Page 1203 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 66 Acute Lymphoblastic Leukemia in Adults 1051

DM4, which demonstrated efficacy in vitro and in vivo in ALL, as cells, and 90% of these patients were MRD negative. Six patients
well as safety in a lymphoma phase I study. The results of a phase II remain in remission after 1 year. Three out of five patients that
trial of CoR in relapsed/refractory adult B-ALL are awaited. relapsed received repeat CAR-T cell infusion and two of these patients
Combotox is constructed from two antibody–drug conjugates, regained CR. Cell levels expanded and peaked at 1–2 weeks and were
consisting of a monoclonal anti-CD19 antibody and an anti-CD22 low or undetectable by 2–3 months.
antibody conjugated to the toxin deglycosylated ricin A chain in In both studies all responding patients experienced cytokine-
equal parts. In relapsed/refractory pediatric pre-B-ALL only 18% of release syndrome (CRS). CRS timing correlated with peak T-cell
patients achieved a CR; however, 35% had a greater than 95% expansion and severity correlated with disease burden prior to treat-
decrease in their peripheral blood blast counts. In adults Combotox ment and appears to be mediated by release of interleukin-6 (IL-6)
reduced the leukemic disease burden in all patients, but no CRs were and other inflammatory cytokines. MSKCC defined severe CRS
observed. In an ALL xenograft model Combotox acted synergistically (sCRS) requiring treatment for fevers for greater than or equal to 3
with cytarabine, leading to a phase I trial of Combotox and cytarabine consecutive days and at least one clinical sign of toxicity such as
in adults with relapsed/refractory ALL. hypotension requiring a vasopressor, or hypoxia, or neurologic
In addition to the relapsed/refractory disease setting, antibody- symptoms (confusion, obtundation, and seizures). Neurologic
based therapies are also being investigated for MRD. Blinatumomab toxicities were also common, ranging from delirium during CRS to
was initially evaluated in MRD positive B-ALL after induction or encephalopathy independent of CRS; however, the pathophysiology
molecularly relapsed disease. Eighty percent of patients achieved a of this is unclear. Recently, CAR-T investigators have successfully
molecular remission, including 57% of patients who had never previ- employed tocilizumab, an anti-IL-6 antibody to treat and reverse the
ously been MRD negative. Based on these promising results, a United symptoms associated with CRS. Several patients received T cells of
States Intergroup Trial, ECOG 1910, is comparing blinatumomab donor origin after prior allogeneic stem cell transplant; interestingly,
plus chemotherapy to chemotherapy alone in adults with newly no graft-versus-host disease occurred following CAR-T cell infusions
diagnosed B-ALL. Another study in older adult patients, SWOG in either study.
1318, will investigate blinatumomab and POMP (prednisone, vin-
cristine, methotrexate, 6-mercaptopurine) chemotherapy in newly Philadelphia Chromosome Positive Acute
–
diagnosed Ph ALL and dasatinib, prednisone and blinatumomab for Lymphoblastic Leukemia
+
newly diagnosed Ph ALL. Bosutinib 500 mg daily has been found to be safe in relapsed/
+
Although less prevalent than CD19 or CD22 antigen expression, refractory Ph ALL, with diarrhea being the most common toxicity.
70% of all (both precursor B-cell and precursor T-cell) ALL patients However, further investigation is required to assess efficacy. Other
express CD52. Alemtuzumab, a humanized anti-CD52 monoclonal agents, such as the dual BCR-ABL/LYN TKI INNO-406 and the
+
antibody, has been evaluated in ALL as an agent for eradication of aurora kinase inhibitor MK-0457, have also been evaluated in Ph
MRD during postremission therapy. Alemtuzumab decreased MRD ALL, but demonstrated limited efficacy. ABL001 is an allosteric
and improved DFS compared to chemotherapy alone in adult ALL. BCR-ABL inhibitor that mimics the myristoylated N-terminus of the
However, alemtuzumab failed to demonstrate significant activity in kinase domain by occupying its vacant binding site, thus restoring
relapsed/refractory pediatric ALL. Additional studies have been the negative regulation of the kinase activity. ABL001 is currently
conducted with alemtuzumab and other agents in order to further being investigated in a phase I study as a single agent and was also
assess their role in frontline therapy of ALL (CALGB 10102) and developed to be dosed with nilotinib.
