Prednisone Induction Therapy Research Articles

Long-Term Follow up for SWOG 1318: Combination of Dasatinib, Prednisone, and Blinatumomab for Older Patients with Philadelphia-Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Many older patients (pts) are not good candidates for intensive chemotherapy and are treated with TKIs plus corticosteroids or low-intensity chemotherapy. Although the remission rates with this approach have been high, the median disease-free survival (DFS) has been short. Therefore, novel treatment strategies are needed. This trial evaluated the feasibility of combining the TKI dasatinib with prednisone and blinatumomab in older pts with Ph+ ALL. Here we present updated results (median follow-up, 4.3 years). Methods: This trial was activated through the NCTN in January 2015 and closed to accrual in April 2021. Pt eligibility included: age ≥ 65 years; Ph+ or Ph-like ALL (with dasatinib-sensitive fusions or mutations); newly diagnosed or relapsed/ refractory; no evidence of central nervous system (CNS) disease; and adequate organ function. Treatment: For induction, pts received dasatinib 140 mg/d orally (PO) Days 1-56 along with prednisone 60 mg/m 2/d PO Days 1-24. Pts achieving complete remission (CR) or CR with incomplete count recovery (CRi) (Day 28 or Day 56) continued dasatinib until Day 84, followed by 3 cycles of post-remission therapy (PRT) with blinatumomab/ dasatinib. Pts not achieving CR or CRi by Day 56 received re-induction with blinatumomab. The response rate was assessed on Day 35 of blinatumomab. Pts not achieving CR/ CRi could receive a second cycle of blinatumomab. This was followed by 3 cycles of PRT with blinatumomab/ dasatinib. Maintenance therapy consisted of prednisone 60 mg/m 2/d x 5 days every 28 days for a total of 18 cycles, along with dasatinib 140 mg po qd indefinitely. CNS prophylaxis included intrathecal (IT) methotrexate every 4-6 weeks x 8 doses. IT methotrexate was given at least 2 days apart from blinatumomab. Response was assessed at Days 28, 56, and 84, and additional time points were dependent on response. Minimal residual disease (MRD) was assessed centrally by multi-color flow cytometry on Day 28. Statistics: A total of 24 eligible patients were accrued. The primary objective was the feasibility of the combination therapy. The combination was to be deemed feasible if the dose-limiting toxicity (DLT) was < 33%. DLT included: > Grade 3 non-hematologic toxicities (excluding nausea, vomiting, diarrhea) and Grade 4 neutropenia lasting > 42 days. The primary results were reported in 2022 with a median of 2.7 years of follow-up. Herein, we report long-term outcomes for these patients. Results: The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL; 79% of Ph+ pts had additional cytogenetic abnormalities. During induction, 2 pts experienced treatment-related non-hematologic Grade 4 toxicities. No Grade 4 or higher treatment-related non-hematologic toxicities occurred during post-remission therapy or maintenance. The toxicity of the combination was deemed acceptable. Twenty-two of 24 pts (92%) achieved a CR during dasatinib and prednisone induction therapy. Four did not receive PRT (2 due to adverse events, 1 to receive a transplant, and 1 because of insurance issues). Sixteen pts who achieved CR had MRD data. Six of 16 pts (38%) were MRD undetectable by multi-color flow cytometry on Day 28. Most sites also monitored patients' blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed, 17 (89%) were in a major or complete molecular remission at some time point after treatment, with at least 12 of these patients achieving complete molecular remission. Four patients remain on maintenance. The median follow- up for pts who are alive is 4.3 years (range 2.6-6.5 years). The median overall survival (OS) is 6.5 years (95% CI 3-NA) and the median DFS has not been reached as of June 29, 2023. Kaplan-Meier 3-year estimates of OS and DFS are 75% (95% CI 52%-88%) and 72% (95% CI 49%-87%), respectively (Figure). Of the 8 relapses, 4 patients were CD19+ and 3 had T315I mutations. Conclusions: Median DFS and OS with dasatinib and blinatumomab in this older group of Ph+ ALL patients remain excellent despite only 1 patient proceeding to an allogeneic transplant. Further correlative studies (single cell transcriptomics and DNA methylation sequencing) are being planned to evaluate predictors of relapse and will be presented at the meeting.

