Quality of life is impaired in MDS, but the role of hemoglobin level is unclear. To study the Hb–QoL correlation at diagnosis and 1 year later, patients filled out the EQ-5D questionnaire, assessing ...their mobility, self care, daily activities, pain/discomfort, and anxiety/depression, using scores of 0 (normal), 1 (mild/moderate), or 2 (poor). They also evaluated their health using a visual analogue scale, scoring from 0 (poor) to 100 (excellent). The anemia subgroups were: none/normal (Hb ≥ 12.5 g/dL), mild (10 ≤ Hb < 12.5), moderate (9 ≤ Hb < 10), severe (8 ≤ Hb < 9), or very severe (Hb < 8). LR-MDS patients (n = 127) and inpatient controls (n = 141) participated. The anemic patients had a poor QoL and the MDS patients had a lower QoL with a lower Hb. The controls had no QoL difference among the various anemia subgroups. In addition, the MDS QoL sharply decreased with an Hb of < 9. The MDS patients showed a wide QoL variability, i.e., different QoL scores in the same Hb subgroup, suggesting that other factors affect QoL (e.g., age and comorbidities). After 1 year (n = 61), the QoL was still poor for most MDS patients (including 27 patients with an increased Hb). In summary: (1) a poor QoL in MDS-anemia is non-linear, suggesting other influencing factors on QoL. (2) The sharp QoL drop with Hb < 9 g/dL challenges the transfusion Hb threshold. (3) The QoL in anemic MDS patients might differ from that in non-MDS patients. (4) Raising Hb, while recommended, does not guarantee an improved QoL.
Background Tyrosine kinase inhibitors (TKIs) have significantly improved the life expectancy of individuals with chronic myeloid leukemia (CML), bringing it closer to that of the age-matched general ...population 1. However, clinical trial data from the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program indicates that only 3.8% of CML patients aged 75 or above participate in trials, despite this age group representing about 30% of CML patients 2. This study aims to assess the outcomes of elderly patients aged 75 years or older diagnosed with CML. Methods We conducted a retrospective study, using electronic medical records of consecutive CML patients aged ≥ 75 years, diagnosed between January 2002 and December 2021 at four hematological centers in Israel and Moffitt Cancer Center in Florida, United States (MCC). One-year and five-year overall survival (OS) rates were calculated for the whole cohort and for octogenarians (above 80 years). In addition, to assess if CML diagnosis affected life expectancy, we estimated the expected OS of the Israeli cohort based on life expectancy data from the central bureau of statistics (CBS). Kaplan-Meier curves were used to compare expected and observed median OS with the Log-rank analysis. Local Institutional Review Boards approved the study. Results A total of 123 patients (78 treated in MCC and 45 in Israel) aged ≥ 75 years were diagnosed with CML, with a median age of 79 (range: 75 - 100) years, and 55 patients (45%) were octogenarians. At the time of CML diagnosis 84% of had comorbidities, including cardiovascular risk factors in 90 patients (73%), while 50 patients (41%) had cardiovascular/cerebrovascular diseases. Most patients (93%) were diagnosed in chronic phase CML and high/intermediate EUTOS-LTS risk score (96%) treated with imatinib in the 1 st line treatment (69%). After a median duration of 15 (range:1-153) months on 1 st line treatment, 71 patients (58%) discontinued therapy primarily due to intolerance (n=51) while other causes included resistance (n=15), noncompliance/insurance issues (n=4) or progression to blast crisis (n=1). The 2 nd -line treatment included mainly 2 nd generation TKIs (n=53, 74%) (dasatinib-26, nilotinib -19 and bosutinib-8), while 9 patients received imatinib, 1 patient received nilotinib and imatinib, 5 patients received hydroxyurea and 3 patients were lost to follow-up. 35 patients (28%) reached 3 rd line of treatment (imatinib- 5, dasatinib- 3, bosutinib-12, nilotinib-5, ponatinib-2, asciminib-1, hydroxyurea -1, loss to follow up- 6) chiefly (28 patients) due to intolerance and others (7 patients) due to resistance. The best response assessed by RQ-PCR showed deep molecular response (DMR) in 50%, major molecular response (MMR) in 16%, and complete cytogenetic response (CCyR) in 11% of patients with a median time to maximal response of 19 (range: 0.5-111) months. Nevertheless, treatment-free remission (TFR) was rare (n=1). During a median follow-up of 45 (0.4-198) months, 55 (45%) patients died, with cardiovascular complications (n=9), disease progression (n=8), infection (n=7), and secondary malignancy (n=4) being the main known causes. The median OS for the whole cohort was 72.4 (53.1-91.7) months. Improved OS was documented in patients with an age adjusted charlson