【Lancet Haematol】Ponatinib and Belintoumab bring Ph+ ALL into deep remission, is there no need for transplantation?

Ph+ ALL

Newly diagnosed Philadelphia chromosome-positive (Ph+) adult acute lymphoblastic leukemia (ALL) patients are treated with intensive chemotherapy plus TKI, followed by allogeneic hematopoietic stem cell transplantation (HSCT)
after the first remission.
The addition of TKI to conventional chemotherapy significantly improves treatment outcomes, but treatment-related resistance and toxicity lead to unsatisfactory
long-term efficacy.

Patient outcomes and toxicity have improved over the past decade, including the inclusion of third-generation TKI ponatinib as first-line use, which is active against the gatekeeper mutation Thr315Ile in the ABL1 tyrosine kinase domain, circumventing resistance mechanisms common to first- and second-generation TKIs, resulting in improved patient outcomes with a 3-year overall survival rate of 83% and higher
complete molecular response rates 。 Achieving a complete molecular response (defined as 1 leukemia blast in 10,000 mononuclear bone marrow cells <) is strongly associated
with improved overall survival in Ph+ ALL patients who have not undergone allogeneic hematopoietic stem cell transplantation (HSCT).

Bellintolumab is a CD3–CD19 bispecific T cell articulation system, and its combination with dasatinib as a consolidation regimen after dasatinib plus glucocorticoid induction therapy in newly diagnosed Ph+ adult ALL patients increased the proportion of patients with complete molecular response from 29% after induction to 60% after 2 cycles of belintolumab, and 38% of patients received HSCT with a 4-year OS of up to 78%, confirming the feasibility of TKI combined with berintolumab as a chemotherapy-free regimen
。

ABL1 944C→T (Thr315Ile) is detected in up to 75% of relapsed patients, and this mutation is the main mechanism of resistance in Ph+ ALL in primary or second-generation TKIs, while Ponatinib is a potent pan-BCR–ABL1 TKI that remains active
at ABL1 944C→T (Thr315Ile).

Given the well-defined efficacy of Ponatinib and Belintopolab in patients with Ph+ ALL, and the relapse of many patients treated with first- or second-generation BCR–ABL1 TKIs with ABL1 944C→T (Thr315Ile), Professor Elias Jabbour of MD Anderson Cancer Center et al.
hypothesized that chemotherapy-free combination therapy with Ponatinib plus Belintolumab would produce deep and durable remission, It is possible to overcome the need
for allogeneic HSCT.
A Phase 2 study was conducted in patients with Ph+ ALL (including newly diagnosed and relapsed/refractory) and blast-stage chronic myeloid leukemia, published today in Lancet Haematology
.

Study design

The study is a single-center Phase 2 study conducted at MD Anderson Cancer Center to evaluate the efficacy and safety
of ponatinib in combination with berintoumab in patients with Ph-positive acute lymphoblastic leukemia or blast-stage chronic myeloid leukemia (CML).

Main inclusion criteria: age ≥ 18 years; Patients with confirmed newly diagnosed Ph-positive acute lymphoblastic leukemia, relapsed or refractory Ph-positive acute lymphoblastic leukemia, or chronic myeloid leukemia in blast stages who have received 1 or 2 courses of chemotherapy (regardless of BCR–ABL1 TKI use) may be enrolled in the newly diagnosed cohort; ECOG performance status score ≤ 2; Total bilirubin ≤ 2×ULN or ≤2.
4 mg/dL, ALT and AST≤3×ULN, serum lipase and amylase ≤3×ULN
.
Patients with uncontrolled cardiovascular disease or clinically significant CNS abnormalities are excluded, but patients with CNS leukemia (positive leukemia blast cytology in cerebrospinal fluid) are enrolled
.

Cycles every 6 weeks, up to 5 cycles
.
Belintoumab is administered 9 micrograms/day on days 1 to 4 of cycle 1, then increased to 28 micrograms/day on days 5 to 28, followed by a 2-week treatment-free interval; Cycles 2-5 are administered at a dose of 28 μg/day for 4 weeks, followed by a 2-week withdrawal period
.
Ponatinib is orally 30 mg daily in cycle 1 and panatinib is reduced to 15 mg
daily once complete molecular remission.
After completion of treatment with bellintoumab, ponatinib should be continued as maintenance therapy for at least 5 years
.
In addition, intrathecal methotrexate 12 mg and cytarabine 100 mg were alternately given as CNS prophylaxis administered 3 times per cycle for a total of 12 doses; Patients with CNS involvement at enrollment received CNS intrathecal chemotherapy according to standard care; Prophylactic antimicrobials, aspirin 75-100 mg per day, and a statin are recommended
.