A Phase 2 Study of Dasatinib, Prednisone, and Blinatumomab for Older Patients with Philadelphia-Chromosome (Ph) Positive or Ph-like Acute Lymphoblastic Leukemia (ALL) (with Dasatinib Sensitive Fusions/ Mutations)

A Phase 2 Study of Dasatinib, Prednisone, and Blinatumomab for Older Patients with Philadelphia-Chromosome (Ph) Positive or Ph-like Acute Lymphoblastic Leukemia (ALL) (with Dasatinib Sensitive Fusions/ Mutations)

Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial

Biomarkers of intestinal inflammation, such as faecal calprotectin and C-reactive protein, have been recommended for monitoring patients with Crohn's disease, but whether their use in treatment decisions improves outcomes is unknown. We aimed to compare endoscopic and clinical outcomes in patients with moderate to severe Crohn's disease who were managed with a tight control algorithm, using clinical symptoms and biomarkers, versus patients managed with a clinical management algorithm. CALM was an open-label, randomised, controlled phase 3 study, done in 22 countries at 74 hospitals and outpatient centres, which evaluated adult patients (aged 18-75 years) with active endoscopic Crohn's disease (Crohn's Disease Endoscopic Index of Severity [CDEIS] >6; sum of CDEIS subscores of >6 in one or more segments with ulcers), a Crohn's Disease Activity Index (CDAI) of 150-450 depending on dose of prednisone at baseline, and no previous use of immunomodulators or biologics. Patients were randomly assigned at a 1:1 ratio to tight control or clinical management groups, stratified by smoking status (yes or no), weight (<70 kg or ≥70 kg), and disease duration (≤2 years or >2 years) after 8 weeks of prednisone induction therapy, or earlier if they had active disease. In both groups, treatment was escalated in a stepwise manner, from no treatment, to adalimumab induction followed by adalimumab every other week, adalimumab every week, and lastly to both weekly adalimumab and daily azathioprine. This escalation was based on meeting treatment failure criteria, which differed between groups (tight control group before and after random assignment: faecal calprotectin ≥250 μg/g, C-reactive protein ≥5mg/L, CDAI ≥150, or prednisone use in the previous week; clinical management group before random assignment: CDAI decrease of <70 points compared with baseline or CDAI >200; clinical management group after random assignment: CDAI decrease of <100 points compared with baseline or CDAI ≥200, or prednisone use in the previous week). De-escalation was possible for patients receiving weekly adalimumab and azathioprine or weekly adalimumab alone if failure criteria were not met. The primary endpoint was mucosal healing (CDEIS <4) with absence of deep ulcers 48 weeks after randomisation. Primary and safety analyses were done in the intention-to-treat population. This trial has been completed, and is registered with ClinicalTrials.gov, number NCT01235689. Between Feb 11, 2011, and Nov 3, 2016, 244 patients (mean disease duration: clinical management group, 0·9 years [SD 1·7]; tight control group, 1·0 year [2·3]) were randomly assigned to monitoring groups (n=122 per group). 29 (24%) patients in the clinical management group and 32 (26%) patients in the tight control group discontinued the study, mostly because of adverse events. A significantly higher proportion of patients in the tight control group achieved the primary endpoint at week 48 (56 [46%] of 122 patients) than in the clinical management group (37 [30%] of 122 patients), with a Cochran-Mantel-Haenszel test-adjusted risk difference of 16·1% (95% CI 3·9-28·3; p=0·010). 105 (86%) of 122 patients in the tight control group and 100 (82%) of 122 patients in the clinical management group reported treatment-emergent adverse events; no treatment-related deaths occurred. The most common adverse events were nausea (21 [17%] of 122 patients), nasopharyngitis (18 [15%]), and headache (18 [15%]) in the tight control group, and worsening Crohn's disease (35 [29%] of 122 patients), arthralgia (19 [16%]), and nasopharyngitis (18 [15%]) in the clinical management group. CALM is the first study to show that timely escalation with an anti-tumour necrosis factor therapy on the basis of clinical symptoms combined with biomarkers in patients with early Crohn's disease results in better clinical and endoscopic outcomes than symptom-driven decisions alone. Future studies should assess the effects of such a strategy on long-term outcomes such as bowel damage, surgeries, hospital admissions, and disability. AbbVie.