comorbidity index< 5 (vs. ≥5, p=0.007), those who achieved DMR (vs. no DMR, p=0.001) and median time to best response of 0-18 months (vs. ≥18, p=0.004). Moreover, OS was improved in patients who received 2 nd generation TKIs in 1 st line treatment, 91.1 (81.5-131) vs. 57.7 (35.4-79.9) months in those who received imatinib, (p=0.023). Older age did not affect OS; 1 and 5-year OS for the whole cohort was 86% and 29%, respectively, and 84.3% and 19.6% for the octogenarians, respectively (p=0.076). In the Israeli cohort, while the median expected OS was 103.7 (24-164.7) months, the median observed OS was only 54.77 (2.1-195) months (p=0.03). Conclusions Elderly CML patients were often diagnosed in chronic phase with high/intermediate risk scores. The majority received imatinib as 1 st line treatment and achieved CCyR and MMR, with half of patients achieving also DMR. Surprisingly, patients treated with imatinib had worse OS compared to those receiving 2nd generation TKIs as 1st line treatment. Furthermore, the Israeli cohort analysis supports reduced life expectancy in the very elderly patients with CML.
Multiple myeloma (MM) cells specifically attract peripheral-blood monocytes, while interaction of MM with bone marrow stromal cells (BMSCs) significantly increased monocyte recruitment (p<0.01). The ...CXCL12 chemokine, produced by both the MM and BMSCs, was found to be a critical regulator of monocyte migration. CXCL12 production was up-regulated under MM-BMSCs co-culture conditions, whereas blockage with anti-CXCR4 antibodies significantly abrogated monocyte recruitment toward a MM-derived conditioned medium (p<0.01). Furthermore, elevated levels of CXCL12 were detected in MM, but not in normal BM samples, whereas malignant MM cells often represented the source of increased CXCL12 in the BM. Blood-derived macrophages effectively supported MM cells proliferation and protected them from chemotherapy-induced apoptosis. Importantly, MM cells affected macrophage polarization, elevating the expression of M2-related scavenger receptor CD206 in macrophages and blocking LPS-induced TNFα secretion (a hallmark of M1 response). Of note, MM-educated macrophages suppressed T-cell proliferation and IFNγ production in response to activation. Finally, increased numbers of CXCR4-expressing CD163+CD206+ macrophages were detected in the BM of MM patients (n=25) in comparison to MGUS (n=11) and normal specimens (n=8). Taken together, these results identify macrophages as important players in MM tumorogenicity, and recognize the CXCR4/CXCL12 axis as a critical regulator of MM-stroma interactions and microenvironment formation.
Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor ...type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis.
MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1–4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting.
195 patients were randomly assigned to either the momelotinib group (130 67%) or danazol group (65 33%) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 25% of 130 vs six 9% of 65; proportion difference 16% 95% CI 6–26, p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 61% of 130 vs 49 75% of 65) and thrombocytopenia (36 28% vs 17 26%). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four 3% of 130 vs six 9% of 65) and pneumonia (three 2% vs six 9%).
Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia.
Sierra Oncology.
Since the discovery of mutant Janus Kinase 2 (JAK2), JAK2V617F, in a major proportion of myeloproliferative neoplasm (MPN) patients, there has been a flurry of activity in the development of JAK2 ...inhibitors. Pan-JAK, predominantly JAK2 and off-target JAK2 inhibitors have been developed in the short span of the past 5 years. These compounds have since been tested to varying success in both in vitro and in vivo settings with several proceeding on to advanced clinical trials. Although it was hoped that these inhibitors would be the silver bullet in the manner than imatinib was to chronic myeloid leukemia, it is becoming apparent that this is not the case for various reasons, chief of which is that a significant reduction of the underlying pathogenic clone is not achieved. In fact, the very notion that the target of JAK2 inhibitors (be it pan-JAK or JAK2 specific) is the mutant JAK2V617F is being challenged with findings from several clinical trials showing a poor correlation between the reduction in JAK2V617F mutant allele burden and clinical response. In view of this, it is not surprising that several groups are now investigating combinations of JAK2 inhibitors and other agents in MPN. Although much knowledge has been added in this short span of time, it is apparent that our understanding of the role of JAK2 inhibitors in the treatment scheme of MPN is only beginning.