The primary endpoint for patients with newly diagnosed Ph+ ALL is complete molecular response (defined as BCR–ABL1 transcript not detected by PCR, sensitivity 0.
01%), and the primary endpoint for patients with relapsed/refractory or blast-stage CML is overall response (defined as complete response and complete response with incomplete haematological recovery); Secondary endpoints included safety, event-free survival, and overall survival
.

Study results

patient

A total of 60 patients were enrolled, including 40 (67%; median age 57 years) newly diagnosed Ph+ ALL patients, 14 (23%; median age 38 years) patients with relapsed/refractory Ph+ ALL, 6 (10%; median age 69 years) blast phase CML
.
Thirty-two (53%) patients were male and 28 (47%) were female; Fifty-one (85%) patients were white or Hispanic (Table 1).

Thirty of the 40 patients with newly diagnosed Ph+ ALL (75%) carry the P190 fusion protein
.
The median CD19 expression in the three cohorts was 99.
8%.

efficacy

Newly diagnosed Ph+ ALL cohort: 12 of 40 (30%) had a complete response
at enrollment.
Of the 28 evaluable patients, 26 (93%) achieved a complete response and one (4%) achieved a complete response with incomplete hematologic recovery (Table 2).

Thirty of the 32 evaluable patients (94%) were MRD-negative by flow cytometry after cycle 1, and all 32 (100%) evaluable patients achieved MRD negative after cycle 2
.
After 1 cycle of treatment, 26 of the 38 evaluable patients (68%) achieved a complete molecular response, and 33 (87%) achieved a complete molecular response
at any point during the course of treatment.
Overall, of the 25 patients tested in the newly diagnosed Ph+ ALL cohort, 22 (88%) achieved MRD-negative (NGS; 1 × 10-6）； BCR–ABL1
was detectable by PCR in 3, 6, and 29 months in 3, 6, and 29 patients.

Relapsed/refractory Ph + ALL cohort: 1 patient achieved a complete hematologic response at enrollment, and 13 of 14 (93%) assessed hematologic response
.
11/13 patients achieved a complete response (85%) and 1 (8%) achieved a complete response with incomplete recovery of haematology; All hematologic remissions occur after
one cycle.
12 of the 14 patients (86%) achieved MRD negative after cycle 1 and 13 (93%) achieved MRD negative (flow cytometry)
after 2 cycles.
Ten (71%) patients achieved complete molecular remission after cycle 1 and 11 (79%) patients achieved complete molecular response
after 5 cycles.

Blast-phase CML cohort: CNS involvement
in 2 patients.
Five (83%) of 6 patients achieved a complete response or a complete response with incomplete haematological recovery, and 1 (17%) had a partial response with an optimal response
.
Four of the six patients (67%) were confirmed to be MRD-negative by flow cytometry after cycle 1, and five patients (83%) achieved MRD negative at any time in the study
.
1 in 5 patients with complete response or incomplete recovery of haematology also achieved a complete molecular response
in cycle 1.
The optimal overall response in only 2 (33%) of 6 patients was a full molecular response
.

Research profile and transplantation

Newly diagnosed Ph+ ALL cohort: median number of cycles accepted was 5,38 (97%) patients with ongoing hematologic remission; Only one patient who received allogeneic HSCT on first remission received transplantation
due to persistently detectable BCR–ABL1 transcription levels of 0.
01–0.
05%.
The median duration of response in 37 patients who did not receive allogeneic HSCT was 15 months
.
Six of the 40 patients (15%) discontinued the regimen (Figure 1).

Relapsed/refractory Ph+ALL cohort: median number of cycles accepted is 3
.
Six of the 13 patients in remission (46%) underwent allogeneic HSCT (1 subsequently relapsed; Five were alive), four (31%) patients were transplanted but subsequently relapsed, one died in complete remission, and two patients continued remission
without transplantation.
Ten (71%) patients did not complete 5 cycles of treatment
.

Blast-phase CML cohort: The median number of accepted periods is 3
.
Three (50%) of 6 patients subsequently relapsed, with one patient's immunophenotype changing to myeloid blast-phase CML with loss of CD19 expression; The other 2 patients continued remission
without allogeneic HSCT.
Five patients (83%) did not complete 5 cycles of treatment
.