have demonstrated feasibility; outcome data have not yet been for-
mally reported. Philadelphia Chromosome-Like Acute
Lymphoblastic Leukemia
Immunotherapy There has been an increasing understanding of the molecular biology
of ALL, which may translate into newer therapeutic options. Mul-
lighan and colleagues reported loss of the IKZF1 gene on 7p12, which
Chimeric Antigen Receptor T Cells encodes the early lymphoid transcription factor Ikaros in 84% of
BCR-ABL–positive ALL and in 28% of BCR-ABL–negative B-cell
+
Potentially one of the most exciting breakthroughs in ALL therapy is ALL. An IKZF1 deletion was reported in 63% of 83 adult Ph ALL
the development and early results from trials evaluating chimeric patients treated in various GIMEMA trials. The presence of the
antigen receptor (CAR)-T cells (Table 66.11). deletion of the IKZF1 gene has been associated with poor prognosis,
CAR-T cells are genetically engineered autologous T cells that with worse DFS and increased relapse risk. Patients with IKZF1
+
express antigen receptors that result in recognition and killing of alteration have a gene expression profile similar to that of Ph ALL
targeted malignant cells. In ALL, the CAR-T cells contain antibody- (Ph-like ALL described earlier), and one-third of such patients have
binding domains of single-chain variable fragments linked to T-cell- rearrangements of the lymphoid cytokine receptor gene CRLF2,
stimulating moieties, most commonly CD3ζ with either CD28 or either alone or with mutations of the Janus kinase (JAK) genes JAK1
CD137 (41BB) costimulatory domains. The chimeric receptor and JAK2. This has been further identified in pediatric and young
CTL019 binds CD19 on malignant B cells and leads to tyrosine adult ALL patients. Among 1725 B-ALL cases analyzed, the preva-
kinase-mediated activation of the T cell through the CD3ζ-chain lence of Ph-like ALL increased from 10% in children to 27% in
portion and costimulatory activity of CD137 or CD28. Investigators young adults. Kinase activating mutations in ABL1, ABL2, CRLF2,
at the University of Pennsylvania treated 25 pediatric and five adult CSF1R, EPOR, JAK2, and PDGFRB were found in 91% of Ph-like
patients with relapsed/refractory ALL with anti-CD19-CD137/ ALL cases observed. CRLF2 mutations were present in up to 60% of
CD3ζ CAR-T cells. CRs were achieved in 90% of patients. Two young adults and 55% of patients with CRLF2 mutations had con-
patients also achieved CNS remission without evidence of disease current JAK mutations, most commonly in JAK2. Twelve patients
recurrence at 6 months. The probability of CAR-T cell persistence with ABL, JAK2, or PDGFR mutations were ultimately treated with
at 6 months was 68%. B-cell aplasia continued as long as CTL019 dasatinib, imatinib, or ruxolitinib, and achieved rapid and sustained
cells persisted; however, increased rates of infection were not reported. responses. This provides rationale to test ABL and JAK inhibitors as
After a limited 6-month follow-up the EFS was 67% and OS 78%, a targeted strategy for this group of patients.
suggesting promise compared to standard salvage chemotherapy.
Investigators at the Memorial Sloan Kettering Cancer Center
(MSKCC) treated 24 relapsed/refractory adult B-ALL patients with Targeting Intracellular Signaling Pathways
CD19-specific CD28/CD3ζ CAR-T cells. Prior to CAR-T cell treat-
ment, of 22 evaluable patients, 10 were MRD positive and 12 had The NOTCH1 gene encodes a transmembrane receptor protein that
morphologic evidence of disease. Overall, 91% responded to CAR-T drives stem cell commitment to T-cell differentiation. NOTCH1