 0·03) as independent predictors for OS. Interestingly, this analysis also identified platelet doubling after the first cycle of azacitidine as a simple and independent positive predictor for OS (HR 5·4, 95% CI 0·73–39·9; P = 0·10). In conclusion, routine administration of azacitidine to patients with variable risk groups of MDS, CMML and AML is feasible, and subgroups with distinct efficacy of azacitidine treatment can be identified.     

L-PROBe: A Novel Non-anthracycline Combination Chemotherapy Regimen for Aggressive B Cell Non-Hodgkin Lymphoma in Elderly Patients

The management of aggressive B cell lymphomas in elderly patients is associated with poor tolerability of commonly used chemotherapeutic agents. The safety and tolerability of a novel combination chemotherapy regimen utilizing rituximab, lenalidomide, bendamustine, vincristine and prednisolone was assessed in a series of elderly patients with new onset or relapsed/refractory aggressive B cell lymphoma and inability to receive conventional chemotherapy due to poor performance status and/or significant comorbidities. Ten patients (7 male, 3 female) with a median age of 72 years (range 58–79 years) received therapy with lenalidomide (10 mg/day on days 1–14), rituximab (375 mg/m² on day 1), bendamustine (90 mg/m² on days 1 and 2), vincristine (1.4 mg/m² on day 1) and prednisolone (60 mg/m²/day on days 1–5) with cycles repeated every 28 days. Grade 3/4 hematological toxicities included neutropenia (30 %), anemia (30 %) and thrombocytopenia (10 %). An overall response rate of 40 % was observed with a median survival of 120 days (range 14–286 days). Three of the patients who responded achieved complete remission at the end of six cycles of therapy. This combination chemotherapy appears to be well tolerated and effective in elderly patients with poor performance status. Larger controlled studies are indicated to clearly demonstrate applicability of this novel regimen.     

Efficacy and safety of a 5‐day regimen of azacitidine for patients with high‐risk myelodysplastic syndromes

Although a 7‐day (d) regimen of azacitidine (AZA) is the standard treatment of high‐risk myelodysplastic syndromes (MDS), AZA is difficult to administer during weekends in an outpatient setting. We retrospectively investigated the outcome of a 5‐d regimen of AZA in patients with high‐risk MDS. High‐risk MDS was defined as MDS with intermediate‐2‐ or high‐risk MDS according to the International Prognostic Scoring System. Every months AZA was given at 75 mg/m² per day for 5–7 d in hospital for first cycle and 5 d in outpatient for second cycle and later. Between April 2011 and December 2013, AZA treatment was initiated in 25 patients (men, 22; women, 3; median age, 75 yr; age range, 59–86 yr). The median number of AZA cycles was 10 (range, 1–24). Twenty patients received more than three cycles of AZA and 13 (52%) achieved any hematological improvement (HI). The median time to first response was two cycles (1–3). The most common non‐hematological adverse events were neutropenia in 21 patients and thrombocytopenia in 17 patients. Nineteen patients died. The main cause of death was disease progression (five patients) and infectious complications (11 patients). The median overall survival was 13.2 months. The 5‐d AZA regimen showed a good continuation rate of more than three cycles and an equivalent HI with the 7‐d regimen.     

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes

Bortezomib (bort)–dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m² on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort–dex. The median number of bort–dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort–dex a single line of prior therapy. Bort–dex was an effective salvage treatment for MM patients, particularly for those in first relapse.     

Prolonged treatment with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA) for relapsed acute promyelocytic leukemia previously treated with ATRA and chemotherapy

Prolonged therapy with all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is highly effective in newly diagnosed acute promyelocytic leukemia (APL) but there is limited data on the efficacy of this regimen in the relapse setting. We report here on 22 APL patients treated with prolonged ATRA-ATO therapy at the time of disease relapse. Twenty patients obtained molecular complete remission (CRm) after 2 cycles (90%). Of these, two patients underwent hematopoietic stem cell transplant (HSCT) while the remaining proceeded to receive additional cycles (up to a total of 5) of ATRA-ATO. With a median follow-up of 58 months from the time of relapse (range: 21–128 months), the 4-year OS probability was 0.85 (95% CI 0.61–0.94), DFS was 0.74 (95% CI 0.49–0.88), and EFS 0.68 (95% CI 0.45–0.83). Two patients were resistant to ATRA-ATO salvage and five relapsed at a median of 19 months. Of these, four died due to progressive disease while three relapsed achieved a new CRm after further salvage therapy. This experience confirms the potentially curative effect of prolonged ATRA-ATO therapy in relapsed APL, especially in patients with long first complete remission.     