The understanding of the basic molecular mechanisms of myeloproliferative neoplasms in the last few years led to updating of their diagnostic criteria in the recent classification of myeloid and ...lymphoid neoplasms by the WHO, which was published in 2017. The major changes relating to the diagnosis of myeloproliferative neoplasms include lowering of the hemoglobin threshold and mandatory bone marrow biopsy as major criteria for the diagnosis of polycythemia vera, as well as adding acquired mutation in either CALR or MPL in addition to the common JAK2V617F mutation as a major criterion for diagnosing essential thrombocythemia or myelofibrosis. We review the newest discoveries on the pathogenesis of myeloproliferative neoplasms, highlighting the relevant new additions to their diagnostic criteria, and relevant therapeutic considerations.
Background:
Despite improvement in survival of newly diagnosed adult ALL, the results of relapsed/refractory disease are still poor, with long term survival of < 10%. Blinatumomab, a bispecific ...monoclonal antibody directed against CD19/CD3 show clinical activity against relapsed/refractory B-ALL as well as in MRD positive patients. Given in a continues 28 days infusion, and its unique side effects profile are potential drawbacks to using blinatumomab in routine care. We report our initial experience with blinatumomab in widespread use, in real-world experience.
Methods:
Data from adult patients with B-ALL/B-LBL treated with blinatumomab in 4 hospitals in Israel was collected. Blinatumomab was given at the standard dose of 9 mcg/day in the first week of the first cycle, and 28 mcg/day thereafter for 28 days cycles, repeated every 6 weeks. Safety data including cytokine release and neurological symptoms was collected. Efficacy outcome included overall and complete response rates, overall survival, and leukemia free survival.
Results:
13 patients are included in this analysis, median age 51.6 years (range 28.9-80.3) 7 male and 6 females. Diagnoses were B-ALL in 10, Ph+ B-ALL in 2, and B-LBL in 1 patient. Median time from diagnosis to blinatumomab treatment was 9.8 months (range 3.4-26.3), and 12/13 patients received blinatumomab for hematological relapse with 1 patient receiving treatment due to severe fungal infection and inability to continue standard chemotherapy or proceeding to SCT. Four patients (30.7%) received blinatumomab after allogeneic SCT. Three patients (23%) had CNS disease at the time of relapse. Blinatumomab was given as first salvage in 7, and after prior salvage in 6 patients. Median number of blinatumomab cycles were 1 (range 1-6), and patients spent on average 18.9 days in-hospital, and 18.8 days as outpatients during the treatment period.
Response was evaluable in 12 patients with 5/12 patients achieving CR and 1 patient maintaining a previously achieved CR. CR was achieved in 2/2 Ph+ ALL patients, 1/4 patients relapsing after SCT and 1/3 patients with CNS disease at relapse. Following blinatumomab, 4 patients received allogeneic SCT, 1 in CR, 2 failing blinatumomab and entering CR after CAR-T therapy within a clinical trial and 1 after combination chemotherapy.
Non-hematological side effects consisted of neurological symptoms in 1 (grade 2), GI symptoms in 1 (grade 3), infection in 1 (grade 3) and cytokine release syndrome in 3 patients (2-grade 2; 1-grade 4).
At a median follow up of 13.3 months (range 1-20.6), 8 (62%) patients are alive, 6 (46%) in CR. Reasons for death included infection in 3 and disease progression in 2 patients. No patient died during blinatumomab administration. Median LFS is 8.7 months and median OS was not reached.
Conclusions:
The current cohort show a slightly higher CR rate and similar OS compared to the TOWER and ALCANTARA trials. Treatment with blinatumomab was safe, with manageable toxicity profiles. This, however, was achieved at a cost of prolonged hospitalizations in the majority of patients.
Ofran:Novartis: Other: Served on a Novartis advisory board.