Secondary endpoints

The median duration of follow-up for the entire cohort was 16 months, with 15 months in the newly diagnosed Ph+ ALL cohort, 22 months in the relapsed/refractory Ph+ ALL cohort, and 25 months
in the blast-phase CML cohort.

Newly diagnosed Ph+ ALL cohort: estimated 1-year event-free survival was 95% (Figure 2A) and overall survival was 95% (Figure 2B), and no recurrence and leukemia-related death
were observed in this cohort.
In post-hoc analysis, 1-year event-free survival was not observed between patients with complete response at enrollment and those with active disease at enrollment (100% in patients with complete response versus 92% in patients with active disease; p = 0.
33) and 1-year overall survival (100% vs 92%; p=0.
33).

Relapsed/refractory Ph+ ALL cohort: estimated 1-year event-free survival is 57% and overall survival is 79%.

Five of the 13 patients (38%) had sustained remission for more than 12 months (4 received allogeneic HSCT and 1 did not transplant), 4 (29% died of progressive leukemia, and 1 (7%) died of unknown cause
after loss to follow-up.

Blast-phase CML cohort: estimated 1-year event-free survival of 50 and overall survival of 100%.

security

No grade 4-5 drug-related adverse events occurred (Table 3).

≥5% of the most common serious adverse events were infection and febrile neutropenia (22/60 [37%]), elevated lipase and amylase concentrations (5/60 [8%]), elevated ALT or AST (4/60 [7%]), hypertension (4/60 [7%]), pain (4/60 [7%]), and hyperglycemia (3/60 [5%]).

。 Post-hoc analysis found that 115 (64%) of the 181 adverse events occurred in cycle 1, 55 (30%) occurred in cycles 2-5, and 11 (6%) occurred during
maintenance therapy with ponatinib monotherapy.
Five of the 60 patients (8%) reduced the dose
of the study drug due to adverse events.

Three (5%) patients discontinued ponatinib due to associated adverse events, and one (2%) patient discontinued belintoumab
due to related adverse events.
In a post-hoc analysis, three (18%) of 17 patients aged ≥ 60 years discontinued one study drug due to treatment-related adverse events, while none of the <60-year-old patients discontinued due to
treatment-related adverse events.
In addition, no drug-related deaths
were observed.

discuss

There were multiple innovations in the study: no chemotherapy in the treatment regimen except for intrathecal chemotherapy; The previous study was sequential administration of belintoumab and TKI, whereas this study was given in combination over the same treatment cycle; Studies included adults of all ages, including patients with CNS lesions, who were often excluded from other Belintoumab studies2
.

This study found that the chemotherapy-free combination regimen of ponatinib plus berintoumab was safe and effective
in patients with Ph+ ALL or blast-stage CML.
The complete molecular response rate was 87% in patients with newly diagnosed Ph+ ALL, the 1-year overall survival rate was 95%, and no recurrence was observed; Although only 1 patient in this cohort received allogeneic HSCT consolidation therapy, this encouraging result
was observed.
The allogeneic transplant rate is extremely low (2.
5%), in contrast to most other prospective studies of Ph+ ALL (where a significant proportion of patients receive allogeneic HSCT on first response), perhaps without routine allogeneic HSCT
at first remission.

Of note, there was no toxicity associated with conventional cytotoxic chemotherapy and no treatment-related grade 4- to 5 adverse events were reported, but some patients had reduced or discontinued study drug doses due to low-grade adverse events
.
The median number of cycles for patients with newly diagnosed Ph+ ALL was 5 versus 3
for patients with relapsed/refractory Ph+ ALL and blast-stage CML.

In summary, the deep molecular response and initial disease-free follow-up of this study suggest that ponatinib in combination with berintoumab has lower toxicity and may cure Ph+ adult ALL patients
without HSCT.

In addition, patients with relapsed/refractory Ph+ ALL and blast-stage CML had lower rates of complete molecular response (11/14 [79%] and 2/6 [33%], respectively).

References

1.
Elias Jabbour, Nicholas J Short, Nitin Jain,et al.
Ponatinib and blinatumomab for Philadelphia chromosomepositive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial.
Lancet Haematol .
2022 Nov 16; S2352-3026(22)00319-2.
doi: 10.
1016/S2352-3026(22)00319-2.

2.
Judith M Boer, Inge M van der Sluis.
Towards chemotherapy-free treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia.
Lancet Haematol .
2022 Nov 16; S2352-3026(22)00351-9.
doi: 10.
1016/S2352-3026(22)00351-9.

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