Aleukemic Leukemia Cutis Presenting as a Sole Sign of Relapsed Paediatric Acute Lymphoblastic Leukemia

Only one-third of elderly (>60 years) AML and MDS-RAEB2 patients may receive intensive chemotherapy treatment alternatives that are limited in this patient group due to the potential of severe toxicity. Previous studies have shown that azacitidine and low dose cytarabine treatments may be a beneficial treatment option for these patients. In this study, we aimed to good results with low toxicity in elderly patients. We retrospectively analyzed the AML and MDS-RAEB2 patients who received azacitidine monotherapy and azacitidine and LDL-ara-c combination therapy for a comparison of their response to therapy, survival rates, and toxicity rates and for determining the factors that could affect their overall survival. A total of 27 patients who were diagnosed with de novo AML and MDS-RAEB2 and who received at least four cycles of chemotherapy were included in the study, and the data were evaluated retrospectively. When monotherapy and combination therapy groups were compared, the pretreatment bone marrow blast count was observed to be greater in the combination therapy group. A statistically significant difference was not detected between the groups regarding the response to therapy ratios (p = 0.161) (42.9 and 57.1 %, respectively). No difference was detected between the groups regarding therapy-related toxicity. Infections were the most common complication. Progression-free survival was 30.3 % for the azacitidine monotherapy group and 66.7 % for the combination (azacitidine + LD-ara-c) group. The factors influencing the overall survival rate were determined based on the response to the first-line therapies, more than a grade 2 infection, fever, and relapse in a multi-variance analysis. The combination therapy may be a well-tolerated treatment option for the elderly, vulnerable AML patients whose blast count is high in response to therapy rates, overall survival rates, and toxicities are not different, although the pre-treatment bone marrow blast count was greater in the combination therapy groups compared with the monotherapy group.     

Long-term survey of survival time,histological transformation,and secondary malignancies in Japanese patients with advanced-stage follicular lymphoma in the rituximab era: Hokkaido Hematology Study Group

Following the introduction of rituximab, the long-term overall survival (OS) rate of advanced-stage follicular lymphoma (FL) cases was expected to improve after the introduction of rituximab: however, there is a lack of large-scale survey data in Asia due to the relatively low incidence of FL. We conducted a retrospective survey to assess the treatment outcomes in patients with newly diagnosed advanced-stage FL in 29 institutions in Hokkaido from January 2001 to December 2010. The total number of patients was 443 (men 47.6 %, women 52.4 %), with a median age of 55 years (range 20–80 years). Of the cases examined, 42.2 % had stage III and 57.8 % had stage IV disease. Furthermore, 62.5, 19.7, 9.2, 5.2, and 3.4 % had performance statuses of 0, 1, 2, 3, and 4, respectively. The 5-year OS was 91.2 %, and no survival plateau was observed. Seventeen patients experienced secondary malignancies (six hematological diseases and 11 solid cancers; 5-year probability, 4.2 %). Eighteen patients experienced transformation (5-year probability, 4.5 %). The overall survival at 5 years after therapy for transformation was 50 %. Before the introduction of rituximab, the 5- to 10-year OS of advanced-stage FL patients in Japan was reported to be about 30–60 %. Although these data are limited, improvement in OS has been observed in Japan during the rituximab era.     

Retrospective Study of Pegaspargase,Gemicitabine, Oxaliplatin and Dexamethasone (Peg-GemOD) as a First-Line Therapy for Advanced-Stage Extranodal NK/T Cell Lymphoma

This study was conducted to retrospectively investigate the efficacy and safety of pegaspargase, gemicitabine, oxaliplatin and dexamethasone (Peg-GemOD) combination chemotherapy as a first-line therapy for advanced-stage extranodal NK/T cell lymphoma (ENKTL). Eighteen patients with newly diagnosed stage III/IV ENKTL were subjected to 3–6 cycles of Peg-GemOD chemotherapy. After 3 cycles of therapy, the overall response rate was 67 % (12/18) with a complete response rate of 28 % (5/18) and a partial response rate of 39 % (7/18). The median overall survival (OS) and progression-free survival (PFS) time were 10 and 8.5 months respectively. For those responders, the median OS and PFS time were significantly better than those of non-responders (median OS, 15 vs. 10 months; P = 0.001 and median PFS, 15 vs. 7 months; P = 0.001). Furthermore, patients with low plasma EBV-DNA levels after induction chemotherapy had a remarkably longer OS and PFS time. The toxicity of Peg-GemOD regimen was acceptable.     

A phase II study of 5‐day intravenous azacitidine in patients with myelodysplastic syndromes

The approved 7‐day schedule of subcutaneous azacitidine for myelodysplastic syndrome is associated with injection site reactions and bruising and may be inconvenient because of the need for weekend doses. Although pharmacokinetic data with IV azacitidine suggests equivalence, there are no efficacy data published. Patients with all myelodysplastic syndromes (MDS) FAB subtypes were enrolled and received 75 mg/m²/d of azacitidine by 20‐min intravenous infusion for 5 days in every 28 days. Global methylation studies were performed at baseline and prior to Cycle 3. Twenty‐five patients were enrolled and 22 were evaluable. Median age was 69.5 years; 9 (41%) patients had lower‐risk disease (IPSS Low or Int‐1) and 13 (59%) had higher‐risk disease (IPSS Int‐2 or High). Twenty‐seven percent of patients responded (5 CRs and 1 PR). The median time to response was 108 days. The median PFS was 339 days (11.3 months), the median OS was 444 days (14.8 months) and the median duration of response (DOR) was 450 days (15.0 months). Global methylation studies suggest a greater degree of demethylation in responders. This regimen appeared to offer a PR + CR rate and median DOR somewhat similar to what has been reported with the 7‐day subcutaneous regimen; however, OS was shorter. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