Methotrexate in Combination With Infliximab Is No More Effective Than Infliximab Alone in Patients With Crohn's Disease

Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone. In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15-40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50. Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62-2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated. The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

Reply to V. Procházka et al

In their letter, Prochazka et al raise several issues as to the validity of our conclusion that in patients with relapsed or refractory follicular lymphoma, the presence of tumor cells in blood or bone marrow—as detected by BCL2/IgH major break point region polymerase chain reaction (PCR) at the end of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone induction therapy—is not predictive of progression-free survival (PFS). First, they suggest that we should have analyzed separately patients with clinical complete (CR) and partial remission (PR). We agree that this would have been a relevant subgroup analysis. Unfortunately, the four subgroups (PCRpositive CR, PCR-negative CR, PCR-positive PR, and PCR-negative PR) were too small to allow for a meaningful statistical comparison. However, as mentioned in our report, there was no difference between patients in clinical CR or PR with regard to the proportion of bone marrow (BM) or peripheral blood PCR negativity at the end of induction treatment (50% v 55%). This is clearly indicative of the compartmentalization effect and at least partly explains the lack of prognostic value of PCR status post induction treatment. Second, the authors state that our finding that PFS was not different between patients who converted to PCR negativity and those who did not is in contrast with previous publications by others. We agree and consider this to be an important message of our report. Prochazka et al mention two observations in our article that they consider to be supportive of the predictive value of PCR status. Their first consideration is based on our finding that there was highly significant improved PFS by rituximab maintenance in patients with postinduction PCR-negative BM, whereas the improvement was not significant in patients with PCR-positive BM (Figs 4A, 4B). In fact, there was a clear difference in the PCR-positive BM group, but this did not reach statistical significance because of limited numbers. However, highly significant improvement in PFS by rituximab maintenance was observed in both patients with postinduction PCR-negative blood and those with postinduction PCR-positive blood (Figs 4C, 4D). These observations do not change our conclusion that benefit from rituximab maintenance is independent of postinduction PCR status. Second, they mention our observation that patients who were still PCR positive at the end of maintenance treatment progressed rapidly after stopping maintenance therapy. In our opinion, this observation is not indicative of the predictive value of postinduction PCR status, but it is a strong argument for prolonging maintenance treatment.

Reply to U. Dührsen et al

In their letter, Duhrsen et al disagree with our conclusion that in patients with relapsed or refractory follicular lymphoma, the presence of tumor cells in blood or bone marrow, as detected by BCL2/IgH major break point region (MBR) polymerase chain reaction (PCR) at the end of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone induction therapy, is not predictive of progression-free survival (PFS). Their major argument is that we have compared inappropriate groups because the BCL2/IgH MBR–negative group might have contained patients with tumor cells in blood or bone marrow that have escaped detection because they have t(14;18) with a break point outside the MBR. On the basis of cited literature, they mention that up to 50% of t(14;18) patients have break points outside the MBR, whereas in fact, this figure is 32%. Nevertheless, regardless of the exact frequency of BCL2/ IgHMBRpositivityamongpatientswitht(14;18), intheDiscussionofour article, we already have addressed rather extensively the issue raised by Duhrsen et al. At present, we are in the process of performing an additional minor break point region PCR analysis to further corroborate our conclusions. However, when we restricted our analysis to the group with initial BCL2/IgH MBR–positive results in blood and/or bone marrow, we found no difference in PFS between patients who converted from PCR positive to PCR negative and patients who remained PCR positive. This was true for both bone marrow and peripheral blood. This observation, which was mentioned in our article under Results, strongly supports the conclusion that in patients with relapsed or refractory follicular lymphoma, the BCL2/IgH status in peripheral blood and bone marrow at the end of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone induction therapy is not predictive for PFS.