Background
Newly diagnosed AML patients who cannot tolerate intensive chemotherapy have limited treatment options and poor long-term outcomes. Recently, the U.S FDA approved combination of ...venetoclax, an anti BCL-2 oral agent with hypomethylating agents or LDAC for this patient population based on a series of phase 1b/2 trials showing high CR/CRi rates.
Methods
Venetoclax combinations are available in Israel since January 2019 following approval and reimbursement by the health authority. Medical centers participating in the Israeli Acute Leukemia Group were approached for data collection. We specifically sought to collect safety parameters, and short term outcomes were a secondary outcome in this report.
Results
35 patients from 5 medical centers are included in this analysis. Median age was 80 years (range 62-95), 16 males and 18 females. Diagnoses were de novo AML in 17, secondary AML (to MDS/MPN) in 16, and t-AML in 2 patients. High risk AML seen in 15 patients, followed by intermediate (n=11) and favorable (n=7) risk categories (data NA in 2). Median ECOG PS was 0 (7 with ECOG≥2). Patients were considered not eligible for intensive therapy due to age (n=28), comorbidity (n=10), poor performance status (n=4) or other reasons (n=3).
Median bone marrow blasts at diagnosis was 36% (range 8-90%). The median WBC, ANC, Hb and PLT were 8.0 K/µl (range 0.9-108), 1.7 K/µl (range 0.3-16.4), 8.6 g/dL (range 4.4-13.9) and 77 K/µl (range 9-306), respectively. Median LDH, uric acid and creatinine levels were 1.5 times ULN (range 1-5), 5.3 mg/dl (range 2.3-16), and 0.98 mg/dl (range 0.73-2.25), respectively.
The median time from AML diagnosis to start of treatment was 1 month (range 0-6). Venetoclax was combined with azacitidine in most cases (32/35); 2 patients received LDAC as a combination, and 1 additional patient received one cycle with LDAC followed by azacitidine combination. At the time of data analysis, treatment was given for a median 3 cycles (range 1-10). Azacitidine was most commonly administered in a 5+2 regimen (20/33, 61%), followed by a 7 day regimen (12/33, 37%). One patient received 5 days courses. Venetoclax was given with a short ramp up (median 3 days, range 2-11) and then at a median daily dose was 400 mg (range 200-400). Dose reductions occurred in 14 (40%) patients, mainly for potential drug-drug interactions. Therapy was started during hospitalization in 16 patients, with a median hospitalizations duration of 7 days (range 4-30); 12 patients were treated with hydroxyurea for cytoreduction prior to commencing venetoclax combination.
Treatment was associated with side effects in all patients, including grade 3-4 neutropenia in 26 (84% of evaluable patients) and grade 3-4 thrombocytopenia in 18 patients (58% of evaluable patients). The most common non-hematologic side effects were infections; Febrile neutropenia in 16 (46%) and non-febrile infections in 19 patients (54%)- 2 pneumonia, 1 periorbital cellulitis, 1 herpes zoster, and 1 pulmonary aspergillosis. Gastrointestinal side effects occurred in 9 (26%), 1 grade 3, and tumor lysis syndrome occurred in 5 patients (14%), 1 grade 4. Cardiac adverse events were reported in 2 and 1 patient experienced ischemic stroke.
Responses were assessed after 2 treatment courses and are available in 22 patients, with 15 patients (68%) achieving CR/CRi. Response (CR+CRi) was achieved in 55%, 70% and 50% of patients with high, intermediate and favorable risk groups, respectively. Complete response was seen in 2/2 patients with available data, with prior hypomethylating agents.
At a median follow up of 4.1 months (range 0.2-13), 25 patients are alive (70%), with 13/16 (81%) patients with evaluable data in CR/CRi. The most common causes for death were infectious complications (n=4 including 1 in CR), and disease progression (n=3). The median EFS are 3.8 months, and median OS 13 months.
Conclusions
Treatment with venetoclax combinations in AML patients ineligible for intensive treatment outside of clinical trials was associated with high rates of hematologic and non-hematologic side effects, including tumor lysis syndrome in 14% of patients, which is higher than reported in the original trials. Although the follow up in this cohort is rather short, the CR/CRi rates are similar to those achieved in published clinical trials and encouraging.
Wolach:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaker.
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