At least partial hematological response after first cycle of treatment predicts organ response and long-term survival for patients with AL amyloidosis receiving bortezomib-based treatment

AL amyloidosis is a rare plasma cell dyscrasia characterized by multi-organ involvement and poor prognosis. We retrospectively evaluated the organ response (OR) and long-term survival of newly diagnosed AL amyloidosis patients who received first-line bortezomib-containing induction therapy, aiming to identify the clinical indication of a 50% reduction in the difference between involved and uninvolved free light chains (dFLC) after first cycle of treatment. Among the 89 patients included, 78.7% had cardiac involvement and 42.7% were diagnosed with 2004 Mayo stage III disease, while 75.3% of patients achieved a hematological response, including 37.1% with complete response and a median response time of 1 month. Cardiac and renal responses were observed in 44.3 and 53.1% of patients, respectively. Sixty-one (68.5%) patients achieved at least 50% reduction in dFLC after the first cycle of therapy. After a median follow-up duration of 12 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 61.3 and 61.7% respectively. At least 50% reduction in dFLC after the first cycle of therapy was predictive of achieving an OR (p = 0.002), as well as superior PFS (HR = 0.119; 95% CI = 0.045–0.313; p < 0.001) and OS (HR = 0.206; 95% CI = 0.078–0.541; p = 0.001). Additionally, the median PFS and OS were not reached for patients with rapid reduction of dFLC. These results demonstrated that early reduction of dFLC after the first cycle of treatment is predictive of achieving an OR and long-term survival in AL patients receiving bortezomib.     

Platelet count doubling after the first cycle of azacitidine therapy predicts eventual response and survival in patients with myelodysplastic syndromes and oligoblastic acute myeloid leukaemia but does not add to prognostic utility of the revised IPSS

Reliable clinical or molecular predictors of benefit from azacitidine therapy in patients with myelodysplastic syndromes (MDS) are not defined. Doubling of platelet count at start of second cycle of azacitidine therapy compared to baseline was associated with achieving response and survival advantage in a Dutch cohort. To validate this observation, we analysed a larger cohort of North American patients, whose data was collected in a prospective clinical trial with a longer median follow‐up. We found a significant association between platelet count doubling after first cycle of azacitidine therapy and probability of achieving objective response. Among patients with MDS or oligoblastic acute myeloid leukaemia (<30% bone marrow blasts, n = 102), there was a statistically significant reduction in risk of death for patients who achieved platelet count doubling (n = 23, median OS, 21·0 months) compared to those who did not (n = 79, median OS, 16·7 months, adjusted hazard ratio (no/yes)=1·88, 95% confidence interval, 1·03–3·40, P = 0·04). Nonetheless, the addition of this platelet count doubling variable did not improve the survival prediction provided by the revised International Prognostic Scoring System or the French Prognostic Scoring System. Identification of reliable and consistent predictors for clinical benefit for azacitidine therapy remains an unmet medical need and a top research priority.     

Azacitidine in the ‘real‐world’: an evaluation of 1101 higher‐risk myelodysplastic syndrome/low blast count acute myeloid leukaemia patients in Ontario,Canada

The outcome of myelodysplastic syndrome (MDS) patients with uniformly higher‐risk disease treated with azacitidine (AZA) in the ‘real‐world’ remains largely unknown. We evaluated 1101 consecutive higher‐risk MDS patients (International Prognostic Scoring System intermediate‐2/high) and low‐blast count acute myeloid leukaemia (AML; 21–30% blasts) patients treated in Ontario, Canada. By dosing schedule, 24·7% received AZA for seven consecutive days, 12·4% for six consecutive days and 62·9% by 5‐2‐2. Overall, median number of cycles was 6 (range 1–67) and 8 (range 6–14) when restricted to the 692 (63%) patients who received at least 4 cycles. The actuarial median survival was 11·6 months [95% confidence interval (CI) 10·7–12·4) for the entire cohort and 18·0 months (landmark analysis; 95% CI 16·6–19·1 months) for those receiving at least 4 cycles. There was no difference in overall survival (OS) between the 3 dosing schedules (P = 0·87). In our large ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML, we demonstrated a lower than expected OS. Reassuringly, survival did not differ by dosing schedules. The OS was higher in the 2/3 of patients who received at least 4 cycles of treatment, reinforcing the necessity of sustained administration until therapeutic benefits are realised. This represents the largest ‘real‐world’ evaluation of AZA in higher‐risk MDS/low‐blast count AML.