A Randomized Trial of Methotrexate in Combination With Infliximab for the Treatment of Crohn's Disease

Both methotrexate (MTX) and infliximab (IFX) are effective therapies for active Crohn's disease (CD); however, it is unknown whether the combination is superior to IFX alone. Methods: We conducted a 50-week, double-blind, multicenter, controlled trial that compared combination therapy to IFX alone in patients with active CD. Eligible patients had initiated prednisone induction therapy within 6 weeks. Patients previously treated with IFX and those at risk for MTX or IFX toxicity were excluded. Patients were randomly assigned to receive MTX 25 mg subcutaneously weekly or placebo (PBO). Both groups received IV IFX, 5 mg/kg, at weeks 1, 3, 7, and every 8 weeks thereafter. Hydrocortisone 200 mg IV was administered pre-IFX infusion. Prednisone was tapered, beginning at week 1, to discontinuation by no later than week 14. The primary outcome was time to treatment failure, (failure to enter prednisone-free remission [Crohn's Disease Activity Index (CDAI) <150] at week 14 or failure to maintain remission through week 50]. Results: Sixty-three patients were randomized to each group. The demographics of the 2 groups were similar (baseline CDAI, 207.8 MTX vs 207.6 PBO; mean age 40.4 years MTX vs 38.5 years PBO; prednisone dose, 26.9 mg MTX vs 31.4 mg PBO). By week 50, 30.6% of patients in the MTX group had failed treatment compared with 29.8% of those assigned to PBO (P = .63). Prespecified subgroup analyses failed to show an effect of treatment in patients with short duration of disease or an elevated C-reactive protein. No differences were observed in CDAI or SF-36 scores. Combination therapy was well tolerated (any infection, 58.7% MTX vs 61.9% PBO). Conclusions: The combination of IFX and MTX, although safe, was no more effective than IFX alone in CD patients requiring treatment with prednisone.

Growth in patients with chronic granulomatous disease

examinations. They reported a higher proportion of clinically unsuspected relapses (58 of 84), but defined relapse to include M-2. In 50 of the 84 relapses there was less than 25% blasts in the bone marrow. They found no difference, however, in the success of second remission induction or second remission duration, and concluded that bone marrow investigation for detecting early relapse in acute lymphatic leukemia of childhood may be unnecessary. There are two purposes for the performance of studies in patients participating in clinical trials: (1) the benefit of the patient, and (2) to compare treatment regimens accurately. For clinical care, it would appear that the majority of relapses will be suspected on clinical or peripheral blood criteria. At present there are no data to suggest that earlier detection of relapse will change curability. It is also highly unlikely that the performance of bone marrow aspiration at frequent intervals (or any interval) will improve the statistical comparability of treatment plans, because 72% of relapses occurred within one month of finding a previous M-1 bone marrow and were clinically suspected prior to the aspiration. REFERENCES 1. Watson DK, Robinson AE, Bailey CC: A reappraisal of routine marrow examination therapy of acute lymphoblastic leukemia. Arch Dis Child 56:392, 1981. 2. Haworth C, Hippleston AD, Morris-Jones PH, et al: Routine bone marrow examination in the management of acute lymphoblastic leukaemia of childhood. J Clin Pathol 34:483, 198I. 3. Leikin SL, Brubaker C, Hartmann JR, etal : Criteria for chemotherapy in acute leukemia. Cancer 21:349, 1968. 4. Komp DM, George SL, Falletta J, et al: Cyclophosphamideasparaginase-vincristine-prednisone induction therapy in childhood acute lymphocytic and non-lymphocytic leukemia. Cancer 37:1243, 1976. 5. Berry DH, Pullen J, George S, et al: Comparison of prednisone, vincristine, methotrexate and 6-mercaptopurine vs vincristine and prednisone induction therapy in childhood acute leukemia. Cancer 36:98, 1975. 6. Cox DR: Regression models and life tables. J R Stat Soc 34:187, 1972.